NeuroTOC

Withdrawal StatementThe authors have withdrawn this manuscript due to a duplicate posting of manuscript number BIORXIV/2025/677258. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The correct preprint can be found at doi: 10.1101/2025.09.19.677258

Learning to detect, identify or select stimuli is an essential requirement of many behavioral tasks. In real life situations, relevant and non-relevant stimuli are often embedded in a continuous sensory stream, presumably represented by different segments of neural activity. Here, we introduce a neural circuit model that can learn to identify action-relevant stimuli embedded in a spatio-temporal stream of spike trains, while learning to ignore stimuli that are not behaviorally relevant. The model uses a biologically plausible plasticity rule and learns from the reinforcement of correct decisions taken at the right time. Learning is fully online; it is successful for a wide spectrum of stimulus-encoding strategies; it scales well with population size; and can segment cortical spike patterns recorded from behaving animals. Altogether, these results provide a biologically plausible framework of reinforcement learning in the absence of prior information on the identity, relevance and timing of input stimuli.

Motion speed provides a salient cue for visual segmentation, yet how the visual system represents and differentiates multiple speeds remains poorly understood. Here, we investigated the neural coding of multiple speeds. First, we characterized the perceptual capacity of human and macaque subjects to segment overlapping random-dot stimuli moving at different speeds. We then recorded from neurons in the middle temporal (MT) cortex of macaque monkeys to determine how multiple speeds are represented. We made a novel finding that the responses of MT neurons to two speeds showed a robust bias toward the faster speed component when both speeds were slow ([≤] 20{degrees}/s). This faster-speed bias emerged early in the neuronal response. It occurred regardless of whether the two speed components moved in the same or different directions, and even when attention was directed away from the receptive field. As stimulus speed increased, the faster-speed bias diminished. Our finding can be explained by a modified divisive normalization model, in which the weights for the speed components are proportional to the responses of a population of neurons, referred to as the weighting pool, elicited by the individual speeds. We suggest that the weighting pool include neurons with a broad range of speed preferences. We found that a classifier can differentiate the responses of MT neurons to two speeds versus a corresponding log-mean speed. We further showed that it was possible to decode two speeds from MT population response, supporting the theoretical framework of coding multiplicity of visual features in neuronal populations. The decoded speeds can account for the perceptual performance of segmenting two speeds with a large (x4) but not a small (x2) separation, raising questions for future investigations. Our findings help define the neural coding rule of multiple speeds. The faster-speed bias in MT at slow stimulus speeds could benefit important behavioral tasks such as figure-ground segregation, as figural objects tend to move faster than the background in the natural environment.

The experience of pain, like other interoceptive processes, has recently been conceptualized in terms of predictive coding and free energy frameworks. In these views, the brain integrates sensory, proprioceptive, and interoceptive signals to generate probabilistic inferences about upcoming events, which shape both the state and the perception of our inner body. Here we ask whether it is possible to induce pain expectations by providing false faster (vs. slower) acoustic cardiac feedback before administering electrical cutaneous shocks. We test whether these expectations will shape both the perception of pain and the bodys physiological state toward prior predictions. Results confirmed that faster cardiac feedback elicited pain expectations that affected both perceptual pain judgments and the bodys physiological response. Perceptual pain judgments were biased towards the expected level of pain, such that participants illusorily perceived identical noxious stimuli as more intense and unpleasant. Physiological changes mirrored the predicted level of pain, such that participants actual cardiac response in anticipation of pain stimuli showed a deceleration in heart rate, in line with the well-known orienting cardiac response in anticipation of threatening stimuli (Experiment 1). In a control experiment, such perceptual and cardiac modulations were dramatically reduced when the feedback reproduced an exteroceptive, instead of interoceptive, cardiac feedback (Experiment 2). These findings show that cardiac perception can be understood as interoceptive inference that modulates both our perception and the physiological state of the body, thereby actively generating the interoceptive and autonomic consequences that have been predicted.

Exceptionally long genes and cis-regulatory enhancers are selectively activated in mammalian brain neurons, and these loci are mutation hotspots in neurological disorders. However, the organization of these large genomic elements at the level of chromosome folding, beyond local enhancer-promoter interactions, remains poorly understood. Here, we report the discovery of a nuclear subcompartment in the mouse cerebellum formed by near-megabase long enhancers and their associated long genes encoding synaptic or signaling proteins. Genomic regions within this subcompartment reside in the outer-half of the nucleus, separated from other transcriptionally active structures. Using an in vivo CRISPR genetic mini-screen, we uncover a specific role for the transcription factor Etv1 in coupling the compartmentalization of neuronal long genes with their expression. Together, our study defines mechanisms that organize transcriptionally active genes across chromosomes in the mammalian brain.

Parkinsons disease (PD) is diagnosed after motor symptoms appear, although non-motor symptoms emerge years earlier. Following years of pharmacological treatment, high-frequency stimulation (HFS) of the subthalamic nucleus (STN), a key hub in goal-direct behaviors, can be proposed. While HFS-STN reliably improves motor symptoms, it does not specifically address non-motor symptoms. Clarifying how STN dysfunction contributes to non-motor symptoms could thus improve STN stimulation strategies. Here, we longitudinally recorded STN local field potentials in two macaques performing a counter-demanding task during chronic low-dose MPTP treatment. This progressive model, evolving from an asymptomatic stage to motivational, cognitive and ultimately motor deficits, enabled detailed examination of non-motor stages preceding motor impairment. Each stage was associated with distinct STN electrophysiological alterations, including early loss of reward-related theta activity, subsequent disappearance of decision-related theta oscillations, and later reduction of movement-related beta rebound. In the stable parkinsonian stage, stimulation of different STN territories provided complementary behavioral effect: dorsal HFS-STN improved motor performances, whereas ventral low-frequency stimulation alleviated motivational deficits. These findings reveal a temporal link between STN dysfunction and symptom onset, and suggest site and frequency-specific stimulation as a strategy to address both motor and non-motor symptoms in PD.

Working Memory (WM) enables us to maintain and directly manipulate mental representations, yet we know little about the neural implementation of this privileged online format. We recorded electroencephalography data as human subjects engaged in a task requiring continuous updates to the locations of objects retained in WM as well as in a visually identical task with WM demands removed. Analysis of neural data suggested WM-related contralateral delay activity reversed polarity as objects held in WM moved to the opposite hemifield. This was partially but not fully explained by visual attention demands. Thus, the cortical location of activity related to both attention and WM was updated to meet behavioral demands as the spatial location of remembered objects changed.

Humans routinely anticipate upcoming language, but whether such predictions come at a cognitive cost remains debated. In this study, we demonstrate the resource-dependent nature of predictive mechanisms in language comprehension across the lifespan: Experimentally limiting executive resources through a concurrent task reduces the effect of language predictability on reading time. Participants (N=175, replication N=96) read short articles presented word-by-word while completing a secondary font colour n-back task, thus varying cognitive demand. Language predictability was indexed by word surprisal as derived from a pre-trained large language model (GPT-2). Across two independent samples, our findings reveal that language predictions are not cost-free: They draw on executive control resources, and this dependency becomes more pronounced with age (18 to 85 years). These results help resolve the debate over cognitive demands in language comprehension and highlight prediction as a dynamic, resource-dependent process across the lifespan.

Maladaptive self-beliefs are a core symptom of major depressive disorder. These beliefs are perpetuated by a negatively biased integration of self-related feedback. Understanding the neurocomputational mechanisms of biased belief updating may help to counteract maladaptive beliefs and the maintenance of depression. The present study uses a belief-updating task and functional neuroimaging to examine the neurocomputational mechanisms associated with self-related feedback processing in individuals with major depression and matched healthy controls. We hypothesized that increased symptom burden in depression is associated with negatively biased self-belief updating and altered neural tracking of social feedback. Our findings show that depression is related to reduced incorporation of unexpected positive feedback, with higher symptom burden alongside heightened insula reactivity to unexpected negative feedback. The interplay of increased neural responsiveness to negative feedback and the reduced learning from positive feedback provide new insights into cognitive distortions in depression and may explain the persistence of maladaptive self-beliefs and, thus, the maintenance of depression.

Parallel processing is a fundamental organizing principle in the nervous system and understanding how parallel neural circuits generate distinct outputs from common inputs is a key goal of neuroscience. In the mammalian retina, divergence of cone signals into multiple feedforward bipolar cell pathways forms the initial basis for parallel retinal circuits dedicated to specific visual functions. Here, we used patch-clamp electrophysiology, electron microscopy and two photon imaging of a fluorescent glutamate sensor to examine how kinetically-distinct responses arise in transient versus sustained ON alpha RGCs (ON-T and ON-S RGCs) of the mouse retina. We directly compared the visual response properties of these RGCs with their presynaptic bipolar cell partners, which we identified using 3D electron microscopy reconstruction. Different ON bipolar cell subtypes (type 5i, type 6 and type 7) had indistinguishable light-driven responses whereas extracellular glutamate signals around RGC dendrites and postsynaptic excitatory currents measured in ON-T and ON-S RGCs in response to the identical stimuli used to probe bipolar cells were kinetically distinct. Anatomical examination of the bipolar cell axon terminals presynaptic to ON-T and ON-S RGCs suggests that bipolar subtype-specific differences in the size of synaptic ribbon-associated vesicle pools may contribute to transient versus sustained kinetics. Our findings indicate that feedforward bipolar cell synapses are a primary point of divergence in kinetically distinct visual pathways.

Organisational gradients refer to a continuous low-dimensional embedding of brain regions and can quantify core organisational principles of complex systems like the human brain. Mapping how these organisational principles are altered or refined across development and phenotypes is essential to understanding the relationship between brain and behaviour. Taking a developmental approach and leveraging longitudinal and cross-sectional data from two multi-modal neuroimaging datasets, spanning the full neurotypical-neurodivergent continuum, we charted the organisational variability of structural (610 participants, N = 390 with one observation, N = 163 with two observations, and N = 57 with three) and functional (512 participants, N = 340 with one observation, N = 128 with two observations, and N = 44 with three). Across datasets, despite differing phenotypes, we observe highly similar structural and functional gradients. These gradients, or organisational principles, are highly stable across development, with the exact same ordering across early childhood into mid-adolescence. However, there is substantial developmental change in the strength of embedding within those gradients: by modelling developmental trajectories as non-linear splines, we show that structural and functional gradients exhibit sensitive periods and are refined across development. Specifically, structural gradients gradually contract in low-dimensional space as networks become more integrated, whilst the functional manifold expands, indexing functional specialisation. The coupling of these structural and functional gradients follows a unimodal-association axis and varies across individuals, with developmental effects concentrated in the more plastic higher-order networks. Importantly, these developmental effects on coupling, in these higher-order networks, are attenuated in the neurodivergent sample. Finally, we mapped structure-function coupling onto dimensions of psychopathology and cognition and demonstrate that dimensions of cognition, such as working memory, are robust predictors of coupling. In summary, across clinical and community samples, we demonstrate consistent principles of structural and functional brain organisation, with progressive structural integration and functional segregation. These gradients are established early in life, refined through development, and their coupling is predicted by working memory.

One of the major challenges in addressing multiple sclerosis is to understand the progression trajectory of patients. The pathological process evolves from acute phases predominantly driven by inflammation transitioning to progressive profiles where neurodegeneration takes precedence. It remains unresolved why this course is highly heterogeneous among patients. Currently we know that sex variable plays a crucial role in its understanding. Females are 2-3 times more likely to suffer from multiple sclerosis while males progression is faster with greater severity. We investigate the potential molecular mechanisms underlying these sex-differential clinical traits analysing transcriptomic data at single cell resolution. 48,919 central nervous system and 336,934 peripheral immune cells, covering the multiple sclerosis spectrum, enabled us to provide the comprehensive landscape of sex differences by cell type. This includes signatures in gene expression patterns, functional profiling, pathways activation and cell-cell communication networks for females, males and their sex-differential profiles. Complete results can be explored in the user-friendly interactive webtool https://bioinfo.cipf.es/cbl-atlas-ms/. Among these findings, we unveiled that female neurons may exhibit protective mechanisms against excitotoxicity, glial cells dysregulated widely stress response genes in a sex-differential manner, and female oligodendrocytes increase expression of axon-myelin contact genes suggesting strong potential for myelin recovery. In the inflammatory-predominant forms, female immune cells present an inflammatory core driven by the AP-1 transcription factor, while male adaptive immune cells exhibit higher mitochondrial impairment. Conversely, larger differences are reported in CD8+ T cells, with females displaying homeostasis recovery patterns and males exhibiting cytolytic profiles. We consider that the molecular description of sex differences in multiple sclerosis progression may be a valuable resource for prevention and diagnosis through biomarker research and the development of personalised therapeutic strategies.

The link between brain health and risk/protective factors for non-communicable diseases (such as high blood pressure, high body mass index, diet, smoking, physical activity, etc.) is increasingly acknowledged. However, the specific effects that these factors have on brain health are still poorly understood, delaying their implementation in precision brain health. Here, we studied the multivariate relationships between risk factors for non-communicable diseases and brain structure, including cortical thickness (CT) and grey matter volume (GMV). Furthermore, we adopted a systems-level perspective to understand such relationships, by characterizing the cortical patterns (yielded in association to risk factors) with regards to brain morphological and functional features, as well as with neurotransmitter systems. Similarly, we related the pattern of risk/protective factors dimensions with a peripheral marker of inflammation. First, we identified latent dimensions linking a broad set of risk factors for non-communicable diseases to parcel-wise CT and GMV across the whole cortex. Data was obtained from the UK Biobank (n=7370, age range=46-81 years). We used regularized canonical correlation analysis (RCCA) embedded in a machine learning framework. This approach allows us to capture inter-individual variability in a multivariate association and to assess the generalizability of the model. The brain patterns (captured in association with risk/protective factors) were characterized from a multi-level perspective, by performing correlations (spin tests) between them and different brain patterns of structure, function, and neurotransmitter systems. The association between the risk/protective factors pattern and C-reactive protein (CRP, a marker of inflammation) was examined using Spearman correlation. We found two significant and partly replicable latent dimensions. One latent dimension linked cardiometabolic health to brain patterns of CT and GMV and was consistent across sexes. The other latent dimension linked physical robustness (including non-fat mass and strength) to patterns of CT and GMV, with the association to GMV being consistent across sexes and the association to CT appearing only in men. The CT and GMV patterns of both latent dimensions were associated to the binding potentials of several neurotransmitter systems. Finally, the cardiometabolic health dimension was correlated to CRP, while physical robustness was only very weakly associated to it. We observed robust, multi-level and multivariate links between both cardiometabolic health and physical robustness with respect to CT, GMV, and neurotransmitter systems. Interestingly, we found that cardiometabolic health and physical robustness are associated with not only increases in CT or GMV, but also with decreases of CT or GMV in some brain regions. Our results also suggested a role for low-grade chronic inflammation in the association between cardiometabolic health and brain structural health. These findings support the relevance of adopting a holistic perspective in health, by integrating neurocognitive and physical health. Moreover, our findings contribute to the challenge to the classical conceptualization of neuropsychiatric and physical illnesses as categorical entities. In this perspective, future studies should further examine the effects of risk/protective factors on different brain regions in order to deepen our understanding of the clinical significance of such increased and decreased CT and GMV.

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown cause, typically affecting individuals aged 50-60 and leading to death within a decade. It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar alpha-synuclein (aSyn), whose formation shows parallels with prion propagation. While fibrils extracted from MSA brains have been structurally characterized, their ability to replicate in a protein-only manner has been questioned, and their capacity to induce GCIs in vivo remains unexplored. By contrast, the synthetic fibril strain 1B, assembled from recombinant human aSyn, self-replicates in vitro and induces GCIs in mice - suggesting direct relevance to MSA - but awaited scrutiny at an atomic scale. Here, we report high-resolution structural analyses of 1B fibrils and of fibrils extracted from diseased mice injected with 1B that developed GCIs (1BP). We show in vivo that conformational templating enables fibril strain replication, resulting in MSA-like inclusion pathology. Remarkably, the structures of 1B and 1BP are highly similar and mimic the fold of aSyn observed in one protofilament of fibrils isolated from MSA patients. Moreover, reinjection of crude mouse brain homogenates containing 1BP into new mice reproduces the same MSA-like pathology induced by the parent synthetic seed 1B. Our findings identify 1B as a synthetic pathogen capable of self-replication in vivo and reveal structural features of 1B/1BP that may underlie MSA pathology, offering insights for therapeutic strategies.

Expectation is beneficial for adaptive behavior through quickly deducing plausible interpretations of information. The profile and underlying neural computations of this process, however, remain unclear. When participants expected a grating with a specific orientation, we found a center-surround inhibition profile in orientation space, which was independent from attentional modulations by task-relevance. Using computational modeling, we showed that this center-surround inhibition could be reproduced by either a sharpening of tuning curves of expected orientation or a shift of tuning curves of unexpected orientations. Intriguingly, these two computations were further supported by orientation-adjustment and orientation-discrimination experiments. Finally, the ablation studies in convolutional neural networks revealed that predictive coding feedback played a critical role in the center-surround inhibition in expectation. Altogether, our study reveals for the first time that expectation results in both enhancement and suppression, optimizing plausible interpretations during perception by enhancing expected and attenuating similar but irrelevant and potentially interfering representations.

Brain aging is a key risk factor for many neurodegenerative diseases, yet its molecular and cellular mechanisms remain elusive. Amyloid-beta precursor protein (APP) is among the most studied proteins linked to brain pathology; however, its role in non-pathological brain aging remains poorly characterized. Here, we investigate the natural impact of APP on normal brain aging using the short-lived turquoise killifish (Nothobranchius furzeri), which exhibits rapid and spontaneous age-related decline. We found that a pyroglutamated APP derivative (APPpE11) accumulates intra-neuronally in an age-dependent manner, co-localizing with a marker of cell death. We found that intraneuronal APPpE11 is also present in brains from healthy elderly humans, suggesting deep evolutionary conservation. To determine APPs role in spontaneous brain aging, we knock-out "amyloid precursor protein a" (appa) in killifish via CRISPR/Cas9. The lack of appa mitigated brain aging from a proteome-wide perspective, reduced age-related cell death and inflammation, and improved neuronal activity and learning capacity in aged individuals. Our findings show an ancestral and previously unrecognized role of amyloid-beta precursor protein in non-pathological brain aging, making it an ideal target for anti-aging interventions.

Neural activity in the dentate gyrus (DG) is required for the detection and discrimination of novelty, context and patterns, amongst other cognitive processes. Prior work has demonstrated that there are differences in the activation of granule neurons in the supra and infrapyramidal blades of the DG during a range of hippocampal dependent tasks. Here we used an automated touch screen pattern separation task combined to temporally controlled tagging of active neurons to determine how performance in a cognitively demanding task affected patterns of neural activity in the DG. We found an increase in the blade-biased activity of suprapyramidal mature granule cells (mGCs) during the performance of a high cognitive demand segment of the task, with a further characteristic distribution of active neurons along the apex to blade, and hilar to molecular layer axes. Chemogenetic inhibition of adult-born granule cells (abDGCs) beyond a critical window of their maturation significantly impaired performance of mice during high- demand conditions but not when cognitive demand was low. abDGC inhibition also elevated the total activity of mGCs and disturbed the patterned distribution of active mGCs even in mice that eventually succeeded in the task. Conversely chemogenetic inhibition of mGCs reduced success in the high cognitive demand portion of this task and decreased the global number of active GCs without affecting the patterned distribution of active cells. These findings demonstrate how a high cognitive demand pattern separation task preferentially activates mGCs in subregions of the DG and are consistent with a modulatory role for abDGCs on the dentate circuit which in part governs the spatially organized patterns of activity of mGCs.

It is known that stress powerfully alters pain, but its underlying mechanisms remain elusive. Here, we identified a circuit, locus coeruleus descending noradrenergic neurons projecting to the spinal dorsal horn (LC[->]SDH-NA neurons), that is activated by acute exposure to restraint stress and is required for stress-induced mechanical pain hypersensitivity in mice. Interestingly, the primary target of spinal NA released from descending LC[->]SDH-NAergic terminals causing the stress-induced pain hypersensitivity was 1A-adrenaline receptors (1ARs) in Hes5-positive (Hes5+) astrocytes located in the SDH, an astrocyte subset that has an ability to induce pain sensitization. Furthermore, activation of Hes5+ astrocytes reduced activity of SDH-inhibitory neurons (SDH-INs) that have an inhibitory role in pain processing. This astrocytic reduction of IN activity was canceled by an A1-adenosine receptor (A1R)-knockdown in SDH-INs, and the A1R-knockdown suppressed pain hypersensitivity caused by acute restraint stress. Therefore, our findings suggest that LC[->]SDH-NA neuronal signaling to Hes5+ SDH astrocytes and subsequent astrocytic reduction of SDH-IN activity are essential for mechanical pain facilitation caused by stress.

While visual working memory (WM) is strongly associated with reductions in occipitoparietal alpha (8-12 Hz) power, the role of frontal midline theta (4-7 Hz) power is less clear, with both increases and decreases widely reported. Here, we test the hypothesis that this theta paradox can be explained by non-oscillatory, aperiodic neural activity dynamics. Because traditional time-frequency analyses of electroencephalography (EEG) data conflate oscillations and aperiodic activity, event-related changes in aperiodic activity can manifest as task-related changes in apparent oscillations, even when none are present. Reanalyzing EEG data from two visual WM experiments (n = 74, of either sex), and leveraging spectral parameterization, we found systematic changes in aperiodic activity with WM load, and we replicated classic alpha, but not theta, oscillatory effects after controlling for aperiodic changes. Aperiodic activity decreased during WM retention, and further flattened over the occipitoparietal cortex with an increase in WM load. After controlling for these dynamics, aperiodic-adjusted alpha power decreased with increasing WM load. In contrast, aperiodic-adjusted theta power appeared to increase during WM retention, but because aperiodic activity reduces more, it falsely appears as though theta "oscillatory" power (e.g., total band power) is reduced. Furthermore, only a minority of participants (31/74) had a detectable degree of theta oscillations. These results offer a potential resolution to the theta paradox where studies show contrasting power changes. Additionally, we have identified novel aperiodic dynamics during human visual WM. Significance statementWorking Memory (WM) is our ability to hold information in mind without it being present in our external environment. Years of research focused on oscillatory brain dynamics to discover the mechanisms of WM. Here, we specifically look at oscillatory and non-oscillatory, aperiodic activity as measured with scalp EEG to test their significance in supporting WM. We challenge earlier findings regarding theta oscillations with our analysis approach, while replicating alpha oscillation findings. Furthermore, aperiodic activity is found to be involved in WM, over frontal regions in a task-general manner, and over anterior regions this activity is reduced with an increase in the number of remembered items. Thus, we have identified novel aperiodic dynamics during human visual WM.

Feedback stabilization of upright standing should be reflected by a time-lagged relationship between the ground reaction force (GRF) and the center of mass (COM) state. In this study, we propose a model relating corrective ground reaction forces (Fcorr) to preceding COM position (PCOM) and velocity (VCOM). We first checked the models validity by simulating an inverted pendulum model with known intrinsic and feedback parameters, to see whether and to what extend we could effectively identify the feedback parameters. Next, we tested the model in 15 young adult volunteers in standing. Our model effectively reconstructed Fcorr in both simulations (R2: 0.77[~]0.99) and human experimental data (R2: 0.92[~]0.98). The effective delay in the mediolateral direction (239 {+/-} 20 ms) was significantly shorter than in the anteroposterior direction (271 {+/-} 28 ms). Additionally, position gains were significantly larger in the mediolateral compared to anteroposterior direction, with values of -1.09 {+/-} 0.04 and -1.03 {+/-} 0.02 times critical stiffness, respectively. No significant differences between the directions were found in velocity gains. Our model can be used to identify feedback control in human standing without applying external perturbations or measuring physiology activity. Although the estimated parameters represent the lumped effects of both intrinsic and feedback contributions, they remain informative of the feedback mechanism because the intrinsic impact is negligible under normal standing. Our results show that stability of upright stance in healthy young adults is achieved by position feedback gains at levels just above critical stability. The proposed model requires easily measurable inputs which may yield value in assessment of balance disorders.

Even without detailed instruction from the brain, spinal locomotor circuitry generates coordinated behavior characterized by left-right alternation, segment-to-segment propagation, and variable-speed control. While existing models have emphasized the contributions of cellular- and network-level properties, the core mechanisms underlying rhythmogenesis remain incompletely understood. Further, neither family of models has fully accounted for recent experimental results in zebrafish and other organisms pointing to the importance of cell-type-specific intersegmental connectivity patterns and recruitment of speed-selective subpopulations of interneurons. In-formed by these experimental findings and others, we developed a hierarchy of increasingly detailed models of the locomotor network. We find that coordinated locomotion emerges in an inhibition-dominated network in which connectivity is determined by intersegmental phase relationships among interneurons and variable-speed control is implemented by recruitment of speed-selective subpopulations. Further, while structured excitatory connections are not necessary for rhythmogenesis, they are useful for increasing peak locomotion frequency, albeit at the cost of smooth transitions at intermediate frequencies, suggesting a basic computational trade-off between speed and control. Together, this family of models shows that network-level interactions are sufficient to generate coordinated, variable-speed locomotion, providing new interpretations of intersegmental excitatory and inhibitory connectivity, as well as the basic, recruitment-based mechanism of speed control.

Quantifying animal behavior is pivotal for identifying the underlying neuronal and genetic mechanisms involved. Computational approaches have enabled automated analysis of complex behaviors such as aggression and courtship in Drosophila. However, existing approaches rely on rigid, rule-based algorithms and expensive hardware, limiting sensitivity to behavioral variations and accessibility. Here, we describe the Drosophila Aggression and Courtship Evaluator (DANCE), a low-cost, open-source platform that combines machine learning-based classifiers and inexpensive hardware to quantify aggression and courtship. DANCE consists of six novel behavioral classifiers trained using a supervised machine learning algorithm. DANCE classifiers address key limitations of rule-based algorithms, capturing dynamic behavioral variations more effectively. DANCE hardware is constructed using repurposed medicine blister packs and acrylic sheets, with recordings performed using smartphones, making it affordable and accessible. Benchmarking demonstrated that DANCE hardware performs comparably to sophisticated, high-cost setups. We validated DANCE in diverse contexts, including social isolation versus enrichment, which modulates aggression and courtship; RNAi-mediated downregulation of the neuropeptide Dsk; and optogenetic silencing of dopaminergic neurons, which promotes aggression. DANCE provides a cost-effective and portable solution for studying Drosophila behaviors in resource-limited settings or near natural habitats. Its accessibility and robust performance democratize behavioral neuroscience, enabling rapid screening of genes and neuronal circuits underlying complex social behaviors.

Translational animal models that can accommodate human-scale implantable devices are essential for advancing chronic brain stimulation and sensing applications. This study establishes a kainic acid (KA)-induced porcine model of mesial temporal lobe epilepsy (mTLE) using a neurotechnology platform integrating clinical imaging, stereotactic surgery, and a fully implantable device for chronic monitoring. In six KA-treated and one saline-control pig bilateral hippocampus (HPC) and anterior thalamus (ANT) local field potentials were monitored using an implantable device, along with synchronized video recordings. Histology was performed to assess neuronal injury and hippocampal reorganization. Intra-hippocampal KA infusion induced acute status epilepticus (6/6 pigs). Surviving KA-treated pigs (4/6) were monitored for a total of 386 days with spontaneous seizures occurring in three subjects. A total of 2,733 hippocampal seizures were recorded with a seizure duration of 27.16{+/-}17.62 seconds. All subjects exhibited bilateral interictal epileptiform discharges, predominantly in the lesioned hemisphere (p <0.0001). Histological analysis revealed cytoarchitectural disorganization consistent with hippocampal injury. This porcine model recapitulates many of the electrophysiological and structural hallmarks of human mTLE. The platform provides a powerful translational bridge for developing novel sensing and stimulating neuromodulation strategies in freely behaving large animals using human-scale implantable devices.

ATP-gated purinergic P2X7 receptors are crucial ion channels involved in inflammation. They sense abnormal ATP release during stress or injury and are considered promising clinical targets for therapeutic intervention. However, despite their predominant expression in immune cells such as microglia, there is limited information on P2X7 membrane expression and regulation during inflammation at the single-molecule level, necessitating new labeling approaches to visualize P2X7 in native cells. Here, we present X7-uP, an unbiased, affinity-guided P2X7 chemical labeling reagent that selectively biotinylates endogenous P2X7 in BV2 cells, a murine microglia model, allowing subsequent labeling with streptavidin-Alexa 647 tailored for super-resolution imaging. We uncovered a nanoscale microglial P2X7 redistribution mechanism where evenly spaced individual receptors in quiescent cells undergo upregulation and clustering in response to the pro-inflammatory agent lipopolysaccharide and ATP, leading to synergistic interleukin-1{beta} release. Our method thus offers a new approach to revealing endogenous P2X7 expression at the single-molecule level.

High-resolution extracellular electrophysiology is the gold standard for recording spikes from distributed neural populations, and is especially powerful when combined with optogenetics for manipulation of specific cell types with high temporal resolution. We integrated these approaches into prototype Neuropixels Opto probes, which combine electronic and photonic circuits. These devices pack 960 electrical recording sites and two sets of 14 light emitters onto a 70 m wide, 1 cm long shank, allowing spatially addressable optogenetic stimulation with blue and red light. In mouse cortex, Neuropixels Opto probes delivered high-quality recordings together with spatially addressable optogenetics, differentially activating or silencing neurons at distinct cortical depths. In mouse striatum and other deep structures, Neuropixels Opto probes delivered efficient optotagging, facilitating the identification of two cell types in parallel. Neuropixels Opto probes represent an unprecedented tool for recording, identifying, and manipulating neuronal populations.

Understanding neuronal connectivity at single-cell resolution remains a fundamental challenge in neuroscience, with current methods particularly limited in mapping long-distance circuits and preserving cell type information. Here we present Connectome-seq, a high-throughput method that combines engineered synaptic proteins, RNA barcoding, and parallel single-nucleus and single-synaptosome sequencing to map neuronal connectivity at single-synapse resolution. This AAV-based approach enables simultaneous capture of both synaptic connections and molecular identities of connected neurons. We validated this approach in the mouse pontocerebellar circuit, identifying both established projections and potentially novel synaptic partnerships. Through integrated analysis of connectivity and gene expression, we identified molecular markers enriched in connected neurons, suggesting potential determinants of circuit organization. By enabling systematic mapping of neuronal connectivity across brain regions with single-cell precision and gene expression information, Connectome-seq provides a scalable platform for comprehensive circuit analysis across different experimental conditions and biological states. This advance in connectivity mapping methodology opens new possibilities for understanding circuit organization in complex mammalian brains.

C-low threshold mechanoreceptors (C-LTMRs) have been highlighted in mediating the pleasantness of slow, caressing touch. This has given rise to the "Affective Touch Hypothesis," which posits that velocity tuning of C-LTMRs underpins pleasantness perception. The known activation preferences of C-LTMRs have been used as a proxy for pleasant touch, yet recent findings have raised questions about the necessity of this peripheral mechanism. This project explored the peripheral and central mechanisms in affective touch through comparing two motion-conditions: gentle brushing-like motion and apparent motion, an illusory perception of movement produced by successive touches along the skin. We used this illusion to examine whether previously established velocity tuning of true lateral motion is observed in apparent motion, when local information provided to individual peripheral afferents is held constant. The sole dependence on peripheral modulation predicts that the characteristic inverted-U-shaped relationship between velocity and pleasantness, regularly associated with C-LTMRs, would only be observed for brushing-like motion. Central modulation would instead predict a more similar relationship between the motion-conditions. To investigate this, pleasantness-ratings and velocity-ratings were collected across different velocities (0.1-30cm/s, N=23) for both conditions. Linear and quadratic regression analyses were performed and for both conditions adding a quadratic term improved the overall model fit, reaching significance (p<0.001). The quadratic term coefficients were negative for both conditions, displaying an inverted-U-shape. Further analyses revealed that motion-condition did not significantly alter the relationship between stimulus-velocity and pleasantness. These findings suggest that the velocity tuning of pleasantness cannot solely be attributed to velocity tuning of individual C-LTMRs. Key pointsO_LIC-low threshold mechanoreceptors (C-LTMRs) have been shown to display a unique inverted-U-shaped relationship between firing frequencies and stroking velocity, which is not seen with any other cutaneous afferents C_LIO_LIAn inverted-U-shaped relationship is also observed between perceived touch pleasantness and stroking velocity, giving rise to a hypothesis which posits that the velocity tuning of C-LTMRs underpins the perception of pleasant touch C_LIO_LIWe compared traditional stroking (brushing-like motion) to an illusory perception of movement produced by successive touches along the skin (apparent motion) to examine if similar velocity-dependent pleasantness patterns would be observed when information provided to individual peripheral afferents is held constant C_LIO_LIIn our experiment, the type of motion did not significantly alter the relationship between perceived pleasantness and stimulus-velocity C_LIO_LIThese findings suggest that the velocity tuning of pleasantness cannot solely be attributed to velocity tuning of individual C-LTMRs C_LI

Genetically encoded differences in value-related functions are believed to influence decision biases in animals, yet direct causal evidence remains scarce. Here, we demonstrate how naturally occurring genetic variation between two Drosophila strains leads to distinct choices in an egg-laying-based decision-making task, where both sucrose and plain substrates are viable options. We identify a pair of long-range GABAergic neurons, Earmuff, that lower an option's intrinsic value and are both necessary and sufficient for shaping the flies' preferences. Further analysis reveals that expression-modifying single nucleotide polymorphisms (SNPs) within introns of the gene encoding the RNA-binding molecule pumilio (pum) - a known negative regulator of the voltage-gated sodium channel NaV+ - exist between the two strains. These SNPs drive variation in pum expression within Earmuff, altering how each strain values the two substrates and biasing its decisions. Our findings establish a mechanistic link between genetic variation and the neural circuitry that governs value-based decision-making.

Oncostatin M receptor (OSMR) plays diverse and important roles in several human malignancies, including brain, breast, and pancreatic cancer. Glioblastoma (GB) is the most malignant genetically diverse brain tumour, with no cure. The most common genetic mutation in GB is a truncated active mutant of epidermal growth factor receptor (EGFR), the EGFRvIII. OSMR orchestrates a feedforward signaling mechanism with EGFRvIII and the signal transducer and activator of transcription 3 (STAT3) to drive GB progression. Beyond EGFRvIII, OSMR promotes brain tumour stem cells (BTSCs) via upregulation of mitochondrial oxidative phosphorylation and contributes to therapy resistance. The molecular mechanisms underlying the multifaceted roles of OSMR in different contexts are largely unclear. Here, we systematically mapped the OSMR interactome using Mammalian Membrane Two-Hybrid High-Throughput Screening (MaMTH-HTS). This unbiased approach led to the identification of OSMR-specific and OSMR/EGFRvIII-specific binding proteins, revealing context-dependent OSMR functions. Among a subset of common interactors, we uncovered chloride intracellular channel 1 (CLIC1) as a critical regulator of both OSMR-STAT3 signaling and the OSMR/EGFRvIII complex in GB. CLIC1 physically associates with both OSMR and EGFRvIII and plays a key role in EGFRvIII packaging into extracellular vesicles (EVs). Genetic deletion of CLIC1 disrupts the OSMR/EGFRvIII interaction, impairs STAT3 activation, reduces EGFRvIII EV content, and slows GB progression. Using whole-cell patch-clamp recordings and a monoclonal antibody that selectively targets transmembrane CLIC1 (tmCLIC1omab), we establish a distinct pharmacologically and biophysically tmCLIC-mediated current in GB indispensable for sustaining EGFRvIII/STAT3 signaling. Importantly, we show that OSMR is required for maintaining CLIC1-mediated ionic balance at the plasma membrane (PM). Our study uncovers a bidirectional crosstalk between OSMR and tmCLIC1 in GB, essential for fueling its malignant growth, and suggests that disrupting the OSMR/tmCLIC1 interaction provides a promising therapeutic avenue for GB treatment.

1Auditory hallucinations are linked to elevated striatal dopamine, but their underlying computational mechanisms have been obscured by regional heterogeneity in striatal dopamine signaling. To address this, we developed a normative circuit model in which corticostriatal plasticity in the ventral striatum is modulated by reward prediction errors to drive reinforcement learning while that in the sensory-dorsal striatum is modulated by sensory prediction errors derived from internal belief to drive self-supervised learning. We then validate the key predictions of this model using dopamine recordings across striatal regions in mice, as well as human behavior across various tasks including a new hybrid learning task. Finally, we find that changes in learning resulting from optogenetic stimulation of the sensory-dorsal striatum in mice and individual variability in hallucinations in humans are best explained by selectively enhancing dopamine levels in the model sensory-dorsal striatum. These findings identify plasticity mechanisms underlying biased learning of sensory expectations as a biologically plausible link between excess dopamine and hallucinations.

Interpersonal neural synchrony is a fundamental aspect of social interactions, offering insights into the neural mechanisms underlying human connection and developmental outcomes. So far, hyperscanning studies have examined synchrony across different dyads and tasks, leading to inconsistencies in experimental findings and limiting cross-study comparability. This variability has posed challenges for building a unified theoretical framework for neural synchrony. This study investigated the effects of interpersonal closeness and social interactivity on neural synchrony using functional near-infrared spectroscopy hyperscanning. We recorded brain activity from 142 dyads (70 close-friend, 39 romantic-partner, and 33 mother-child dyads) across three interaction conditions: video co-exposure (passive), a cooperative game (structured active), and free interaction (unstructured active). Neural synchrony was computed between participants bilateral inferior frontal gyrus (IFG) and temporoparietal junction (TPJ) using wavelet transform coherence. Results showed that true dyads exhibited significantly higher synchrony than noninteracting surrogate dyads (qs <.001, Cohens d range: 0.17-0.32), particularly in combinations involving the right IFG. Mother-child dyads displayed lower synchrony than adult-adult dyads at the network (p <.001) and local level of analysis, pointing to possible developmental and maturational influences on neural synchrony. At the network level, synchrony was highest during video co-exposure, followed by the cooperative game and free interaction (p <.001). However, left IFG-left IFG and left IFG-right TPJ synchrony peaked during the cooperative game. Although these effects were statistically significant, the overall impact of social interactivity on interpersonal neural synchrony was small, suggesting that the complexity and richness of social exchanges alone may only modestly influence neural synchrony in naturalistic contexts. By comparing different types of dyads and interaction contexts, this study highlights factors that may guide future hypothesis-driven hyperscanning research and contribute incremental evidence to ongoing efforts to understand the neural mechanisms underlying human social interactions.

The calyx of Held is a giant, excitatory, cup-like axo-somatic synapse in the auditory brainstem and the only synapse of its kind described in the central nervous system. Here, using PACAP immunohistochemistry combined with confocal and tomographic electron microscopy, we report the discovery of a morphologically analogous calyx-like synapse in the rodent forebrain extended amygdala that exhibits unique neurochemical and structural features. This previously unrecognized terminal forms an enveloping axo-somatic specialization with mixed glutamatergic and cholinergic identities, co-expressing VGluT1, VGluT2, VAChT, and the neuropeptides PACAP, CGRP, and neurotensin, together with calretinin in the presynaptic compartment. We identified a distinct neuronal subpopulation in the pontine Kolliker-Fuse (KF) region of the parabrachial complex that gives rise to these calyceal terminals, which engulf PKC{delta}/GluD1 somata in the capsular central amygdala and oval BNST. Strikingly, GluD1 immunolabeling is concentrated at axo-somatic contact zones apposed to VAChT active zones but is absent from postsynaptic densities of conventional type I synapses within the same terminals. Our findings reveal a previously unrecognized multimodal calyx-like synapse in the forebrain, demonstrating the convergence of fast and modulatory transmission mechanisms and suggesting a structural substrate for high-fidelity signal integration within viscerosensory-emotional circuits. Significance StatementHigh-fidelity axo-somatic synapses, exemplified by the calyx of Held in the auditory brainstem, have never been demonstrated in the forebrain. Here we identify a multimodal calyceal synapse in the extended amygdala formed by PACAPergic neurons of the pontine Kolliker-Fuse nucleus. These giant terminals co-package glutamate, acetylcholine, and multiple neuropeptides, enveloping PKC{delta}/GluD1 neurons in the capsular central amygdala and oval BNST. This discovery expands the structural repertoire of forebrain synapses and reveals a direct anatomical substrate linking viscerosensory input from the hindbrain to limbic autonomic centers. Such high-fidelity multimodal transmission may underlie the precise synchronization of emotional and homeostatic control circuits.

Leukemia Inhibitory Factor (LIF) is an injury-induced cytokine that peaks 48 hours after a traumatic brain injury (TBI). Juvenile LIF haplodeficient mice exhibit desynchronized glial responses, increased neurodegeneration, decreased axonal conductivity and behavioral deficits after a concussive head injury. Given the necessity of LIF during the acute recovery phase after injury, we hypothesized that intranasal LIF (IN-LIF) treatment would prevent neurodegeneration when administered during the chronic recovery period from a mild TBI (mTBI). Young adult male CD1 mice were subjected to a midline, closed-head frontal cortex injury using a flat metal impactor with a 3mm tip to induce a mTBI. In the 6-8 weeks post-mTBI, known to precede axonal atrophy in this mTBI model, two doses of 40 ng and 100 ng of LIF were administered twice daily, 5 days/week for two consecutive weeks. Sensorimotor functions were assessed at 4 and 8 weeks post mTBI, followed by ex-vivo brain magnetic resonance imaging at 9.4T and histopathology. mTBI mice showed sensorimotor deficits at 4 weeks, which worsened by 8 weeks post-injury. IN-LIF treatment prevented the progressive sensorimotor loss seen in the vehicle-treated controls. Increased mean diffusivity and decreased fractional anisotropy were observed in the corpus callosum and prefrontal cortex of mTBI brains. In a dose-dependent manner, IN-LIF prevented the mTBI-induced mean diffusivity increase and fractional anisotropy decrease. Histologically, there was significantly less astrogliosis, microgliosis and axonal injury in the IN-LIF treated mice vs. controls. These results support the therapeutic potential of IN-LIF to reduce delayed neurodegeneration and improve neurological outcomes after mTBIs.

Recent studies have suggested the importance of statistical image features in both natural scene and object recognition, while the spatial layout or shape information is still important. In the present study, to investigate the roles of low- and high-level statistical image features in natural scene and object recognition, we conducted categorization tasks using a wide variety of natural scene (250) and object (200) images, along with two types of synthesized images: Portilla-Simoncelli (PS) synthesized images, which preserve low-level statistical features, and style-synthesized (SS) images, which retain higher-level statistical features. Behavioral experiments revealed that human observers could categorize style-synthesized versions of natural scene and object images with high accuracy. Furthermore, we recorded visual evoked potentials (VEPs) for the original, SS, and PS images and decoded natural scene and object categories using a support vector machine (SVM). Consistent with the behavioral results, natural scene categories were decoded with high accuracy within 200 ms after the stimulus onset. In contrast, object categories were successfully decoded only from VEPs for original images at later latencies. Finally, we examined whether style features could classify natural scene and object categories. The classification accuracy for natural scene categories showed a similar trend to the behavioral data, whereas that for object categories did not align with the behavioral results. Taken together, these findings suggest that although natural scene and object categories can be recognized relatively easily even when layout information is disrupted, the extent to which statistical features contribute to categorization differs between natural scenes and objects. Significance StatementHumans can reliably recognize complex natural scenes and objects. Recent studies have suggested that such recognition may rely on statistical image features, but the extent to which these features contribute to the recognition remains unclear. In the present study, we investigated how well statistical image features account for the perception of natural scenes and objects by conducting psychophysical categorization experiments and EEG decoding analyses. We found that natural scene categories could be reliably recognized based on statistical image features, and this recognition was consistent with neural responses. In contrast, although statistical image features also contributed to object category recognition, their effect appeared to be more limited. Together, these findings highlight the utility of statistical image features in visual perception.

Cortical thickness is a widely used biomarker of brain morphology and health, yet it is dependent on local cortical folding. Because gyral crowns are consistently thicker than sulcal fundi and cortical folds vary widely across individuals, these fluctuations introduce unmodeled nuisance variance that can obscure meaningful biological effects of interest. Previous global methods of folding compensation incompletely compensate for folding effects on cortical thickness. Spatial smoothing is commonly used to reduce these effects in the literature, but this markedly degrades spatial localization precision. To address these limitations, we developed a novel method for folding-compensated cortical thickness estimation that uses nonlinear local multiple regression with five folding measures to model and more completely remove folding-related variance from cortical thickness. This approach estimates what cortical thickness would have been in the absence of folding, yielding a more biologically interpretable measure of cortical architecture. We applied this new approach to data from the Young Adult Human Connectome Project (HCP-YA) and Aging Human Connectome Project (HCA), demonstrating substantial reductions in intra-areal and inter-individual variability, substantially increasing standardized effect sizes of age on cortical thickness (41% increase) while preserving neurobiologically expected patterns, and avoiding the loss of spatial precision that occurs with the spatial smoothing that has traditionally been used in the literature. The method has been integrated into the HCP pipelines, facilitating its widespread use. By attenuating folding-induced variability, this technique enhances cortical thickness as a structural phenotype and may support more accurate cortical parcellation, longitudinal tracking, and biomarker discovery in brain health and disease.

Cortical thickness is a widely used biomarker of brain morphology and health, yet it is dependent on local cortical folding. Because gyral crowns are consistently thicker than sulcal fundi and cortical folds vary widely across individuals, these fluctuations introduce unmodeled nuisance variance that can obscure meaningful biological effects of interest. Previous global methods of folding compensation incompletely compensate for folding effects on cortical thickness. Spatial smoothing is commonly used to reduce these effects in the literature, but this markedly degrades spatial localization precision. To address these limitations, we developed a novel method for folding-compensated cortical thickness estimation that uses nonlinear local multiple regression with five folding measures to model and more completely remove folding-related variance from cortical thickness. This approach estimates what cortical thickness would have been in the absence of folding, yielding a more biologically interpretable measure of cortical architecture. We applied this new approach to data from the Young Adult Human Connectome Project (HCP-YA) and Aging Human Connectome Project (HCA), demonstrating substantial reductions in intra-areal and inter-individual variability, substantially increasing standardized effect sizes of age on cortical thickness (41% increase) while preserving neurobiologically expected patterns, and avoiding the loss of spatial precision that occurs with the spatial smoothing that has traditionally been used in the literature. The method has been integrated into the HCP pipelines, facilitating its widespread use. By attenuating folding-induced variability, this technique enhances cortical thickness as a structural phenotype and may support more accurate cortical parcellation, longitudinal tracking, and biomarker discovery in brain health and disease.

Sleep disturbances have been shown to be intimately and bidirectionally related to disease progression across a wide range of neurodegenerative disorders including Parkinson's disease (PD) and Alzheimer's disease. However, the precise neurophysiological mechanisms relating abnormal sleep to aberrant daytime network activity that accelerates disease progression has yet to be determined. We collected chronic, multi-night (n=40), intracranial cortico-basal recordings during sleep from a cohort of patients with PD along with paired polysomnography and morning self-reports. This revealed that longer duration (and shorter latency) of rapid eye movement (REM) sleep predicted reduced daytime resting beta (13-30 Hz) activity and cortico-basal functional and effective connectivity, features established to be pathophysiological in PD. Within REM sleep, stronger cortical delta activity specifically predicted reduced pathophysiological cortico-basal neural network features. Additionally, REM delta power significantly predicted greater self-reported morning alertness. These findings highlight a potentially protective role of REM sleep in cortico-basal network health in PD and daytime subjective experience, representing a potential target for closed loop neuromodulation therapies to impact neurodegenerative disease progression.

Organotypic cultures, specifically brain slices, have been used in neuroscience studies for many years to prolong the lifetime of the biological tissue outside of the host organism. However, the cultures must be kept in a sterile environment, maintaining supply of gas/nutrients for tissue survival and physiological relevance. Electrophysiological recordings from cultured tissue are challenging as the conventional approaches implicate a compromise on biological stability or environmental integrity. In this article, a novel approach has been used to design and print nanoporous microelectrodes on culture wells enabling in situ recording of electrophysiological neural activities. Optimized ink formulations are developed for conductive nanocarbon microelectrodes, and furthermore, fluoropolymer (polytetrafluoroethylene-based AF2400) ink has been inkjet printed for the first time acting as an insulator layer for microelectrodes. To keep the biocompatible nanoporous structure of culture wells, the microelectrodes have been printed on the bottom of the culture cells and only small connector pads have been produced on top of the culture membrane. Neural activity has been recorded by such a microelectrode structure for rodent brain slices cultured for three weeks. Furthermore, aerosol jet printing has been used for printing of nanocarbon microelectrodes allowing to produce much smaller size features compared to the inkjet printing.

Adaptive goal-directed behavior requires dynamic coordination of movement, motivation, and environmental cues. Among these, cautious actions, where animals adjust their behavior in anticipation of predictable threats, are essential for survival. Yet, their underlying neural mechanisms remain less well understood than those of appetitive behaviors, where caution plays little role. Using calcium imaging in freely moving mice we show that glutamatergic neurons in the subthalamic nucleus (STN) are robustly engaged by contraversive movement during cue-evoked avoidance and exploratory behavior. Model-based analyses controlling for movement and other covariates revealed that STN neurons additionally encode salient sensory cues, punished errors, and especially cautious responding, where their activity anticipates avoidance actions. Targeted lesions and optogenetic manipulations reveal that STN projections to the midbrain are necessary for executing cued avoidance. These findings identify a critical role for the STN in orchestrating adaptive goal-directed behavior by integrating sensory, motor, and punitive signals to guide timely, cautious actions via its midbrain projections. Significance statementThis study provides new insights into the neural pathways that mediate adaptive goal-directed behaviors in response to environmental cues, identifying a critical role for glutamatergic projections from the subthalamic nucleus (STN) to the midbrain. We show that STN activation encodes caution and is essential for cued goal-directed actions. These findings deepen our understanding of the circuits involved in cued goal-directed adaptive behaviors used to cope with contextual challenges, which are often altered by brain disorders.

Synaptic dysfunction is a hallmark of Alzheimers disease (AD). Yet due to their plasticity, synapses may also adapt to early AD pathology. Here, we demonstrate that cholinergic neurons mount a presynaptic response to tau pathology in the living human brain. Using multi-tracer positron emission tomography in cognitively normal older adults at risk for AD, we observe that cholinergic neurons increase presynaptic vesicular acetylcholine transporter (VAChT) protein levels when colocalized to tau, but not amyloid. Notably, stronger VAChT responses predict preserved cognitive function over a decade. Whole-brain single-nucleus RNA sequencing in human and mouse tissue reveal that cholinergic neurons are enriched for a plasticity gene-network anchored to the microtubule-associated protein tau (MAPT) gene. In mice, forebrain-specific deletion of VAChT impairs cortical plasticity and hippocampal structural integrity. Overall, our findings identify cholinergic synaptic plasticity, and its failure, as a fundamental mechanism of resilience and vulnerability to tau in presymptomatic AD.

Humans perform tasks involving the manipulation of inputs regardless of how these signals are perceived by the brain, thanks to representations that are invariant to the stimulus modality. In this paper, we present modality-agnostic decoders that leverage such modality-invariant representations to predict which stimulus a subject is seeing, irrespective of the modality in which the stimulus is presented. Training these modality-agnostic decoders is made possible thanks to our new large-scale fMRI dataset SemReps-8K, released publicly along with this paper. It comprises 6 subjects watching both images and short text descriptions of such images, as well as conditions during which the subjects were imagining visual scenes. We find that modality-agnostic decoders can perform as well as modality-specific decoders, and even outperform them when decoding captions and mental imagery. Further, a searchlight analysis revealed that large areas of the brain contain modality-invariant representations. Such areas are also particularly suitable for decoding visual scenes from the mental imagery condition.

When will I see something and what will it be? Temporal predictions are crucial for adaptive interaction with the environment and are typically accompanied by predictions about sensory content, yet these two types of what and when predictions are usually studied separately. Specifically, oscillatory phase-coupling (or entrainment) has been proposed to align our neural sensitivity with likely moments of stimulus appearance, however these accounts ignore that predictions about when something will appear are usually accompanied by predictions about what it will be. Thus, temporal predictions may not enhance all sensory processing but rather modulate particular channels encoding predicted content. We here demonstrate oscillatory phase-coupling in vision and show how it relates to content-specific encoding. In a magnetoencephalography (MEG) study, participants observed rhythmic Gabors at 1.33 or 2 Hz with predictable orientations. They judged the timing or orientation of a delayed probe which manipulated the requirement to covertly maintain the sequence rhythm. We found sustained oscillatory phase-coupling to the entrained rhythm in motor areas specifically when participants judged stimulus timing, where its extent was associated with perceptual performance. Meanwhile, neural decoding revealed content predictions in early visual areas ( what) that fluctuated in line with temporal predictions ( when). These temporally-specific content predictions appeared regardless of task instruction but were correlated with the degree of motor phase-coupling during timing judgements. These findings suggest that temporal predictions may be derived from motor readouts of temporally-specific sensory predictions, with broad implications for our understanding of entrainment and prediction, and how we represent time more generally.

From birth, individuals' interpersonal dimension is underpinned by progressive learning of social interaction rules, their variations rooted in the temporal prediction of sensory events, and the inferences made about the organization of the social world. How this dimension is structured during infancy and articulated at the neural level is a critical question for cognitive and affective neurosciences. This systematic review aims to define the neural signatures of temporal prediction in newborns and infants and to discuss them in the context of the development of proximal cognitive and affective neural functions. Eight peer-reviewed studies were included, with 228 infants from birth to 9 months of age. Studies have evidenced that neural signatures of temporal prediction in infants present a broad cerebral localization, including the anterior and medial parts of the brain, especially in the frontal and central areas. Temporal prediction mechanisms emerge well before birth and evolve from early sensory-driven responses to complex top-down processing within the first year, shaped by both innate and experience-dependent factors, with influences like wakefulness and musical exposure that modulate neural integration across sensory and higher-order brain regions.

Internal bodily signals, notably the heartbeat, influence our perception of the external world - but the nature of this influence remains unclear. Different frameworks, originating in opposing views of the function of interoception, have developed largely in parallel. One line of evidence (Internal/External Competition) indicates that interoceptive and exteroceptive inputs compete for neural resources. Another line (Self-related Facilitation) shows a link between interoceptive and self-related processing, which might include computing the self-relevance of exteroceptive inputs. We contrasted these accounts within a single experimental task for which they yielded distinct predictions. We measured heartbeat-evoked potentials (HEPs, a measure of cardiac interoception) with EEG, and manipulated the self-relevance of an audio-tactile stimulus by placing the audio source either inside or outside the peripersonal space immediately around the body. On one hand, pre-stimulus HEP amplitudes over somatosensory cortex were linked to slower reaction times, and affected audio-tactile stimulus-evoked responses in the same area, indicating competition for shared neural resources. On the other hand, pre-stimulus HEPs over integrative sensorimotor and default-mode network regions facilitated stimulus self-relevance encoding, both in reaction times and audio-tactile evoked responses. Importantly, Competition and Facilitation effects were spatially and statistically independent from each other. We therefore reconcile the two views by showing the co-existence of two independent mechanisms: one that allocates neural resources to either internal bodily signals or the external world, and another by which interoception and exteroception are combined to determine the self-relevance of external signals. Our results highlight the multi-dimensionality of HEPs, and of internal states more generally. Significance StatementDo internal bodily signals distract us from the external world (Internal/External Competition account)? Or do internal signals contribute to conscious perception, by situating the perceived external world relative to the organism (Self-related Facilitation account)? So far, both accounts - reflecting fundamentally different views of brain-body interactions - received experimental support, but have never been compared directly. We measured neural responses to heartbeats, and tested how they influenced perception in an audio-tactile reaction time task where self-relevance was manipulated. We found evidence for both accounts, reflecting independent mechanisms in distinct brain regions. Our results reconcile two hitherto independent and seemingly contradictory research programmes on the relationship between interoception and exteroception. They further highlight the multi-dimensionality of cardiac-brain interactions, and hence of internal state.

How does the brain integrate artificial body extensions into its somatosensory representations? Prior work shows that the body and technology are represented simultaneously, but little is known about how these representations evolve dynamically across different sensorimotor interaction phases. To fill this gap, we investigated the dynamics of somatosensory plasticity using a custom-built exoskeletal device that extended users' fingers by 10 cm. Across four time points, before, during (pre- and post-use), and after exoskeleton wear, participants completed a high-density proprioceptive mapping task to measure representations of biological and exoskeletal fingers. We observed three distinct phases of plasticity. First, wearing the exoskeleton led to a contraction of the perceived length of the biological finger. Second, after active use, the represented lengths of the biological and exoskeletal fingers stretched significantly, an effect absent when participants trained with a non-augmenting control device. Third, a post-removal aftereffect on the biological finger representation was observed. These results demonstrate that wearable augmentations are rapidly integrated into body representations, with dynamic proprioceptive adjustments shaped by structural and functional properties of the device. This work advances our understanding of how the sensorimotor system accommodates artificial extensions and highlights the potential for body-augmenting technologies to be intuitively integrated within the sensorimotor system.

Background: Chronic alcohol exposure is a major driver of alcohol use disorders (AUD), in part through its ability to induce maladaptive plasticity within neural circuits that regulate reward, motivation, and affect. Excitatory projections from the hippocampus (Hipp) to the nucleus accumbens (NAc) play a pivotal role in regulating reward-related behaviors, and this pathway serves as a key locus for establishing associations between rewarding stimuli and related contextual information. Regulation of the strength of Hipp-NAc synapses is critical for supporting these behaviors, and aberrant Hipp-NAc plasticity is associated with anhedonia and disrupted reward learning. Methods: To examine acute ethanol effects, we used whole-cell electrophysiology to record Hipp-NAc synaptic plasticity in acute brain slices in the presence or absence of 50mM ethanol. To examine the effects of chronic ethanol administration, mice were exposed to ethanol vapor in a 3-week chronic intermittent ethanol (CIE) paradigm. Slices from ethanol and air exposed mice were used for whole-cell electrophysiology to examine Hipp-NAc synaptic plasticity. Results: Here, we demonstrate that acute ethanol application to ex vivo brain slices prevents long-term potentiation (LTP) at Hipp-NAc synapses, without altering presynaptic release probability. Furthermore, chronic intermittent exposure to ethanol abolishes LTP at these synapses, even during abstinence, indicating persistent synaptic dysfunction. Conclusions: Together, our findings demonstrate that ethanol has immediate and long-lasting effects on Hipp-NAc plasticity. Given the behavioral relevance of these synapses, this work has important implications for the mechanisms underlying ethanol-dependent effects on reward processing and negative affective states associated with AUD.

Sensory prostheses replace dysfunctional sensory organs with electrical stimulation but currently fail to restore normal perception. Outcomes may be limited by stimulation strategies, neural degeneration, or suboptimal decoding by the brain. We propose a deep learning framework to evaluate these issues by estimating best-case outcomes with task-optimized decoders operating on simulated prosthetic input. We applied the framework to cochlear implants--the standard treatment for deafness--by training artificial neural networks to recognize and localize sounds using simulated auditory nerve input. The resulting models exhibited speech recognition and sound localization that was worse than that of normal hearing listeners, and on par with the best human cochlear implant users, with similar results across the three main stimulation strategies in current use. Speech recognition depended heavily on the extent of decoder optimization for implant input, with lesser influence from other factors. The results identify performance limits of current devices and demonstrate a model-guided approach for understanding the limitations and potential of sensory prostheses.

Corticothalamic layer 6 modulates information flow between cortical and thalamic circuits. Previous research reported contrasting inhibitory or excitatory effects of corticothalamic layer 6 on cortical dynamics, potentially reflecting technological discrepancies or physiological differences in corticothalamic layer 6 function. To resolve these discrepancies, we combined translaminar, multi-channel in vivo electrophysiology in the primary somatosensory cortex of the anaesthetised mouse with optogenetic stimulation across a range of stimulation regimes to manipulate firing rate and frequency of corticothalamic layer 6. Increasing corticothalamic layer 6 firing rates exerted a transition from inhibition to excitation across cortical layers. Furthermore, corticothalamic layer 6 activity imparted population synchrony onto distinct cortical subpopulations, independent of changes in overall corticothalamic layer 6 activity. In the thalamus, corticothalamic layer 6 modulated thalamic bursting in a bidirectional manner, dependent on optogenetic stimulation frequency. These results demonstrate that corticothalamic layer 6 in primary somatosensory cortex can bidirectionally modulate both cortical firing and thalamic firing mode, elucidating a more nuanced function of somatosensory corticothalamic layer 6 in thalamic and cortical signalling than previously recognised.

Leading theories of episodic memory argue that when events from the past are remembered, temporally-adjacent events are also reinstated ( temporal context reinstatement). However, direct evidence for temporal context reinstatement is surprisingly limited. Here, we tested for temporal context reinstatement in a human fMRI continuous recognition memory experiment in which natural scene images were repeatedly encountered. For the original encounter with each scene, we defined its temporal context as the visual content of temporally-adjacent scenes. Using voxelwise encoding models, we tested whether fMRI activity patterns evoked when a scene was re-encountered carried information about the original encounters temporal context. Indeed, we found robust temporal context reinstatement within high-level visual cortex (lateral occipitotemporal cortex; LOTC), despite the fact that reinstated content was entirely incidental to task demands. However, temporal context reinstatement only occurred when stimuli were successfully recognized, indicating that reinstatement was behaviorally-relevant, even if incidental. Finally, the strength of temporal context reinstatement in LOTC was predicted by the similarity of hippocampal activity patterns across encounters, demonstrating distinct, but complimentary, roles for the hippocampus and neocortex in reinstating temporal context information.

Visual stimuli with constant temporal frequency input is known to induce peaks in the driving frequency of the power spectrum of the electroencephalogram (EEG) over the visual cortex. While EEG responses with random temporal frequencies (m-sequences) have been studied, the underlying mechanisms that shape these responses are not fully understood. We analyze our new EEG data from a controlled experiment with m-sequence inputs and model the EEG using statistical time series models: an autoregressive (AR) model, adding exogenous input to AR (ARX), adding moving average terms (ARMAX), and finally adding a seasonality term (SARMAX). We implement computational methods to robustly handle model instabilities induced by this data, fitting these models with the Box-Jenkins methodology and assessing prediction accuracy for long periods of several seconds out-of-sample. We find in-sample fits are good in all models despite the complexities of the visual pathway, and that all models can predict aspects of EEG: including the distribution of point-wise values in time, the point-wise Pearson's correlation of EEG and model, and the frequency content. Surprisingly, we find little variation in the performance among these models, with the most sophisticated model (SARMAX) performing comparatively poorly in some instances. Our results suggest the simplest AR model is viable and can out perform more complicated models. Since these models are relatively simple and more transparent than contemporary models with numerous parameters, our study could inform future mechanistic studies of the temporal dynamics of human EEG responses to visual stimuli.

In a comprehensive study of genetically and clinically characterized male and female Parkinson's disease (PD) patients and healthy controls, we recently reported a marked downregulation in blood D- and L-amino acids level that regulate glutamatergic NMDAR function, particularly in idiopathic male cases. However, the extent to which disease progression and antiparkinsonian therapies contribute to this systemic dysregulation remains unclear. To address these issues, in the present study we measured by High Performance Liquid Chromatography the concentrations of glutamatergic system-related D- and L-amino acids and their precursors in the plasma of male and female healthy controls (HC) and PD patients across three distinct clinical stages and treatment conditions: (1) early stage L-DOPA naive patients treated with MAO-B inhibitors; (2) mid-stage patients treated with L-DOPA; and (3) advanced stage patients receiving Deep Brain Stimulation in the subthalamic nucleus (STN-DBS) plus L-DOPA. Our results reveal notable reduction of circulating neuroactive D- and L-amino acids exclusively in male PD patients, while female patients remain unaffected regardless of disease stage or treatment. In male patients, this dysregulation manifests early, with L-DOPA-naive individuals showing decreased plasma levels of L-glutamate and L-aspartate. In mid stage L-DOPA-treated PD patients, amino acid reductions extend to L-alanine, L-serine, L-glutamine, L-asparagine, and L-threonine. Remarkably, in advanced PD patients, with a median disease duration of ~23 years, STN-DBS normalizes the blood concentrations of these amino acids to those observed in HC. In conclusion, our study highlights the potential of circulating D- and L-amino acid dysregulation as an early biomarker of PD and demonstrates that, in contrast to L-DOPA therapy, the STN-DBS confers systemic metabolic benefits even at advanced stages of the disease.

The ability to extract structured sensory patterns from a noisy environment is fundamental to cognition, yet how the brain learns complex regularities remains unclear. Using magnetoencephalography during a visuomotor task, we tracked the neural dynamics as humans learned non-adjacent temporal dependencies embedded in noise. We reveal that learning is supported by two temporally dissociable mechanisms. Neural predictive activity emerged rapidly, with stimulus-specific patterns appearing before stimulus onset and preceding measurable behavioral improvements. This is followed by a slower build-up of representational change, characterized by an increased neural pattern similarity between statistically dependent, non-adjacent elements. Both processes are supported by a distributed consortium of networks, with the sensorimotor and dorsal attentional networks playing a central role. These findings suggest that both neural predictive activity and representational changes contribute to learning regularities, revealing a temporal hierarchy in which neural predictive activity precedes behavioral improvement and is followed by neural representational changes, possibly facilitating the gradual consolidation of knowledge into stable neural representations.

Real-world data is often noisy, making it challenging to extract true signals Non-invasively recorded neural activities are among the most difficult data, yet its precise signal reconstruction is highly anticipated by communities developing non-invasive brain-machine interfaces. Several noise sources contribute to this challenge, including unrelated neuronal activity, non-brain bioelectricity, attenuation by the skull and scalp, and environmental noises. Additionally, the accumulation of noise varies significantly across subjects and recording sessions, resulting in widely diverging distributions of degraded observations. In this study, we propose modeling the noise accumulation process as a Schrodinger bridge and decoding the true signal by reversing this process. Compared to conventional guided Diffusion approach, our Schrodinger bridge approach effectively models diverse noise processes within a single framework, exhibiting greater robustness to inter-subject variability. Also, our approach doesnt require pre-aligning brain and image representations, which is an additional compute cost in the conventional approach.

The primary cilia of pyramidal neurons in inside-out laminated regions orient predominantly toward the pia, reflecting reverse soma movement during postnatal neurodevelopment. However, the mechanisms underlying the directional cilia orientation are unknown. Here we show that the primary cilia of pyramidal neurons are localized near the base of the apical dendrites and aligned on the nuclear side opposite to the axon initial segment (AIS). However, this pattern is not observed in atypical pyramidal neurons in the deep neocortex, excitatory neurons in non-laminated regions, interneurons, or astrocytes, where cilia are irregularly positioned around the nuclei and lack preferred orientation. In Reelin-deficient mice (reeler), the directional orientation and apical location of cilia in late-born neocortical and CA1 neurons are disrupted. However, the initial impairments are partially corrected during postnatal development, along with a realignment of apical-basal orientation. In contrast, loss of Reelin drastically disrupts the directional orientation of cilia in early-born neocortical neurons and principal neurons in evolutionarily conserved cortical regions, which lack postnatal correction. Consistently, their cilia do not preferably localize to the apical side. Additionally, Reelin deficiency increases the cilia length of principal neurons across the cerebral cortex at a developmental stage when cilia stabilize in wild-type mice, but this effect is not observed in interneurons, astrocytes, or excitatory neurons in non-laminated regions. Together, Reelin controls the directional orientation, apical localization, and length of primary cilia in principal neurons in the cerebral cortex, underscoring the cilium as a key apical domain particularly prominent in late-born neurons.

Rapid learning is essential for flexible behavior, but its basis in the brain remains unknown. Here we introduce the PRISM plasticity rule, a unifying mechanistic model of three well-established, fast-acting synaptic plasticity rules--in hippocampus, cerebellum and mushroom body--which relies exclusively on pre-synaptic activity and an "instructive signal" from another brain area. Using a multi-region network model we show that guiding PRISM plasticity with instructive signals enables the network to quickly learn extremely flexible nonlinear dynamics underlying behaviorally relevant computations, as well as to emulate unknown external system dynamics from real-time error signals, which we demonstrate with comprehensive simulations supported by exact mathematical theory. Thus, PRISM plasticity guided by instructive signals is well-suited to rapidly learn general-purpose neural computations--in contrast to canonical Hebbian rules. Finally, we show how including this plasticity rule in artificial learning algorithms can solve long-range temporal credit assignment, a long-standing challenge in machine learning. HighlightsO_LIPRISM (PResynaptic and Instructive Signal-Mediated) plasticity--a unifying mechanistic model of three fast-acting plasticity rules in hippocampus, cerebellum, and mushroom body. C_LIO_LIMathematical theory inspired by Support Vector Machine exactly predicts the dynamics learned in a network model through PRISM plasticity. C_LIO_LIExamples of learning nonlinear dynamics in a single shot via sparse instructive signals or from real-time error signals. C_LIO_LIMachine-learning application of instructive signals and PRISM plasticity to solve the long-range temporal credit assignment problem. C_LI

Neuronal activity shapes brain development and refines synaptic connectivity in part through dynamic changes in gene expression. While activity-regulated transcriptional programs have been extensively characterized, the holistic effects of neuronal activity on the full RNA life cycle remain relatively unexplored. Here, we show that neuronal activity influences multiple stages of RNA metabolism in vitro and in vivo. Among these, RNA stability emerges as a previously underappreciated regulator of gene expression, exerting a stronger influence than transcription on total RNA levels for [~]15% of activity-dependent genes. We go on to profile 3'UTR mRNA motifs that are sufficient to modulate activity-dependent mRNA stability and employ machine learning to identify the neuronal-specific RNA-binding protein HuD as a key regulator of activity-dependent mRNA stabilization. We demonstrate that HuD shapes activity-dependent mRNA abundance of hundreds of transcripts in both soma and distal neuronal processes and that neuronal activity drives the reorganization of HuD-interacting proteins, thereby stabilizing HuD-bound mRNAs and directing them into translationally active granules. Finally, we find that many variants associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders disrupt or promote aberrant activity-dependent changes in mRNA stability. These findings reveal mRNA stability as a widespread mechanism of stimulus-responsive gene regulation in neurons with direct implications for the understanding of neurodevelopmental disorders.

Language is one of the most extensively studied lateralised cognitive functions in the human brain, predominantly relying on the left hemisphere in most individuals. However, the mechanisms by which a stable white matter architecture underpins individual language functions remain unclear. Previous studies have employed structural connectivity (SC) and functional connectivity (FC) coupling for individual fingerprinting and task decoding, suggesting that variability in brain entropy may serve as a distinguishing characteristic for language lateralisation. We examined a large cohort of healthy adults (n = 285) to investigate SC-FC coupling and identify markers distinguishing different language laterality groups. Functional connectivity was measured using resting-state fMRI (rsfMRI) time-series data, while structural connectivity was determined via probabilistic fibre tractography. SC-FC coupling was investigated using the SENSAAS language atlas and defined as the Pearson correlation between non-zero elements of regional structural and functional connectivity profiles. Group differences were assessed using the PALM toolbox in FSL. Our findings revealed that increased SC-FC coupling in the left precentral sulcus was associated with typical language lateralisation, while increased coupling in the right middle temporal gyrus and left anterior insula was observed in individuals with atypical language lateralisation (pFDR < 0.05). Non-lateralised individuals exhibited increased coupling in the left anterior insula compared to lateralised (pFDR<0.05). SC-FC coupling offers a promising framework to uncover functional and anatomical differences among individuals with varying language lateralisation. This regional specificity indicates that typical, atypical, and non-lateralised profiles rely on different structural-functional alignments, likely reflecting the recruitment of alternative pathways for language processing.

The ability of neurons to extend axons is governed by tightly regulated genetic programs that vary across developmental stages and cell types. Understanding the molecular features that control axon growth potential is critical for uncovering how neural circuits form, mature, and respond to injury or disease. The Drosophila mushroom body (MB) offers a powerful model to dissect axon growth programs, as lineage-related Kenyon cells (KCs) undergo different developmental events under shared spatiotemporal conditions. During metamorphosis, {gamma}-KCs undergo axon pruning, followed by developmental regrowth at the same time-frame as /{beta}-KCs initiate axon growth - thus providing a unique opportunity to compare these distinct growth paradigms. We thus performed RNA-sequencing of /{beta}-and {gamma}-KCs during their initial growth and developmental regrowth, respectively, revealing dynamic transcriptional changes and identifying 300 shared genes upregulated during both growth states. A targeted loss-of-function screen revealed genes specifically required for either /{beta} initial growth, {gamma} regrowth, or both. Focusing on one such candidate, Pmvk, we found that it plays a crucial role in axon regrowth by acting within the mevalonate pathway. Notably, other enzymes in this pathway were also required, suggesting that the entire metabolic pathway is essential for supporting regrowth. Genetic mutant analyses and rescue exepriements suggest that Pmvk likely controls axon regrowth via Rheb, an effector of the TOR pathway, which we previously found to be required for regrowth. Our developmental transcriptomic atlas not only advances understanding of intrinsic axon growth programs, but also provides candidate genes and a valuable framework for future studies aimed at enhancing axon regeneration in the adult nervous system.

Single-cell proteomics (SCP) is a powerful method for interrogating the molecular composition of neurons, yet its application to acute brain slices has remained limited. Patch-clamp electrophysiology provides direct information on neuronal excitability, synaptic inputs, and ion channel function, making it a natural partner for SCP. However, combining these techniques introduces unique challenges: neurons must be both physiologically characterized and physically collected, and variability during retrieval from the brain slice can affect how faithfully proteomic measurements reflect in situ physiology. Here, we introduce a framework for interpreting patch- SCP outcomes that considers retrieval quality in terms of both the amount of material collected and the synaptic contents being recovered. Using a shotgun strategy in which all patched neurons were collected regardless of electrophysiological outcome, we systematically benchmarked the retrieval of pyramidal neurons in the rat medial prefrontal cortex. Capacitance measured during gigaseal-preserved retrieval correlated with protein identifications, providing a proxy for linking soma size to proteome yield. Preservation of neuronal spiking during relocation was associated with broader synaptic enrichment and recovery of transmembrane proteins. By comparison, torn or aspirated neurons produced small proteomes with poor synaptic representation and neurons with lost gigaseals or no recordings displayed variable outcomes that could still yield substantial molecular information. Together, these results establish shotgun patch-SCP as both proof-of- concept and a practical framework for linking neuronal physiology with proteomics in semi-intact circuits.

In recent years, research on voice processing in the human brain--particularly the study of temporal voice areas (TVA)--was dedicated almost exclusively to conspecific vocalizations. To characterize commonalities and differences regarding primate vocalization representations in the human brain, the inclusion of closely related nonhuman primates--namely chimpanzees and bonobos--is needed. We hypothesized that neural commonalities would depend on both phylogenetic and acoustic proximities, with chimpanzees ranking closest to Homo. Presenting human participants (N=23) with the vocalizations of four primate species (rhesus macaques, chimpanzees, bonobos and humans) and regressing-out relevant acoustic parameters using three distinct analyses, we observed within-TVA, sample-specific, bilateral anterior superior temporal gyrus activity for chimpanzee vocalizations compared to: all other species; nonhuman primates; human vocalizations. Within-TVA activity was also observed for macaque vocalizations. Our results provide evidence for subregions of the TVA that respond principally--but not exclusively--to phylogenetically and acoustically close nonhuman primate vocalizations, namely those of chimpanzees.

The spatial distribution of tau pathology, the core driver of neurodegeneration in Alzheimers disease (AD), varies markedly across individuals. While tau is thought to spread along brain networks, the role of inter-individual variability in shaping these patterns remains underexplored. Using resting-state fMRI and tau-PET from 805 participants across the AD continuum, we studied whether subject-specific functional connectivity (FC) profiles enhance the characterization of tau deposition patterns. A hybrid approach integrating individual and group-average FC outperformed both alone, particularly in symptomatic individuals and at finer spatial resolutions, the latter underscoring a critical but often overlooked role of spatial scale. Individualized FC also better captured individual tau topographies than canonical tau-PET maps derived from cohort-level data. These effects were specific to tau, and not seen for {beta}-amyloid, and their predictive power increased with spatial granularity. Furthermore, baseline FC also predicted future tau accumulation at the individual level, supporting its prognostic value. Together, these findings provide strong evidence that individual functional brain architecture shapes tau propagation in humans, supporting the network spread hypothesis by showing that variability in connectivity translates into heterogeneity in tau distribution. This work advances biological understanding of tau propagation in AD, highlighting functional connectivity as a mechanistic substrate that supports prognostic assessment of tau trajectories.

The amygdala helps prioritize emotional over neutral information. However, it responds similarly to positive and negative stimuli, and so is unlikely to be the source of valence-specific effects within affective networks. We hypothesized that the locus coeruleus (LC) is a key contributor to negative biases in attention. Using ultra-high field 7T magnetic resonance imaging, we tested how arousal modulates processing of emotional faces during an oddball task in twenty-two young adults during two separate sessions. Arousal induced by isometric handgrip increased LC cerebral blood flow and amplified brain responses to target and angry faces, but not to happy faces. The amygdala exhibited valence-general responses that were not modulated by arousal. LC connectivity with the default mode network decreased during processing target and angry faces, and arousal further modulated responses in the salience network and visual cortex. Behaviorally, arousal enhanced recognition of angry faces only when allocating attentional resources and memory performance was linked to left LC brain activity. These findings highlight the LC as a key structure through which arousal shapes valence processing, biases attention, and informs mechanisms related to affective disorders.

Neurons that produce NPS send output to brain regions implicated in circadian function and threat responses, but less is known about the afferent control of NPS neurons. In this study, we used a conventional retrograde tracer, cholera toxin beta subunit (CTb), to identify afferents to the rostral-lateral parabrachial region that contains the main concentration of NPS neurons. We then used Cre-dependent rabies retrograde tracing in Nps-2A-Cre mice to identify inputs specifically to NPS neurons. Nps-expressing neurons receive heavy input from auditory brainstem structures, including the inferior colliculus, nucleus of the lateral lemniscus, superior olivary complex, and cochlear nucleus. These findings suggest an unexpected role for auditory information in controlling the activity of NPS neurons.

Limb dominance is a human behavioral characteristic with many cultural, practical, scientific and clinical implications. Yet why the dominant limb performs better across a range of motor skill-requiring tasks remains unanswered. Is it because of an intrinsic hemispheric advantage or instead is it the result of life-long practice with the dominant side? We tested these alternatives using two tasks. The first was 3D reaching with either an inertial challenge or the need to use a stick-like tool. The second required participants to write with their dominant and non-dominant elbows. We applied a novel geometric analysis to quantify movement-trajectory shape. We show that (1) tool-use unmasks markedly inferior control in the non-dominant arm, and this is because tools impose the need to generate unfamiliarly shaped movement trajectories; and (2) there is no general dominant limb motor control advantage, only task-specific experience or practice. These results reframe dominance as predominantly about learned control of tool kinematics rather than baseline asymmetry in control of limb dynamics.

AO_SCPLOWBSTRACTC_SCPLOWThe seminal reward prediction error theory of dopamine function faces several key challenges. Most notable is the difficulty learning multiple rewards simultaneously, inefficient on-policy learning, and accounting for heterogeneous striatal responses in the tail of the striatum. We propose a normative framework, based on linear reinforcement learning, that redefines dopamines computational objective. We propose that dopamine optimises not just cumulative rewards, but a reward value function augmented by a penalty for deviating from a default behavioural policy, which effectively confers value on controllability. Our simulations show that this single modification enables optimal value composition, fast and robust adaptation to changing priorities, safer exploration in the context of threats, and stable learning amid uncertainty. Critically, this unifies disparate striatal observations, parsimoniously reconciling threat and action prediction error signals within the striatal tail. Our framework refines the core principle governing striatal dopamine, bridging theory with neural data and offering testable predictions.

Notch is a transmembrane receptor expressed at the cell surface that mediates transcriptional responses upon binding to its ligands, in a variety of contexts. Evolutionarily conserved, Notch plays a key role in numerous cell fate decisions during development and is also required in post-mitotic brain neurons for the consolidation of long-term memory and long-term habituation. Notch signaling is highly expressed in glial cells, where it plays a key role in regulating their development and proliferation. More recently, a Notch-dependent neuroglial pathway has been implicated in modulating the susceptibility of short-term memory to sleep deprivation in Drosophila. In this study, we demonstrate that canonical Notch signaling in glia-- mediated by the Delta ligand and the transcription factor Suppressor of Hairless--is activated in a subset of cortex and ensheathing glial cells. This signaling is essential for the formation of short-term memory in the aversive phototaxic suppression assay, which is sensitive to sleep deprivation. Dopaminergic transmission is known to be required for this type of learning and is negatively impacted by sleep deprivation, suggesting a possible interaction between Notch and dopamine pathways. Supporting this idea, we find that modulating dopaminergic transmission downregulates canonical Notch activity in glial cells. Conversely, activating Notch signaling in glia near dopaminergic neurons prevents the learning impairments typically caused by sleep deprivation. Notably, Notch signaling itself does not appear to alter dopamine levels in the brain. Together, these findings indicate that canonical Notch signaling in a specific subset of glial cells is essential for short-term memory formation and is modulated by dopaminergic signaling. This suggests that sleep loss-induced disruption of dopaminergic transmission impairs learning by downregulating canonical Notch signaling. Since Notch homologs are highly expressed in mammalian glia, this pathway may be conserved and functionally relevant in other species, including humans.

The cortical mechanisms that actively suppress consciousness remain poorly understood. Here, we identify a specific subset of prefrontal cortical (PFC) neurons preferentially active under anesthesia while most neurons are suppressed. Chemogenetic activation of these excitatory neurons enhances anesthetic potency and deepens NREM sleep, whereas their inhibition blunts anesthetic effects. We identify these NREM and Anesthesia Promoting (NAP) neurons as PFC Layer 5 extratelencephalic (L5 ET) neurons. Remarkably, NAPs have sparse cortical projections and predominately communicate with subcortical nuclei including anterior and reticular thalamic nuclei, hypothalamus, and claustrum. We identify a transgenic mouse line that labels L5 ET neurons and verify that PFC L5 ET neurons are uniquely activated under anesthesia. Furthermore, we show that activation of PFC L5 ET neurons promotes deep NREM sleep. These findings identify a unique excitatory PFC circuit that promotes both naturally-occurring and drug-induced unconsciousness, with implications for both sleep regulation and anesthetic action.

Menopause affects the aging process in women through significant ovarian hormone production decline in midlife. Women who experience early menopause face an accelerated physiological aging rate, along with impaired memory and increased risks of neurodegenerative diseases. However, it remains elusive how the timing of menopause affects brain activity, which could be crucial for understanding menopause-related acceleration of aging and increased risk of dementia. Recent studies have revealed a highly structured infra-slow (< 0.1 Hz) global brain activity across species and linked it to arousal and memory functions, as well as waste clearance in Alzheimers diseases (AD). In this study, we examined how this global brain activity relates to age of menopause using resting-state fMRI data from the Human Connectome Project-Aging dataset. We found that women who experienced earlier menopause (mean menopausal age 45{+/-}3.5 yr) exhibited weaker global brain activity (p = 5.0x10-4) with reduced coupling to cerebrospinal fluid (CSF) flow (p = 0.017) compared to age-matched later-menopausal women (mean menopausal age 54{+/-}1.2 yr). Differences appeared mainly in higher-order brain regions, where activation levels correlated with memory performance in earlier but not in intermediate or later menopausal women. These findings highlight brain activity changes linked to early menopause, suggesting a potential mechanism underlying memory decline and the increased risk of AD and dementias in early-onset menopausal women.

Microglia, the brains innate immune cells, can adopt a wide variety of activation states relevant to health and disease. Dysregulation of microglial activation occurs in numerous brain disorders, and driving or inhibiting specific states could be therapeutic. To discover regulators of microglial activation states, we conducted CRISPR interference screens in iPSC-derived microglia for inhibitors and activators of six microglial states. We identified transcriptional regulators for each of these states and characterized 31 regulators at the single-cell transcriptomic and cell-surface proteome level in two distinct iPSC-derived microglia models. Finally, we functionally characterized several regulators. STAT2 knockdown inhibits interferon response and lysosomal function. PRDM1 knockdown drives disease-associated and lipid-rich signatures and enhanced phagocytosis. DNMT1 knockdown results in widespread loss of methylation, activating negative regulators of interferon signaling. These findings provide a framework to direct microglial activation to selectively enrich microglial activation states, define their functional outputs, and inform future therapies. HighlightsO_LICRISPRi screening reveals novel regulators of six microglia activation states C_LIO_LIMulti-modal single-cell screens highlight differences between mRNA and protein level expression C_LIO_LIiPSC-microglia models show different baseline distributions of activation states C_LIO_LILoss of DNMT1 leads to widespread DNA demethylation, promoting some states but limiting the interferon-response state C_LIO_LILoss of PRDM1 drives microglial disease-associated state C_LI

Evaluating outcomes to accurately predict which actions lead to reward is crucial for survival. Discrepancies between expected and realized outcomes, termed reward prediction errors (RPEs), serve as a teaching signal to update subsequent predictions and promote adaptive behavior. Neural correlates of RPEs have been identified in several brain regions, including the lateral habenula (LHb), which contains a subpopulation of neurons encoding negative reward prediction error (nRPE) that are excited by worse-than-expected outcomes and inhibited by better-than-expected outcomes. LHb projections to the midbrain shape firing in dopaminergic neurons and play a well-established role in reward learning and decision-making. However, the LHb engages in a wide variety of behaviors beyond reward processing, and it remains unclear whether these diverse functions are mediated by specific transcriptionally defined cell types. Little is known about the transcriptomic identity of nRPE-encoding neurons, limiting our understanding of the specific role of these signals in outcome valuation. Using cell type-specific recording in mice performing reward-guided tasks, we demonstrate neurons expressing the neuropeptide gene Tachykinin-1 (Tac1) represent a subpopulation of LHb neurons that encode nRPE. We found LHbTac1 activity is sensitive to changes in both the expected value and realized value of rewards, and scales with the magnitude of the difference. Further, LHbTac1 neurons show little modulation to other task-related events, or to innately aversive stimuli that engage a broader population of LHb cell types. Together, these data demonstrate that Tac1 marks a subpopulation of LHb neurons that preferentially encodes nRPE. Our results provide insight into cell type-specific contributions of habenular neurons in nRPE signaling and open avenues for more targeted manipulations of nRPE-encoding neurons to understand their role in reward-guided behavior.

The ability to discriminate similar visual stimuli has been used as an important index of memory function. This ability is widely thought to be supported by expanding the dimensionality of relevant neural codes, such that neural representations for the similar stimuli are maximally distinct, or "separated." An alternative hypothesis is that discrimination is supported by lossy compression of visual inputs, efficiently coding sensory information by discarding seemingly irrelevant details. A benefit of compression, relative to expansion, is that it allows the individual to efficiently retain fewer essential dimensions underlying stimulus variation--a process linked to higher-order visual processing--without hindering discrimination. Under the compression hypothesis, pattern separation is facilitated when more information from similar stimuli can be discarded, rather than preserving more information about distinct stimulus dimensions. We test the compression versus expansion hypotheses by predicting performance on the canonical mnemonic similarity task. First, we train neural networks to compress perceptual and semantic factors of stimuli, and measure lossiness of those representations using the mathematical framework underlying compression. Consistent with the compression hypothesis, and not the expansion hypothesis, we find that greater lossiness predicts the ease and performance of lure discrimination, particularly in later layers of convolutional neural networks shown to predict brain activity in the higher-order visual stream. We then empirically confirm these predictions across two sets of images, four behavioral datasets, and alternative metrics of lossiness. Finally, using task fMRI data, we identify signatures of lossy compression--neural dimensionality reduction and information loss--in the higher-order visual stream regions V4 and IT as well as hippocampal subregions dentate gyrus/CA3 and CA1 associated with lure discrimination performance. These results suggest lossy compression may support mnemonic discrimination behavior by discarding redundant and overlapping information.

Diffusion-weighted magnetic resonance spectroscopy (dMRS) is a unique, non-invasive technique capable of probing cell-type specific morphology. However, conventional dMRS methods are limited in their ability to provide detailed morphological information. This study demonstrates the potential of a multi-parametric dMRS approach, combining diffusion-time dependent and double-diffusion encoding MR spectroscopy, to characterize soma and neurite morphology of neuronal and glial cells. This methodology holds promise for developing biomarkers for the diagnosis, monitoring, and phenotyping of neurological pathologies, like Alzheimer's Disease, Parkinson's Disease, or Multiple Sclerosis, where alterations in soma and neurite morphology are reported.

Diffusion-weighted magnetic resonance spectroscopy (dMRS) is a unique, non-invasive technique capable of probing cell-type specific morphology. However, conventional dMRS methods are limited in their ability to provide detailed morphological information. This study demonstrates the potential of a multi-parametric dMRS approach, combining diffusion-time dependent and double-diffusion encoding MR spectroscopy, to characterize soma and neurite morphology of neuronal and glial cells. This methodology holds promise for developing biomarkers for the diagnosis, monitoring, and phenotyping of neurological pathologies, like Alzheimer's Disease, Parkinson's Disease, or Multiple Sclerosis, where alterations in soma and neurite morphology are reported.

The uncinate fasciculus (UF) is a long-range association fiber tract that serves to connect the anterior temporal lobe with the orbitofrontal cortex. The UF has been implicated via neuroimaging studies in the neurobiological vulnerability to psychiatric disorders posed by a history of childhood abuse (CA), as well as in the psychopathology underlying depressive disorders. Since the myelin sheath is highly enriched in lipids, white matter (WM) dysfunction may reflect alterations in the myelin lipid profile. In fact, our previous work showed that in the anterior cingulate cortex WM, there was a specific effect of CA in the choline glycerophospholipid fatty acids (FA) involved in the synthesis of arachidonic acid. Given that the UF does not exist in rodents, its molecular properties are highly understudied and its lipid composition is virtually unknown. As such, we sought to quantify the phospholipid FA and cholesterol quantities of the human postmortem UF and measure whether we could detect lipid-related or myelin-constituent gene/protein changes associated with CA and/or depression. Fresh-frozen left hemisphere UF samples were analyzed from individuals with depression who died by suicide with a history of severe CA (DS-CA), individuals with depression who died by suicide without a history of CA (DS), and non-psychiatric control subjects who died naturally or accidentally (CTRL). Phospholipids were separated by thin-layer chromatography. FA and non-derivatized cholesterol were quantified using gas chromatography-flame ionization detection. Relative expression of myelin-constituent genes (PLP1, MAG, CNP, MOG, PLLP, MBP, and MOBP) was measured by RT-qPCR, and levels of myelin-constituent proteins (MAG, MOG, MBP, and PLP) were measured by immunoblotting. We found no robust relationships between depression or CA and any lipid measures, nor in myelin-constituent gene and protein levels. However, in the phospholipids, we observed striking age relationships that varied across fractions, with an overall pattern of increases in monounsaturates and decreases in long chain omega-6 polyunsaturates with age. In tandem, we observed that most myelin-constituent genes and proteins showed decreasing trends with age, with PLP1 and MAG showing significantly decreasing relationships. We hypothesize that the changes in lipid composition and lipid-protein interactions contribute to age-related myelin deficits and declines in cognition. The absence of group differences highlights the importance of regional specificity in molecular studies assessing neurobiological correlates of psychiatric disorders.

Despite extensive investigation, the neural correlates of metaphor processing remain debated. Poor theoretical and experimental control of variables that drive metaphor activation-- particularly the constructs of novelty and familiarity--may be the reason for past discrepancies between studies. To address this issue, we used functional near-infrared spectroscopy (fNIRS) and a carefully designed paradigm modified from Cardillo et al. (2012) to investigate how neural activation varies by sentence type (metaphorical versus literal sentences) and novelty (completely novel versus familiarized phrases). Activity was significantly greater for metaphorical over literal sentences in the left inferior frontal gyrus, pars triangularis (LIFGtri), left inferior parietal cortex, right IFG, pars opercularis (RIFGop), and right angular gyrus (RAG). Novel metaphors to which participants had no prior exposure had significantly higher (albeit weak) effects within RIFGop, RAG, and right middle temporal gyrus (RMTG) compared to novel metaphors to which participants were exposed just prior to the fNIRS experiment. Pre-exposed, more familiar metaphors significantly activated a wider network of regions compared to novel metaphors, including bilateral middle frontal gyrus (MFG), bilateral IFGtri, and LMTG. A greater response time difference between conditions was associated with less LMFG activity for metaphors over literal sentences but higher LMTG activity for novel over more familiar metaphors. Taken together, these findings suggest that metaphors--particularly novel metaphors--do engage right hemisphere cortex more than other phrase types (literal sentences, more familiar metaphors) but that the effects are weaker than condition differences within canonical left language network and domain-general multiple demand network regions.

BackgroundChild adversity (CA), encompassing emotional, physical, and sexual maltreatment or abuse, affects a substantial number of children worldwide. Moreover, it is the leading predictor of psychiatric disorders such as major depressive disorder (MDD), anxiety, and suicidal behavior. Despite the robust link between CA and psychopathology, individual outcomes vary significantly, with some children demonstrating resilience. Resilience is an adaptive and dynamic process, which mitigates the long-term effects of CA, suggesting potential protective mechanisms that remain underexplored. This study investigates the role of the locus coeruleus-norepinephrine (LC-NE) system, a critical modulator of stress, cognition, and emotion, in mediating resilience and susceptibility following early life stress (ELS). MethodsUsing a maternal deprivation model combined with limited nesting and bedding, we examined behavioral, physiological, and neurobiological markers associated with ELS outcomes in mice of both sex. ResultsBehavioral clustering revealed distinct phenotypes: resilient, anxious, and depressive-like with sex-specific differences in distribution. Early markers, including body weight and ultrasonic vocalization (USV) patterns, predicted long-term susceptibility. Neuroanatomical analyses identified sex-specific LC-NE activation patterns associated with resilience and susceptibility, highlighting the caudal-dorsal LC as a critical region in males and females in different phenotypes, anxious in males and resilient in females. ConclusionThese findings highlight the impact of ELS on the LC-NE system and its role in shaping adaptive and maladaptive trajectories, offering insights into potential interventions targeting resilience mechanisms in children exposed to CA.

Persistent spiking activity and activity-silent mechanisms have been proposed as neural correlates of working memory. To determine their relative contribution, we recorded neural activity from the lateral prefrontal and posterior parietal cortex of two male macaques using high-density microelectrode probes. We found that, when averaged across all neurons, persistent delay activity was observable throughout the duration of single trials in populations of prefrontal neurons with silent periods that did not deviate significantly from chance. However, temporal fluctuations in activity-dependent mnemonic information were present and weakly correlated between the prefrontal and posterior parietal cortices, suggesting at least partial, long-distance synchronization of off-states. Decoding accuracy of neurons recorded simultaneously was also reduced relatively to pseudo-populations constructed by splicing different trials together. Our results support an asynchronous state of working memory, maintained by the distributed pattern of persistent discharges across cortical neurons, which is subject to widely distributed fluctuations in information representation fidelity.

Adult CNS trauma frequently causes neuronal disconnection and persistent deficits due to failed axon regeneration. While model system screening has identified multiple candidate neural repair pathways, ApoE-LRP8 signaling is unique in being implicated clinically. Here, we show that cortical axon regeneration requires LRP8 and is modified by APOE variants. ApoE2-expressing mice show reparative corticospinal and raphespinal axon growth with greater motor function than controls after spinal cord injury. Distinct from ApoE in other settings, there is no change in inflammation or scarring. After axotomy, ApoE exerts allele-specific effects on LRP8 localization and signaling in cortical neurons. APOE alleles regulate synaptic organization gene expression by cortical neurons after injury, with little effect on glial gene expression. AAV-mediated overexpression of ApoE2 in mice after spinal trauma increases locomotor recovery and reparative axon growth. Thus, ApoE-LRP8 signaling for axon regrowth following CNS trauma provides a potential therapeutic intervention site.

An acute session of moderate or vigorous physical exercise (PE) induces a cascade of neurophysiological processes such as release of growth factors, which relate to increased electroencephalogram (EEG) activity. Studies using animal models of Alzheimers disease (AD) showed that these mechanisms are disrupted even at asymptomatic stages of the disease. Specifically, increased neural activity within Theta band observed in healthy mice was not evidenced in mice models of AD, suggesting that EEG could be a suitable non-invasive tool to detect preclinical AD. The present study aims investigating the possible neurophysiological effects after a session of mild intensity PE, which is feasible to carry out in most population, during an EEG recording. Thus, sixteen young humans cycled at a low intensity in a stationary bike to study PE effects on the EEG frequency bands. EEG was acquired before and after PE (immediately after performing the PE, or 20-25 minutes later). Results showed that PE increased Alpha activity in frontal and central electrodes for at least 25 minutes, which aligns with previous studies in humans. Trends to increased Theta activity were observed within the left hemisphere immediately after PE, but not 25 minutes after finishing PE. Studies using larger samples should assess whether mild intensity PE increases Alpha and Theta and induces effects of different duration in both frequency bands, suggesting sensitivity of EEG to detect diverse neurophysiological effects induced by PE. Another pending issue is whether increased Alpha after PE in humans is functionally equivalent to increased Theta observed in mice.

Sensory errors, mismatches between predicted sensory outcomes of movement and reafferent sensory feedback, drive changes in the feedforward control of future motor behavior that correct for those errors. Across a wide variety of motor behaviors, individuals with cerebellar damage show impairments in these corrections, strongly suggesting a key role of the cerebellum in sensorimotor adaptation. However, the extent to which the cerebellum is involved in controlling vocal pitch is currently unknown. Crucially, vocal pitch differs in several ways from other systems that suggest it relies more on feedback than feedforward control. Adaptation itself also differs in vocal pitch: rather than the gradual build-up/decay of learning seen in other systems, pitch adaptation and de-adaptation are almost immediate. Together, this questions whether adaptation in vocal pitch relies on the same mechanism as other motor domains. Here, we test the hypothesis that the cerebellum underlies sensorimotor adaptation in vocal pitch, testing the domain-generality of this neurocomputational process. In both sustained vocalization and a more natural word production task, individuals with cerebellar ataxia fail to adapt to external auditory perturbation of vocal pitch. The complete lack of adaptation observed, compared to the impaired but present adaptation seen in other systems, suggest that the cerebellum plays an especially critical role in maintaining accurate control of vocal pitch. Conversely, we failed to detect a previously observed increase in online compensation to vocal pitch errors in ataxia, potentially suggesting this may be an idiosyncratic change in control rather than a common trait in this population. Significance statementWhen exposed to external perturbations of vocal pitch, individuals with cerebellar ataxia fail to adapt their produced pitch to oppose the perturbation. These results highlight the critical role of the cerebellum in driving adaptation across motor domains, even for motor behaviors that are thought to rely more on feedback compared to feedforward control, such as pitch. Conversely, and despite a large cohort, we failed to replicate previous findings of enhanced online corrections for pitch perturbations in ataxia, suggesting that any such increases are likely due to individual-specific changes in motor function in response to cerebellar-induced control deficits rather than being directly related to cerebellar damage itself.

Reasoning flexibly composes known elements to solve novel problems. Recent theories suggest the brain uses the axis of time to compose elements for reasoning. In this view, elements are packaged into fast neural sequences, with each sequence exploring the implications of a different composition. Using magnetoencephalography, we tested this idea while participants mentally executed programs. Each program contained a set of steps linked to operations, the implications of which had to be computed. We found that behavioral performance scaled with program complexity, and by the end of execution, inferred program solutions were represented in prefrontal and parietal cortices. We identified a possible mechanism by which these solutions were computed. During reasoning, representations of steps in the program reactivated in fast sequences, consistent with sampling candidate partial solutions. Further evidence suggested these reactivations were accompanied by representations of their operations, and were followed by neural patterns reflecting their computed implications. Together, these results suggest replaying sequences supports program execution and reveal a highly organized temporal microarchitecture of reasoning.

The human brain and peripheral systems undergo coordinated changes throughout the lifespan, yet studies of aging have traditionally examined these systems as separate entities. Here we ask how brain health relates to peripheral biomarkers of bodily health including body mass index, blood pressure, and blood biochemistry results. We use partial least squares analysis to identify generalizable patterns of covariance between multi-modal neuroimaging data (structural, functional, diffusion, and arterial spin labeling MRI), demographic, and peripheral physiological markers in two large-scale deeply phenotyped datasets: the Human Connectome Project-Aging and UK Biobank. This data-driven pattern learning approach identifies two principal axes of brain-body associations in both biological sex groups. The first axis is driven by the dominant contribution of age. Across multiple brain measures, aging is associated with loss of brain structural integrity and cerebral vascular dysfunction. The second axis is driven by metabolic features, characterized by low high-density lipoprotein cholesterol, elevated body mass index, blood pressure, glycosylated hemoglobin, insulin, glucose, and alanine aminotransferase, and reduced cerebral blood perfusion. Finally, we show that deviations from a healthy metabolic profile are linked to cognitive deficits, particularly in females. Our study contributes to development of comprehensive translatable biomarkers for brain health assessment, and highlights the importance of metabolic health as a determinant of brain health.

The human brain and peripheral systems undergo coordinated changes throughout the lifespan, yet studies of aging have traditionally examined these systems as separate entities. Here we ask how brain health relates to peripheral biomarkers of bodily health including body mass index, blood pressure, and blood biochemistry results. We use partial least squares analysis to identify generalizable patterns of covariance between multi-modal neuroimaging data (structural, functional, diffusion, and arterial spin labeling MRI), demographic, and peripheral physiological markers in two large-scale deeply phenotyped datasets: the Human Connectome Project-Aging and UK Biobank. This data-driven pattern learning approach identifies two principal axes of brain-body associations in both biological sex groups. The first axis is driven by the dominant contribution of age. Across multiple brain measures, aging is associated with loss of brain structural integrity and cerebral vascular dysfunction. The second axis is driven by metabolic features, characterized by low high-density lipoprotein cholesterol, elevated body mass index, blood pressure, glycosylated hemoglobin, insulin, glucose, and alanine aminotransferase, and reduced cerebral blood perfusion. Finally, we show that deviations from a healthy metabolic profile are linked to cognitive deficits, particularly in females. Our study contributes to development of comprehensive translatable biomarkers for brain health assessment, and highlights the importance of metabolic health as a determinant of brain health.

Synapses are the fundamental unit of neural connectivity. They exhibit dynamic functional and structural changes that enable the brain to learn, adapt, and form memories. Recent advances in endogenous protein fluorescent labeling offer an opportunity to image synaptic strength in vivo and thus study the mechanisms underlying adaptive neural computation in living mice. Studying synaptic dynamics requires tracking individual signals of small, densely packed synapses over days while they change in size, position, and intensity between imaging sessions, and may even appear/disappear entirely. Tracking >100,000 dynamic, submicrometer particles is difficult even for state-of-the-art algorithms. Moreover, most algorithms rely on an isotropic uncertainty ball, assigning equal weight to the lateral plane (XY) and to the noisier axial dimension (Z), leading to poorer performance. To address these challenges and accurately track synapses in vivo, we developed SynTrack. We formulated SynTrack as a Maximum A Posteriori estimation problem under the anisotropic uncertainty ball, along with a fully temporally connected spatio-temporal graph to overcome long-term occlusions. SynTrack achieves a mean track length of 0.51 {micro}m with a Multiple Object Tracking Accuracy (MOTA) score of 88.8%, on par with MOTA scores of expert annotators but with massively increased speed and scalability. Over two weeks, we successfully track 65,000 synapses in 5.6 out of 8 imaging sessions on average, with 20,000 synapses being tracked in at least seven sessions. We present SynTrack as a state-of-the-art algorithm capable of high-resolution and fidelity tracking of synapse dynamics in behaving mice with unprecedented detail.

Resolving the molecular basis for heterogeneous aging in the human brain requires integrating its diverse molecular layers, including the transcriptional, epigenetic, and proteomic states. To provide such a view, we applied a tensor decomposition frame-work to jointly analyze single-nucleus RNA-seq, DNA methylation, histone acetylation, and proteomic data from 276 postmortem human dorsolateral prefrontal cortex samples from the ROSMAP aging cohort. Our analysis revealed two dominant themes defined by components with strong multi-omic coherence. First, we identified a robust immunometabolic axis characterized by microglial activation, suppression of PI3K-Akt-mTOR signaling, and epigenetic signatures suggesting the repurposing of developmental transcription factors. Second our analysis resolved the effect of sex into a mosaic of distinct, cell-type-specific molecular programs within glia. These included male-biased mitochondrial programs in microglia, a shift toward precursor-like states in the female oligodendrocyte lineage, and bidirectional epigenetic remodeling in astrocytes. This work provides a high-resolution atlas of glial aging, demonstrating that broad risk factors manifest as complex, cell-specific vulnerabilities; a critical insight for developing targeted therapeutic strategies.

Preterm birth is a common neurodevelopmental condition that can have lasting impacts on cognition, including attention and working memory. Interventions that strengthen these skills in early childhood could support school readiness. Dino Island is a tablet-based intervention that combines process-specific practice of attention and working memory skills with a compensatory component that teaches metacognitive skills to scaffold learning. In this pilot study, we evaluated the feasibility of parent-delivered Dino Island in young children born preterm (N=10), alongside a control group who played educational games (N=12). Both groups were instructed to play 2-3 times per week for approximately 20 minutes over a 12-week period. Attention and working memory on untrained tasks were assessed before and after completing the intervention. Parents provided fidelity data through tracking sheets and participated in exit interviews to offer feedback and identify barriers and facilitators. We found that the Dino Island program was successfully delivered by parents with high fidelity. Attrition was higher in the Dino Island group, likely reflecting the challenges of delivering cognitive remediation in home settings. Comparison of attention and working memory scores on untrained tasks pre- and post-showed practice effects but no specific benefit of Dino Island. However, parent reports suggested behavioral improvements specific to the Dino Island group, noting far-transfer effects where children applied metacognitive strategies in other contexts. Overall, this work shows feasibility and tolerability of Dino Island in young children born preterm. Future research should examine its potential impact on school readiness and longer-term academic outcomes in this population.

Study objectivesAdolescence is a period of distinct maturational changes in sleep characteristics. Historically, age trends in sleep physiology have been captured using laboratory-based polysomnography (PSG). However, multiple challenges associated with PSG, including logistical issues, budgetary constraints and ecological validity questions, limit large-scale use. The current study aims to address these challenges by using the Dreem3 headband to measure sleep at home and replicate well-established age-related trends in sleep physiology from late childhood through early adulthood. Methods100 typically developing youth (9-26 years) wore a sleep electroencephalography (EEG) device (Dreem3) for 3-4 consecutive nights at home. Sleep EEG data were processed using the Luna pipeline. We used linear mixed models to estimate age-related trends across 8 macro-architecture and 15 micro-architecture variables previously found to be associated with age, and explored age relationships in 24 additional macro- and micro-architecture variables. ResultsAt-home sleep studies using Dreem3 replicated established age trends in sleep macro- and micro-architecture, including decreases in percent time spent in non-rapid eye movement (NREM) stage 3 (N3%) sleep and decreases in NREM delta power with increasing age. Exploratory analysis revealed age effects in seven other variables, including decreases in integrated slow spindle activity and NREM cycle duration with increasing age. ConclusionSleep EEG wearables may offer an accessible way to characterize sleep physiology development in large cohorts, setting the stage for understanding how deviations from normative age patterns may put young people at risk for adverse outcomes. Statement of SignificanceAdolescence is a dynamic period characterized by changes in sleep physiology and behavior. While polysomnography has long been widely used for capturing age-related trends, it is resource-intensive and laboratory-bound, which limits the ability to track sleep in an accessible, scalable, and ecologically valid manner. Here, we used a sleep EEG headband, the Dreem3, to examine age-related trends in sleep macro- and micro-architecture across late childhood, adolescence, and early adulthood. We assessed sleep features with previously replicated age effects and explored age associations in other macro- and micro-architecture measures. The at-home wearable sleep EEG device replicated many of the age trends seen in traditional polysomnography. Leveraging accessible sleep EEG devices may provide a more scalable and comprehensive understanding of how sleep changes over adolescence.

Absence seizures are episodes of impaired consciousness and responsiveness that impact an individuals ability to interact with the world around them. Childhood absence epilepsy, a condition defined by these seizures, can have profound effects on childrens social, educational, and psychological development. Absence seizures are accompanied by a distinctive electrographic signature called a spike-wave discharge. The impairment of consciousness associated with a spike-wave discharge can be variable: some people maintain responsiveness during some absence seizures, and some rodent oscillations resembling spike-wave discharges may not have any behavioral impact. We previously observed that spike-wave discharges in the Genetic Absence Epilepsy Rat from Strasbourg model sometimes terminated shortly after presentation of a conditioned auditory stimulus. In this study we found that these terminations were caused by the stimuli and that they occurred after approximately 50% of stimuli. We also found that the probability of a spike-wave discharge being interrupted depended on stimulus timing, degree of conditioning, and electrographic signal power. These data provide insight into the factors that determine the mechanisms of absence seizure termination, with possible implications for therapy.

One of the most important events in the pathogenesis of Parkinsons disease and related disorders is the formation of abnormal fibrils via the aggregation of -synuclein (-syn) with {beta}-sheet-rich organization. The use of Cryo-EM has uncovered different polymorphs of the fibrils, each having unique structural interfaces, which has made the design of inhibitors even more challenging. Here, a structure-guided framework incorporating AI-assisted peptide generation was set up with the objective of targeting the conserved {beta}-sheet motifs that are present in various forms of -syn fibrils. The ProteinMPNN, then, AlphaFold-Multimer, and PepMLM were employed to create short peptides that would interfere with the growth of the fibrils. The two selected candidates, T1 and S1, showed a significant inhibition of -syn fibrillation, as measured by a decrease in the ThT fluorescence and the generation of either amorphous or fragmented aggregates. The inhibitory potency of the peptides was in line with the predicted interface energies. This research work illustrates that the integration of cryo-EM structural knowledge with the computational design method leads to the quick discovery of the wide-spectrum peptide inhibitors, which is a good strategy for the precision treatment of neurodegenerative diseases.

Understanding the mechanisms by which astrocytes regulate neural circuits is crucial for elucidating the mechanisms underlying cognitive and behavioral abnormalities in psychiatric disorders and for exploring potential therapeutic or intervention strategies. Viral tracers are powerful vehicles for comprehending the complex relationship between neurons and astrocytes. Despite adeno-associated virus 1 (AAV1) based anterograde trans-neuronal tools have been successfully applied for identifying astrocytes connected with presynaptic neurons, analogous retrograde trans-neuronal tools for labeling astrocytes connected to postsynaptic neurons remain under development. Here, we first demonstrate that GfaABC1D promoter embedding AAV11 can transfer retrogradely from axons of postsynaptic neurons to astrocytes. Furthermore, we established an AAV11-based dual-viral recombination strategy for labeling astrocytes connected to specific postsynaptic neurons. Finally, by employing targeted neuronal ablation technology to ablate neurons in a specific brain region, we observed that injection of AAV11 into the downstream brain region of this targeted area exhibited minimal labeling of astrocytes functionally associated with the ablated neurons. This finding indicates that AAV11 holds utility for deciphering pathological alterations in disease-related astrocyte-neuron connectivity networks. This work fills a key gap in tools used for studying astrocyte-neuron connectivity networks.

Alzheimers disease is triggered by amyloid-{beta}, with symptoms linked to synapse loss. Oligomeric amyloid-{beta}, rather than monomeric or fibrillar amyloid-{beta}, has been proposed to be the proximate mechanistic cause, but the relevant molecular characteristics have remained unclear. Here, we define a distinct receptor-bound amyloid-{beta} pool in Alzheimers brain by release with a receptor antagonist and purification to homogeneity. Receptor-bound amyloid-{beta} is ten times more abundant than free unbound amyloid-{beta}. The amyloid-{beta} associated with receptor is composed of 65 nm long filaments with prion protein binding at its tips. There is no evidence for an oligomeric A{beta} state interacting with human brain receptors. Cryo-electron microscopy shows two symmetric S-shaped monomers per filament rung. The tilt between rung monomers, twist along the filament axis, amino terminal conformation and amyloid seeding properties distinguish this structure from plaque-associated amyloid-{beta} filaments of the same brain. High tip:length ratio is critical for prion protein receptor interaction and synaptic damage. Characterizing receptor-bound amyloid-{beta} filament provides insight into neuronal dysfunction separate from plaque aggregation.

In our society, the aging of the population is a major concern of public health. Recently we have identified a new snoRNA (jouvence) in Drosophila, and showed that its deletion (F4) reduces lifespan, while its overexpression increases it. F4 deleted flies also present neurodegenerative lesions and a deregulation of metabolic parameters as triglycerides and sterol. However, a deeper characterization of this genomic locus has revealed the presence of two other snoRNAs. Here, we have characterized at the whole organismal level, the role of each them. First, we show that each snoRNAs are expressed in the epithelium of the gut (enterocytes), and in the fat body. Second, in F4 deletion, the re-expression of each snoRNA in the enterocytes or in the fat body is sufficient to improve lifespan, and protect against neurodegeneration in old flies. In addition, depending of the snoRNAs, it rescues the expression of specific deregulated genes within the epithelium of the gut, involved in lipids and sterol metabolism. Consequently, these two metabolic parameters are also rescued, establishing a relationship between the lesions of the brain, the metabolic disorders, the lifespan, and each snoRNAs respectively. Finally, histological stainings as Nile Red and BODIPY C11-581/591 have revealed that the neurodegenerative lesions are due to an increase of free sterol within the brain, and lipid peroxydation in the pericerebral fat body. Altogether, these results point-out a causal relationship between the epithelium of the gut and the neurodegenerative lesions through the metabolic parameters, indicating a gut-brain axis.

BackgroundCranial radiotherapy (cRT), a common treatment for central nervous system tumors, induces progressive cognitive problems in over half of patients. In mice, microglial depletion via CSF1R inhibition can mitigate this effect, but the underlying cellular mechanisms remain unclear. We hypothesized that CSF1R inhibition-induced microglial ablation and repopulation improves brain health by modulating microglial reactivity to radiotherapy, which attenuates glial responses to radiotherapy. MethodsNine-week-old male C57BL/6JRj mice received either a CSF1R-inhibitor supplemented diet (pexidartinib, PLX3397) or control diet, followed by fractionated CT-guided cRT (30 Gy) or sham treatment. The pexidartinib diet was discontinued 10 days post-radiotherapy. Animals were sacrificed at three intervals post-radiotherapy, allowing the assessment of temporal changes. Multiple brain regions were assessed by immunohistochemistry for markers of microglia, astrocytes, oligodendrocytes and proliferating cells. Microglial morphological changes were assessed using the semi-automated microglia morphology analysis pipeline mGlia. ResultsRadiotherapy alone reduced microglial numbers and induced a progressive reactive morphology; mild at 30 days and pronounced at 6 months post cRT. CSF1R inhibition before cRT markedly decreased microglial markers but increased general macrophage markers at 30 days and 6 months after cRT, consistent with monocyte-derived cell engraftment. Morphometric analysis revealed rapid and severe morphological change towards a reactive morphotype at 30 days that persisted until 6 months. Microglial depletion did not prevent loss of neurogenesis or oligodendrocyte progenitor cells (OPCs) and accelerated reactive astrogliosis, though partial OPC recovery in the hippocampus and thalamus was observed at 6 months. ConclusionCSF1R inhibition combined with cRT accelerates reactive gliosis and monocyte-derived macrophage engraftment without protecting vulnerable neural cell populations, though limited long-term OPC recovery occurred. Thus, with this set-up CSF1R inhibition-induced microglial ablation and repopulation does not improve overall brain health, but is beneficial for OPCs on the long term after cRT. Key pointsO_LIPexidartinib and cranial radiotherapy have synergistic effects on microglial ablation C_LIO_LIInfiltrating monocytes repopulate the irradiated brain once the pexidartinib diet is discontinued C_LIO_LIIn the absence of microglia, astrocytes show an accelerated reactivity to radiotherapy C_LIO_LILong-term after cranial radiotherapy oligodendrocyte progenitor cell repopulation is enhanced in the pexidartinib treated animals C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/681366v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1153d64org.highwire.dtl.DTLVardef@171a100org.highwire.dtl.DTLVardef@1013e1borg.highwire.dtl.DTLVardef@949893_HPS_FORMAT_FIGEXP M_FIG C_FIG

Neuropathic pain results from peripheral lesion, causing maladaptive plasticity and central sensitization. Clinical and preclinical studies demonstrate that modifications of primary sensory cortex (S1) activity are essential for neuropathic pain persistence. Rodent studies report heightened S1 pyramidal cell excitability in neuropathic pain model, the origins of which remain debated. The axon initial segment, the action potential trigger zone, is a major determinant of neuronal excitability and is known to undergo structural changes after neural perturbation but its role in chronic pain is poorly understood and no studies have explored its role in cortical hyperexcitability in chronic pain models. Besides, despite a higher prevalence of chronic pain in women, most of preclinical studies have been conducted in males. By integrating electrophysiology, immunohistochemistry, and computational modeling, this study demonstrates that in a trigeminal neuropathic pain rat model, sex-specific structural plasticity of the axon initial segment enhances the excitability of layer 5 pyramidal cells in the somatosensory cortex, potentially driving network-level hyperactivity.

Flexible behavioral responses rely on the ability of neural circuits to adapt their physiology and output to changing social and environmental contexts. Neuromodulation plays a central role in this flexibility, dynamically tuning neuronal activity and gene expression to align behavior with experience and internal states. Yet how specific experiences and motivational conditions are encoded within neuromodulatory neurons remains underexplored. Here, we show that distinct motivational outcomes drive discrete, largely non-overlapping transcriptional programs across three neuromodulatory neuronal populations in male Drosophila brains. Using cell-type-resolved RNA sequencing, we profiled the transcriptomes of serotonergic (Trh), octopaminergic/tyraminergic (Tdc2), and neuropeptide F receptor (NPFR) neurons under three conditions: successful mating, sexual rejection, and the absence of social or sexual interaction. Each experience induced a unique "molecular engram" within specific neuron types. NPFR neurons exhibited the strongest transcriptional remodeling following rejection, Tdc2 neurons preferentially represented the naive-single state, and Trh neurons displayed balanced, experience-specific tuning. Shared differentially expressed genes across neuronal classes were few and often were oppositely regulated, revealing divergent circuit-specific logic. Experience triggered multilayered reprogramming across chromatin organization, RNA metabolism, translation, proteostasis and synaptic machinery, with selective recalibration of vesicle trafficking, and neuroplasticity. We further identified a compact, cross-circuit "rejection core" enriched for circadian, stress, metabolic, neuropeptidergic, and synaptic components. Together, these findings demonstrate how neuromodulatory circuits translate social experience into coordinated molecular and synaptic adaptations that enable behavioral flexibility.

Physiological artifacts pose persistent challenges in electroencephalo-gram (EEG) data acquisition, often compromising interpretation and post-analysis of EEG signals across research and clinical applications. To address such limitations, including various artifact types, insufficient annotations, and low spatial resolutions, we present PhysioMotion Artifact, a large-scale, task-driven EEG dataset with channel-level artifact annotations. EEG data was acquired from 30 healthy participants performing 16 systematically designed single-type and multi-type movement tasks, inducing 14 distinct types of physiological artifacts. To demonstrate the utility of the dataset, we implemented a Convolutional Neural Networks-Transformer hybrid model for artifact detection and classification, achieving 98% accuracy in binary classification and 85% in 14-class classification tasks.

Parkinsons Disease (PD) is characterised by accumulation of -synuclein (-Syn), but how elevated -Syn alters presynaptic architecture during prodromal phases of the disease remains unclear. We investigated presynaptic morphology and two key presynaptic proteins: MYCBP2; and the Active Zone (AZ) protein ELKS. Primary rat cortical neurons were transfected with wildtype -Syn, or the familial A30P mutant, and nanoscopic changes to bouton morphology and protein localisation were investigated using super-resolution microscopy. Variant specific accumulation patterns for overexpressed -Syn were observed without changes to bouton structure. Additionally, increases of both -Syn variants affected presynaptic proteins, decreasing MYCBP2 puncta count and intensity, and reducing ELKS protein density. Since MYCBP2 potentially regulates ELKS, these findings suggest that elevated -Syn perturbs AZ components whilst presynaptic structure is preserved. Our study supports growing evidence that increased -Syn disturbs presynaptic function potentially through a MYCBP2-ELKS axis, a mechanism which may provide a valuable target for PD therapeutics.

The genetic and spatial determinants of cell type diversity in human cerebral cortices remain poorly defined. Here, we present a population-level single-cell spatial transcriptomic atlas of human cortices from 71 donors across the lifespan. We identified 906 layer-specific genes showing conserved and divergent laminar expression patterns between humans and other species. Spatial analysis revealed neuronal vulnerability and glial activation during aging, together with a decline in the proportion of superficial SST neurons and their interactions with other cells. Disease-associated genes exhibited high cell-type and layer-specific expression, implicating the pathogenic role of spatially specific gene expression. Spatial cis-eQTL analysis identified regulatory variants linked to genes related to diseases like Tourette syndrome. Cross-species comparison demonstrated glial expansion in the human cortex, accompanied by enhanced neuron-glia communication via the neuregulin signaling. Together, we provide a comprehensive single-cell atlas of the human cortex that is essential for understanding aging, evolution, and disease pathogenesis.

Brain network formation unfolds on a non-uniform developmental timetable, with different cortical regions generating connections at different developmental phases. Generative network models (GNMs) aim to uncover the principles underpinning the organisation of connectomes by creating synthetic networks according to simple computational rules. These models capture the connectome's topology, operationalised here as the overall distributions of network metrics (e.g., modularity, small-worldness, rich-club structure). However, they typically ignore the differential timing of connectivity formation. By omitting this temporal programme, GNMs often misplace topological features in physical space. Here, we add a heterochronous growth term to GNMs and use a new model fitness function that weighs topology and topography equally. Topography refers to the spatial embedding of the network, the actual anatomical positions of tracts. With these advances, we can generate synthetic networks that more faithfully reproduce the spatial layout of diffusion-MRI connectomes from two independent adult cohorts. Compared with classical, temporally agnostic models, heterochronous simulations improve model fit, accurately locate cortical hubs and modules, and converge on a single caudal-to-rostral gradient of brain maturation. Integrating heterochronicity makes GNMs more faithful to brain development, setting the stage for using them to explain and ultimately predict individual differences in network formation.

Brain network formation unfolds on a non-uniform developmental timetable, with different cortical regions generating connections at different developmental phases. Generative network models (GNMs) aim to uncover the principles underpinning the organisation of connectomes by creating synthetic networks according to simple computational rules. These models capture the connectome's topology, operationalised here as the overall distributions of network metrics (e.g., modularity, small-worldness, rich-club structure). However, they typically ignore the differential timing of connectivity formation. By omitting this temporal programme, GNMs often misplace topological features in physical space. Here, we add a heterochronous growth term to GNMs and use a new model fitness function that weighs topology and topography equally. Topography refers to the spatial embedding of the network, the actual anatomical positions of tracts. With these advances, we can generate synthetic networks that more faithfully reproduce the spatial layout of diffusion-MRI connectomes from two independent adult cohorts. Compared with classical, temporally agnostic models, heterochronous simulations improve model fit, accurately locate cortical hubs and modules, and converge on a single caudal-to-rostral gradient of brain maturation. Integrating heterochronicity makes GNMs more faithful to brain development, setting the stage for using them to explain and ultimately predict individual differences in network formation.

IntroductionAtypical sensory processing, particularly auditory hypersensitivity, is a common and debilitating phenotype of Fragile X Syndrome (FXS). Electrophysiology studies in FMR1-knockout (KO) mice previously observed hyperexcitability at the auditory cortex (AC), with enhanced neuronal firing to auditory stimuli. Prepulse inhibition (PPI), a behavioral measure of sensorimotor gating, is robustly impaired in FXS individuals. Interestingly, a related paradigm called gap-induced inhibition of the acoustic startle (GPIAS) is mediated by the AC, and a previous study observed decreased GPIAS in mature FMR1-KO mice. Further, habituation is also an important sensory filtering mechanism, which has been reported to be impaired in mature FMR1-KO mice. However, not much is known about GPIAS and habituation in FMR1- KO mice during early development. MethodsWe evaluated GPIAS in male and female FMR1-KO mice at post-natal days 15 (P15), 20 (P20) and 30 (P30). The paradigm consisted of a prepulse stimulus (a gap in a continuous background noise) followed by a startle stimulus, with an inter-stimulus interval of 50 or 100 ms. Habituation was assessed prior to the GPIAS trials, with a series of startle only stimulus. ResultsWe observed a trend for genotype difference in acoustic startle response (ASR) magnitude, particularly in the female mice at P30. No significant genotype differences were noted in GPIAS or latency of ASR. Response duration was significantly increased in the male FMR1-KO mice compared to their WT counterparts during early development. Significant genotype differences were also observed in habituation and sensitization. In terms of development, we observed a significant increase in GPIAS with maturation. Furthermore, we also observed significant changes in the magnitude, response latency and duration of ASR with maturation. Finally, significant sex differences were observed in ASR magnitude and duration. ConclusionOur findings suggest that behavioral responses to auditory stimuli are dynamic during development and differ between females and males, an important consideration for future study design. Additionally, the FMR1-KO mice display habituation deficits during early development, which could be an ideal window for addressing auditory hypersensitivity in FXS.

This study investigates the neural dynamics of phoneme processing in 7-year-old children with and without dyslexia (25;9 [male]), using EEG recordings collected during continuous speech listening. By applying temporal generalization to phonetic descriptor decoding, we can disentangle whether potential phoneme processing deficits are due to the maintenance of phonemes in verbal short-term memory and/or inferred differences in phonetic processing speed, both of which are thought to be impaired in dyslexia. We investigated whether phonetic processing depends on the phonemes position or its lexical competition. Our results reveal two key findings that may help explain the challenges faced by children with dyslexia. First, these children exhibit reduced decoding accuracy for word-onset phonemes, suggesting disruptions in either predictive, word-level anticipatory mechanisms or in the intrinsic rhythmic processing aligned with word boundaries. Second, they exhibit increased decoding accuracy for non-onset phonemes with low lexical competition approximately 400 ms after phoneme onset. This pattern suggests that children with dyslexia retain linguistically less relevant sounds longer in verbal short-term memory and process them more slowly compared to their typical reading peers. Together, these findings suggest that dyslexia is characterized by altered phonetic encoding strategies, specifically inefficient prioritization of relevant phonological information. This work provides new insight into the neural mechanisms underlying phonological deficits and contributes to a deeper understanding of the cognitive basis of dyslexia. Significance statementDyslexia is associated with difficulties in phonological processing. Investigating EEG during continuous speech listening, we show that children with dyslexia exhibit weaker encoding of word-onset phonemes and prolonged processing of less informative phonemes. These altered encoding strategies suggest inefficient prioritization of linguistic information, offering new insight into the neural basis of dyslexia.

Variables relevant to behavior and cognition are often synthesized via computations that combine external cues and internal states. Especially salient and ubiquitous among these variables are time, space, and reward, but how they are simultaneously represented throughout the neocortex and the entorhinal cortex is not well understood. Here, we devised a behavioral task in virtual reality that includes timing, navigation, and reward components and, using a multifocus microscope that permits simultaneous mesoscopic Ca2+ imaging of neocortex and entorhinal cortex, we uncover dedicated and distinct subnetworks for interval timing, spatial navigation, and reward. Interestingly, the timing subnetwork includes a strong contribution from barrel cortex, pointing towards a previously unknown role for this cortex in interval timing.

The role of the hippocampus in resolving memory interference has been greatly elucidated by considering the relationship between the similarity of visual stimuli (input) and corresponding similarity of hippocampal activity patterns (output). However, these input-output functions can take surprisingly different forms. Here, we reconcile seemingly conflicting findings by considering the possibility that the hippocampus prioritizes different dimensions of visual similarity across different stages of learning. First, we generated a set of natural scene images from two visual categories and rigorously characterized visual similarity using a wide array of methods: neural networks, artificial intelligence models, and human perceptual and memory decisions. We then identified two orthogonal dimensions of visual similarity that each predicted memory interference, but that did so at distinct stages of learning. Using high-resolution fMRI, we then tested for dimension-specific input-output functions within the hippocampus. Within CA3 and dentate gyrus (CA3/DG), we show that dimensions of visual similarity were inverted (negative functions) at stages of learning when they contributed to memory interference. When the dimensions did not contribute to interference, functions were positive. These findings reveal that hippocampal representations of visually-similar stimuli are highly dynamic and critically depend on the dimensions of similarity that currently contribute to memory interference.

Human vision critically relies on the foveola, a tiny region of the retina with the highest photoreceptors density. Although it spans only[~] 0.1% of the visual field, the foveola accounts for nearly one third of projections to the visual cortex. Accurate assessment of foveal function is therefore essential for monitoring visual processes and visual health. However, probing this region is challenging because of its minute size and the incessant eye movements that humans perform, even when fixating on a single point. Here, we leverage recent advances in eye-tracking and gaze-contingent display control to develop a visual field test capable of mapping foveal sensitivity with high precision and reliability. Applied to healthy observers, this method reveals substantial idiosyncratic variability both across and within individuals, with peak sensitivity consistently shifted toward the temporal visual field. By enabling high-resolution individualized assessment of foveal vision, this approach opens new avenues for both clinical diagnostics and basic research.

Obesity, a major global health issue, results from disrupted energy balance driven by chronic hypothalamic inflammation and altered intercellular communication. Among the diverse cells orchestrating this regulation, tanycytes--specialized ependymal cells at the brain-blood interface--have emerged as key modulators, yet the molecular mechanisms by which they influence surrounding cells remain poorly understood. Here, we identify Annexin A1 (ANXA1) as a tanycyte-derived anti-inflammatory signal whose expression, localization, and secretion are dynamically regulated by nutritional state and altered under high-fat diet. During positive energy balance, ANXA1 is secreted in CD9 extracellular vesicles (EV), remodeling hypothalamic networks by altering microglial morphology, synaptic density, and neuronal activation. These EV-mediated effects extend systemically to regulate brown adipose tissue thermogenesis, glucose homeostasis, and overall energy balance. Our findings reveal a previously unrecognized tanycyte-microglia-neuron signaling axis and highlight EV-mediated glial communication as a potential therapeutic target in obesity-associated neuroinflammation.

Mitochondrial dysfunction is a convergent hallmark of neurodegenerative diseases and represents a promising biomarker for early diagnosis and therapy. However, current in vitro assays rely on fluorescence or electron microscopy, which are invasive, low-throughput, and incompatible with longitudinal analysis. Here, we present a noninvasive framework by integrating label-free optical diffraction tomography (ODT) with organelle-aware representation learning to detect subtle mitochondrial dysfunction in live human induced pluripotent stem cell (hiPSC)-derived neurons. Through virtual staining of the nuclei, lysosomes, and mitochondria, we establish two complementary and interpretable classification pipelines: a deep learning model with organelle-aware encoder and a logistic regression model on morphometric descriptors. Both models achieve approximately 85% accuracy: the deep model provides end-to-end prediction with minimal feature engineering, whereas the logistic regression model offers a more interpretable, feature-based approach. To our knowledge, this is the first demonstration of ODT-based organelle-resolved virtual staining in live human neurons, establishing a scalable, non-invasive platform for mitochondrial disease modeling, drug discovery, and neurodegeneration research.

Brain-derived neurotrophic factor (BDNF) is a key modulator of synaptic function, acting through activation of TrkB receptors. This neurotrophic factor mediates synaptic plasticity and plays an important role in epileptogenesis, but the underlying molecular mechanisms have not been fully elucidated. In this work, we investigated the role of BDNF-TrkB signaling in the regulation of synaptic GluN2A-containing NMDA receptors (NMDAR), and the impact on network synchronization in cultured hippocampal neurons. Incubation with BDNF increased the synaptic surface expression of GluN2A-containing NMDAR in rat hippocampal synaptoneurosomes and in cultured hippocampal neurons. The effect in the latter preparation was time-dependent and required new protein synthesis. Mechanistically, we identified a signaling cascade involving hnRNPK, the non-receptor tyrosine kinase Pyk2, and protein kinase C (PKC) as essential for mediating BDNF-induced upregulation in the synaptic expression of GluN2A-containing NMDAR. Knockdown of hnRNPK or Pyk2, pharmacological inhibition of PKC, or expression of a phosphorylation -deficient Pyk2 mutant abolished BDNF-induced synaptic surface accumulation of Glu2A. Moreover, Pyk2 phosphorylation at Y402 was necessary for both basal and BDNF-induced synaptic GluN2A expression. Functional multielectrode array (MEA) recordings showed that endogenous BDNF and GluN2A-containing NMDAR contributed to the increase in network activity in cultured hippocampal neurons evoked by stimulation with a cocktail including bicuculline, 4-aminopyridine, and glycine. Importantly, BDNF-TrkB signaling also mediated the upregulation in the hippocampal synaptic surface expression of GluN2A-containing NMDAR, as determined in rats subjected to the pilocarpine model of temporal lobe epilepsy, where increased GluN2A synaptic expression was observed and shown to be TrkB-dependent. These findings unveil a crucial BDNF/TrkB-PKC-Pyk2-hnRNPK signaling axis that regulates synaptic GluN2A levels and network excitability, offering novel insights into the molecular basis of synaptic plasticity.

BackgroundIntestinal immune and inflammatory response plays a detrimental role following a stroke. This study aims to evaluate the brain protective efficacies of a novel intestinal cooling (CC) technique relative to the body surface cooling (SC) and the normothermic (NT) condition in a mouse stroke model. MethodsMice were randomly assigned to CC (n=13), SC (n=15), or NT (n=11) groups. They underwent 60 min of middle cerebral artery occlusion (MCAO) followed by 7-day reperfusion. Both head and intra-colon temperatures were maintained at 37{degrees}C for 30 min before, during, and 30 min after MCAO. At 30 min reperfusion, a cooling catheter was placed to maintain intra-colon at 37{degrees}C in NT or 12{degrees}C in CC. The head temperature was maintained at 37{degrees}C in NT and 30{degrees}C in CC. In SC, both intra-colon and head temperatures were maintained at 30{degrees}C. Cooling lasted 3 hours. Bodyweight, behavioral deficits (nesting and pole test), and survival rate were assessed post-MCAO. At day 7 post-MCAO, mice were perfusion-fixed for histopathological analysis. ResultsPost-stroke histopathological brain injury areas and volume were significantly reduced in CC, and appeared reduced though not statistically significant in SC, relative to NT. Compared with NT, body weight, nest building activity, and pole test were all significantly recovered in CC post-MCAO. In SC, only nest building improved significantly, while body weight and pole test showed marginal, nonsignificant trends. Consistent with functional recovery, survival was significantly improved in CC but not in SC, compared with NT. ConclusionIn a murine model, our novel CC technique successfully achieved targeted intestinal cooling while preserving safe upper-body temperatures necessary for normal cardiopulmonary function. Targeted intestinal cooling provides significant benefits superior to SC and NT, including smaller stroke volume, fewer functional deficits, and lower mortality rates, thus supporting the novel concept that the intestines are potential therapeutic targets for stroke management. Graphical Abstracts O_FIG O_LINKSMALLFIG WIDTH=131 HEIGHT=200 SRC="FIGDIR/small/681764v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1aa07cdorg.highwire.dtl.DTLVardef@1e64569org.highwire.dtl.DTLVardef@d6f178org.highwire.dtl.DTLVardef@1871862_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPost-stroke body surface cooling-induced hypothermia demonstrated marginally neuroprotective effects compared to normothermic conditions in the mouse model. C_LIO_LITargeted deep cooling of the intestine after a stroke resulted in a significantly greater reduction in stroke injury areas and volume, as well as lower mortality rates and fewer functional deficits, compared to body surface cooling-induced hypothermia and normothermic conditions. C_LI

Mating decisions are often attributed to the sensory signaling between prospective sexual partners. Yet these interactions are also shaped by the broader environmental context in which they unfold, to appropriately align sexual arousal with reproductive opportunities. Here we show that in the host specialist Drosophila erecta mating is strictly contingent on the ecological and social environment generated as flies densely aggregate in groups on a food patch. We find that food volatiles directly promote male sexual arousal, triggering individuals to sample and pursue potential mates, giving rise to dynamic interactions across the group. The ensuing visual motion transforms each males visual field, which in turn further amplifies his arousal, generating a multisensory feedback loop that coordinately promotes courtship across individuals. D. erectas strict dependence on environmental cues appears latent in related species, such as D. melanogaster, where food odor can promote arousal but is dispensable for vigorous courtship. Comparative circuit analyses reveal that species-specific thresholds for sexual arousal reflect variation in how olfactory input modulates conserved nodes controlling courtship drive, rendering food volatiles a strict sensory gate only in D. erecta. Together, our findings highlight how ecological cues not directly tied to sexual signaling can profoundly influence reproductive behavior and reorganize the social landscape to ensure mating occurs in contexts where reproductive opportunities are abundant.

Change detection of social cues across individuals plays an important role in human interaction. Here we investigated the automatic change detection of facial and vocal attractiveness in 19 female participants by recording ERPs. We adopted a deviant-standard-reverse oddball paradigm where high- or low-attractive items were embedded as deviants in a sequence of opposite attractive standard stimuli. Both high- and low-attractive faces and voices elicited mismatch negativities (MMNs). Furthermore, low-attractive versus high-attractive items induced larger mismatch negativities in the voice condition but larger P3 amplitudes in the face condition. These data indicate that attractiveness can be automatically detected but that differences exist between facial and vocal attractiveness processing. Generally, change detection seems to work better for unattractive than attractive information possibly in line with a negativity bias.

ObjectiveMicroRNAs regulate the brain vascular integrity and are involved in the lesion development of cerebral cavernous malformations (CCM). This study examines the role of microRNA-21-3p in CCM-related cerebral hemorrhage and its underlying mechanisms. MethodsThe expression of miRNA-21-3p and its target genes of NADPH oxidase 4 (NOX4) and vascular endothelial growth factor A (VEGFA) in brain microvascular endothelial cells (BMECs) and pericytes were assessed in cavernous malformation lesions of 20 sporadic CCM patients by fluorescence in situ hybridization. The association of their expression with hemorrhage manifestation was evaluated. Cell proliferation, permeability, reactive oxygen species (ROS), migration, tubule formation, and the expression of NOX4 and VEGFA were assessed in CCM2 gene-depleted human BMECs and pericytes after miRNA-21-3p intervention. Cerebral hemorrhage, vascular permeability, vascular dilation, and angiogenesis after miRNA-21-3p intervention were evaluated in the ccm2 gene-knockdown zebrafish. ResultsDecreased miRNA-21-3p and increased NOX4 and VEGFA were shown in BMECs and pericytes of the CCM lesions compared to peri-lesion normal vessels from epilepsy patients, which were also correlated with the presence of cerebral hemorrhage in CCM patients. Increasing miRNA-21-3p attenuated cell proliferation, permeability, ROS expression, cell migration, and tubule formation by targeting NOX4 and VEGFA in CCM2 gene-depleted BMECs and pericytes. In vivo studies revealed that increasing miRNA-21-3p reduced cerebral hemorrhage, vascular permeability, vascular dilation, angiogenesis, and the overexpression of nox4 and vegfa in ccm2 gene-knockdown zebrafish. ConclusionMiRNA-21-3p can be a novel therapeutic target by regulating NOX4 and VEGFA, thereby stabilizing vascular integrity and reducing cerebral hemorrhage in CCM lesions.

Immoral decisions, which engage both cognitive control and reward system, bring both cognitive and neural consequences. However, how dishonesty has an impact on the brains dynamic alterations is still unclear. In this work, we attempt to understand the impact of immoral decisions on the brain states dynamics using both resting-state and task-state fMRI data collected before, during, and after an information-passing task involving dishonest choices with rewards. We employed the Hidden Markov Model (HMM) to capture the changes in the brain dynamics state, in which the changes that happen between pre- and post-task are hypothesized to be linked to behavior and brain dynamics during the task. First, we identified 4 intrinsic brain states across both resting scans and task scans, including one reward state (state 1) and one control network (state 3). The fractional occupancy (FO) of the control network decreased after the task, and subsequent analysis showed that it was linked to brain dynamics during the task: as dishonesty persisted, FO of the control network decreased while FO of the reward network increased. Moreover, the post-task control network was negatively correlated with motivated dishonesty, suggesting that stronger control network recruitment counteracts immoral tendencies. In contrast, early in the task, the reward network positively correlated with motivated dishonesty, indicating that the representation and sensitivity to reward attribution were tied to dishonest choices. A complementary analysis using drift diffusion modeling confirmed that the reward network tracked the weightings placed on monetary rewards, and the level of activation of the reward network before the task is associated with a bias in dishonesty. Together, these findings suggest that the post-moral decision brain operates not as a static system but as a set of dynamically shifting states, whose adaptive trajectories may underlie the lasting effect of moral erosion during sustained dishonest behavior.

This study proposes a novel spatiotemporal connectome-based framework to characterize the human brains action network, namely network affinity, moving beyond traditional static temporal connectivity measures by leveraging full functional connectivity profiles on large-scale neural wave dynamics. We applied this method to map the action network for the first time in a non-Western young adult cohort from the Chinese Human Connectome Project (CHCP). Our results delineate the action networks detailed functional affinity architecture, capturing its integrative topology across the cerebral cortex, cerebellum, and subcortical nuclei, and its characteristic anticorrelation with the default network. All the findings are replicated in HCP samples. Crucially, all derived high-resolution action network affinity maps and the associated computational code are publicly shared to foster open science and reproducibility (https://ccndc.scidb.cn/en). This work provides a foundational atlas and a new analytical approach, establishing a critical resource for future basic research across diverse populations and lifespans. It also holds significant translational potential for understanding and treating neurological and psychiatric disorders affecting goal-directed behavior, such as apathy and Parkinsons disease.

Background and PurposeGiven the increase in recreational psychedelic use and ongoing efforts to explore psychedelics as therapeutic agents for mental health disorders, there is an urgent need to understand the effect of psychedelics such as psilocybin and N,N-dimethyltryptamine (DMT) on sleep-wake states, which share a bidirectional relationship with mental health. Here, we investigated the effects of intravenous psilocybin and DMT on sleep-wake states and EEG spectral power and functional connectivity in rats. Experimental ApproachSprague Dawley rats (n=25, 13 male) were surgically instrumented to record high-density EEG (27 electrodes) and EMG during 12-h light and 12-h dark cycle after intravenous psilocybin (2.5 mg/kg, 10 mg/kg), DMT (3.75 mg/kg, 7.5 mg/kg) or 0.9% saline. The EEG/EMG data were scored in 4-second epochs into wake, slow-wave sleep (SWS), and rapid eye movement (REM) sleep. EEG spectral power and corticocortical coherence, a surrogate for functional connectivity, were computed in 12-second epochs. Key ResultsPsilocybin and DMT delayed the onset of SWS and REM sleep, and caused a short-lasting increase in wakefulness and decrease in SWS. Psilocybin also produced a 1) decrease in REM sleep, 2) decrease in theta power and coherence and increase in high gamma power and coherence during wake and SWS, and 3) increase in high gamma coherence during REM sleep. DMT increased gamma coherence only during wakefulness. Conclusions and ImplicationsSerotonergic psychedelics have minimal effects on sleep-wake states. The enhanced high gamma functional connectivity suggests that the psychedelic-induced changes in EEG/neural dynamics can occur independent of the arousal states.

Individuals with Autism Spectrum Disorder (ASD) and related neurodevelopmental conditions, like Phelan-McDermid syndrome (PMDS), exhibit social recognition deficits. Previous reports using Shank3B knockout (KO) mice, a genetic model with relevance to ASD and PMDS, revealed deficits in social memory in adulthood, but the postnatal onset and mechanisms underlying this dysfunction remain unknown. In the hippocampus, area CA2 contributes to the emergence of social memory during development and remains important for this ability through the lifespan. Perineuronal nets (PNNs), extracellular matrix structures, support social memory in CA2 and help orchestrate critical periods of plasticity in other brain regions. We found that Shank3B KO pups exhibit specific deficits in short-term social recognition and social novelty preference, which become evident at the end of the second postnatal week and persist into adulthood along with CA2 network aberrations. Excessive PNNs in area CA2 were detected in KO pups at the postnatal time when social recognition function typically emerges in healthy pups. This time was also characterized by greater sequestration of the guidance cue semaphorin-3A (sema3A) and overgrowth of afferents from the supramammillary nucleus (SuM) in KOs, suggesting that inordinate PNNs during a sensitive period may disorganize developing CA2 circuitry. Reduction of CA2 PNN levels prior to the onset of social dysfunction recovered social recognition function during development, as well as reduced sema3A and SuM inputs to the CA2. The restoration of behavioral function persisted into adulthood along with partial normalization of CA2 network activity. Together, these findings reveal how excess PNN formation in the developing hippocampus may give rise to impaired social memory by disrupting afferent input, effects that are reversible by early life intervention.

The voltage-gated potassium channel Kv2.1, which is encoded by the epileptic encephalopathy-associated gene KCNB1, is a primary driver of delayed-rectifier K+ currents in neurons. These currents contribute to high frequency firing by preventing depolarization block due to Na+ channel inactivation. Wild-type (WT) channels are localized at the soma, proximal dendrites and axons, forming large aggregates (clusters) via their C-terminal proximal restriction and clustering domain (PRC). This study investigates the biophysical and functional consequences of two C-terminal truncation mutations (Y529* and R579*), identified in patients with epileptic encephalopathy, which disrupt this critical clustering domain. Cluster formation was impaired, though not abolished, in neurons expressing mutated subunits together with endogenous WT subunits. Consistent with this clustering deficit, single-molecule imaging revealed altered channel dynamics, with WT channels remaining largely immobile, while mutated forms exhibited intermittent diffusion punctuated by transient immobilization events. This behavior was reproduced by diffusion-capture simulations considering channels with different number of PRC domains (i.e. with mutant subunits) and labile scaffolding interactions. Patch-clamp recordings revealed no significant difference in excitability between WT and mutant-expressing neurons. However, we observed increased firing in both conditions compared to non-transfected neurons. This suggests that Kv2.1 overexpression (for both WT and mutant channels) counterintuitively enhances neuronal excitability. Our data challenge a canonical role of this voltage-gated potassium channel in dampening neuronal firing, indicating that its overall expression level can be a critical and paradoxical driver of hyperexcitability.

BACKGROUNDIn Parkinsons disease (PD), the degeneration of nigrostriatal dopaminergic neurons leads to motor symptoms. Positron emission tomography (PET) using radioligand [18F]fluorodopa detects reduced striatal dopamine synthesis capacity in PD patients. Demographic factors such as sex and BMI are also associated with dopamine synthesis capacity. The combined contribution of demographic and clinical effects however remains elusive. It also remains unresolved how the dopamine synthesis capacity is correlated between striatal subregions and how the dopamine synthesis capacity and dopamine receptor function across striatal regions are associated with each other in PD patients and healthy controls. MATERIAL, AIMS, AND METHODSFor this retrospective register-based study, we used baseline [18F]fluorodopa PET data acquired at the Turku PET Centre between the years 1988-2016 with three different scanners (Ecat 931, GE Advance, HRRT). The data included scans of 350 adult human subjects, including 132 healthy controls (65 males and 67 females), and 218 PD patients (134 males and 84 females). The primary aim was to simultaneously investigate the effects of PD, age, sex and BMI on regional dopamine synthesis capacity (influx rate constant Kiref quantified with Patlak) using Bayesian linear regression. Secondary aims were to assess interregional correlations of dopamine synthesis capacity, and the association between regional presynaptic dopamine synthesis and postsynaptic dopamine type 2 receptor (D2R) availability in subjects who also had a proximal [11C]raclopride PET scan. RESULTSWe found modest support for age-dependent decline in dopamine synthesis capacity, increased capacity for higher BMIs, and for higher capacity in females versus males. These effects were smaller than the effect of PD status. Dopamine synthesis capacity across regions was correlated in both patients and controls. Support for positive correlation between the synthesis capacity and the D2R was observed in caudate nucleus. CONCLUSIONSPD and demographic effects are independently associated with the striatal dopamine synthesis capacity. The capacity is reduced by PD, decreased through age (particularly after the age of around 50), higher in females versus males, and weakly increased in higher BMIs. Synthesis capacity is correlated between the striatal and thalamic regions in both PD patients and controls. The dopamine synthesis capacity was positively correlated with the D2R availability in caudate. Scanner affects the estimates of dopamine synthesis capacity measured with [18F]fluorodopa PET, and it is preferrable to adjust for such variation in the data.

Despite the increasing adoption of deep neural networks (DNNs) in brain-computer interfaces (BCIs), developing high-degree-of-freedom (DOF) systems capable of decoding continuous movements, such as limb kinematics, remains a significant challenge. This difficulty stems from limited availability of task-specific neural features within individual neural signal datasets. To overcome this, we proposed a generative adversarial network (GAN) framework to enrich training features within neural signal datasets. Specifically, we synthesized artificial neural signal waveforms of the primary motor cortex (M1) from functionally related cortical regions, thereby enhancing neural datasets for improved motor kinematics decoding via DNN. Using magnetoencephalography (MEG) recordings during goal-directed arm-reaching tasks, our results showed that enhancing individual datasets with GAN-synthesized M1 signals significantly improved decoding performance by about 10% (p < 0.05). Such improved performance is sustained even in the absence of real M1 signals. Our results highlight the potential of signal generative networks for improving and augmenting high DOF motor BCIs to achieve freely intended movements.

Analyzing temporal spike patterns in nociceptors recorded via microneurography is challenging due to the use of a single recording electrode, waveform variability, and high similarity of spike shapes across neurons limiting interpretation of sensory coding such as pain and itch. We present a data-driven, supervised spike sorting approach to improve the analysis of nociceptive discharges, identified through activity-dependent conduction velocity changes. Our method integrates three feature sets and applies machine learning models including one-class SVM, SVM, and XGBoost. Validation used experimentally derived ground truth data acquired by controlled electrical stimulation, allowing precise spike time-locking. Compared to Spike2 software, our approach achieved higher F1-scores and reduced false positives, indicating improved spike sorting. Although XGBoost achieved the highest median F1-scores, optimal performance was dependent on individual combinations of feature sets and models for each recording. In some recordings with many nerve fibers and a low signal-to-noise ratio, reliable sorting was not feasible. This highlights the necessity to determine sortability and optimal configures using a ground truth protocol for each recording. These findings represent an important step toward reliable analysis of nociceptive activity. The openly accessible framework supports analyzing pruritogen-induced and spontaneous activity in neuropathic pain patients, advancing tools for peripheral neural decoding.

Learning is associated with activation of multiple protein kinases, but few details are known about the activation dynamics in response to different learning protocols. We addressed this issue by examining the long-term dynamics of kinases critical for long term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse. Three serotonin (5-HT) protocols have been found to induce LTF with distinct effectiveness: the five-pulse regular-spaced Standard protocol; the five-pulse irregular-spaced Enhanced protocol; and the two-pulse protocol with an interval of 45 min. We previously compared long-term dynamics of the mitogen-activated protein kinase (MAPK) isoform ERK after these protocols. Here we examined the long-term dynamics of additional kinases critical for LTF: p38 MAPK, protein kinase A (PKA), and p90 ribosomal S6 kinase (RSK). All four kinases showed complex dynamics of activity during 24 h, with a first wave of increase occurring shortly after 5-HT treatment and ending within 5 h, and a second wave from [~] 5 h to 18 h. After the Standard and two-pulse protocols, all kinase activities returned towards basal at 24 h, but after the Enhanced protocol some remained elevated at 24 h. Interactions and multiple feedback loops among the kinase pathways, and with the growth factors Aplysia neurotrophin (NT) and transforming growth factor-{beta} (TGF-{beta}), contribute to development of molecular clocks underlying these complex dynamics. These results help to delineate the molecular mechanisms underlying the induction of LTF and provide insights that may help design improved training protocols for induction and maintenance of LTF and long-term memory.

Patients with central vision loss due to macular degeneration (MD) must rely on their peripheral vision for tasks normally performed by the fovea. Many patients develop a preferred retinal locus (PRL), an eccentric retinal location used as a substitute for the damaged fovea in tasks such as face recognition, navigation, and reading. However, the mechanisms underlying PRL development remain elusive, and no single hypothesis fully explains its characteristics. Investigations into PRL development are hindered by oculomotor assessments, which often focus on fixation ability while neglecting other eye movement characteristics and potentially conflating different behaviors over time. In previous work, we introduced a series of oculomotor metrics in cases of simulated central vision loss, demonstrating that complex profiles of eye movement behavior can be extracted from a simple visual task. Here we present longitudinal data from 10 patients with MD as evidence of the feasibility of using these metrics to characterize different profiles of eye movements following central vision loss. Consistent with findings in healthy individuals using artificial scotoma, the metrics reveal substantial individual differences in behavior, both at baseline and after visual training. Overall, patients exhibit significantly higher saccadic re-referencing than controls, despite larger inter-individual differences. These metrics provide a detailed evaluation of oculomotor behavior in patients with central vision loss and offer a valuable tool for assessing progress in training protocols.

BackgroundBeta bursts are brief, transient increases in beta-band (13-30 Hz) EEG activity that play a key role in motor control, particularly in processes like movement initiation and inhibition. While most existing methods detect these bursts using simple amplitude thresholds, they often ignore variability in burst duration and task context. More advanced techniques exist but are computationally demanding, often opaque, and dependent on large datasets and strong modeling assumptions. ObjectivesThis study aims to develop an automated, machine learning- based approach to classify beta bursts using nonlinear dynamic features, considering both burst duration and task condition. MethodEEG data were collected from 26 healthy, right-handed participants during three motor tasks: (1) a right-hand isometric pinch grip at 10% maximum voluntary contraction (MVC), (2) rhythmic right-hand finger opening-closing in response to auditory cues (3-4 seconds), and (3) the same right-hand opening-closing task and concurrent with a steady left-hand isometric pinch grip at 10% MVC. Beta bursts were extracted from the left motor cortex, categorized by duration (short, medium, long), and time-locked to task events. From each burst, four nonlinear features, Fractal Dimension (FD), Wavelet Entropy (WE), Sample Entropy (SE), and Nonlinear Energy Operator (NEO) were calculated to train machine learning (ML) models. ResultsStatistical tests and feature selection revealed that FD, SE, and WE varied significantly with burst duration and task type, while NEO was more limited in sensitivity. ML models trained on these features achieved up to 91.1% validation and 85.7% test accuracy, especially when distinguishing bursts of different durations within the same task. ConclusionsThese findings suggest that beta bursts reflect structured, task-specific neural dynamics rather than random fluctuations. By using nonlinear features and ML, we introduce a scalable, interpretable framework for burst classification that outperforms traditional methods. This approach advances the understanding of transient beta activity and holds promise for real-time neural decoding in neuroscience and neurotechnology.

Tauopathies, including Alzheimers disease, are neurodegenerative disorders characterized by the accumulation of microtubule-associated protein tau, which is closely linked to cognitive decline. Reduction of tau is a potential and promising strategy for addressing tau-linked brain disorders. We report the development of a therapeutic approach using adeno-associated virus mediated delivery of an artificial microRNA targeting human tau. In a tauopathy mouse model, we demonstrate that a one-time intra-cisterna magna administration of vector resulted in reduced total tau, decreased pathological tau seeds, fewer tau inclusions, and amelioration of tau-related neuropathology. Notably, intervention at late disease stages, after onset of tau deposition and neurodegeneration, improved quality of life and extended survival. We further demonstrated the durability of therapeutic benefit and defined the minimally effective dose in tauopathy mice. These findings provide preclinical support for the advancement of a vectorized tau-lowering strategy as a disease-modifying approach for tauopathies and enable progression towards an investigational new drug application.

Artificial Recurrent Neural Networks (RNNs) are widely used in neuroscience to model the collective activity of neurons during behavioral tasks. The high dimensionality of their parameter and activity spaces, however, often make it challenging to infer and interpret the fundamental features of their dynamics. In this study, we employ recent nonlinear dynamical system techniques to uncover the core dynamics of several RNNs used in contemporary neuroscience. Specifically, using a data-driven approach, we identify Spectral Submanifolds (SSMs), i.e., low-dimensional attracting invariant manifolds tangent to the eigenspaces of fixed points. The internal dynamics of SSMs serve as nonlinear models that reduce the dimensionality of the full RNNs by orders of magnitude. Through low-dimensional, SSM-reduced models, we give mathematically precise definitions of line and ring attractors, which are intuitive concepts commonly used to explain decision-making and working memory. The new level of understanding of RNNs obtained from SSM reduction enables the interpretation of mathematically well-defined and robust structures in neuronal dynamics, leading to novel predictions about the neural computations underlying behavior.

BackgroundHow general anesthesia alters the dynamics of electrocortical activity is crucial to understand the neural mechanisms of unconsciousness. Local cortical activity undergoes spontaneous transitions at constant anesthetic concentration. The spatial organization and temporal dynamics of state transitions in large-scale electrocortical activity is incompletely understood. MethodsEpidural electrocorticogram was recorded from the right hemisphere in 8 rats (14 experiments) using chronically implanted 32-channel flexible electrode arrays during desflurane anesthesia at 6%, 4%, 2%, 0% inhaled concentrations, each maintained for 1 hour. Cortical states were identified by principal component analysis of power spectrograms followed by density-based clustering simultaneously across all anesthetic conditions. State-specific spatiotemporal complexity was quantified by the normalized Lempel-Ziv algorithm to capture signal variability beyond spectral effects. Temporal dynamics were assessed by state occurrence, dwell times, and transition probabilities. ResultsSeven cortical states were identified. Six states generally tracked anesthetic depth with an increase in delta power and decrease in complexity, but their occurrence was not tied to any anesthetic level (p<0.001). The 7th state was a paradoxical, activated state that mostly occurred during deep anesthesia and was marked by reduced delta (p<0.001) and elevated complexity (p<0.001). Cortical activity was more likely to remain in a given state than to switch (mean dwell time of 136.55 s, persistence likelihood of 99.36%). When transitions occurred, they followed structured, non-random dynamics, primarily within light- or deep-anesthesia states (FDR-corrected p<0.05), with a mild tendency to exit deep states and enter light states (p=0.0039), consistent with anesthetic emergence. ConclusionsElectrocortical activity is not a unitary function of anesthetic concentration but involves spontaneous dynamics and paradoxically activated states with increased global complexity during deep anesthesia. The results suggest ongoing spontaneous reorganization of cortical activity during prolonged anesthetic challenge and provide new insight into anesthesia-induced brain dynamics that may inform future strategies for monitoring and manipulating the state of consciousness and facilitating recovery from general anesthesia.

Social coordination in primates relies on parieto-frontal networks encoding self- and others actions. These areas send convergent projections to the putamen, but its role in representing self- and others actions remains unknown. We recorded neuronal activity from anatomically characterized putamen regions during a Mutual Action Task (MAT), where a monkey and a human took turns grasping a multi-affordance object based on sensory cues. Cortico-striatal synaptic input, indexed by local field potentials, mirrored known cortical dynamics during sensory instructions and movement, while single neurons selectively encoded the monkeys action, the humans action, or both. Grip type was encoded only during the monkeys trials. Viewing the partners action was neither necessary nor sufficient: neurons fired even when the partners action occurred in darkness, but not when viewed through a transparent barrier. These findings support a pragmatic role for the putamen in gating cortical representations of self- and others actions in social contexts.

Social coordination in primates relies on parieto-frontal networks encoding self- and others actions. These areas send convergent projections to the putamen, but its role in representing self- and others actions remains unknown. We recorded neuronal activity from anatomically characterized putamen regions during a Mutual Action Task (MAT), where a monkey and a human took turns grasping a multi-affordance object based on sensory cues. Cortico-striatal synaptic input, indexed by local field potentials, mirrored known cortical dynamics during sensory instructions and movement, while single neurons selectively encoded the monkeys action, the humans action, or both. Grip type was encoded only during the monkeys trials. Viewing the partners action was neither necessary nor sufficient: neurons fired even when the partners action occurred in darkness, but not when viewed through a transparent barrier. These findings support a pragmatic role for the putamen in gating cortical representations of self- and others actions in social contexts.

Post-mortem magnetic resonance imaging (MRI) offers high resolution and histological correlation, so protocols have been developed by brain banks using hemispheres fixed by immersion in Neutral-buffered formalin (NBF), but they provide limited tissue samples. Conversely, anatomy laboratories could supply complete brains perfused either with a salt-saturated (SSS) or an alcohol-formaldehyde (AFS) solution. These fixation methods alter the brains molecular properties, potentially affecting MRI quality and structural characteristics. T1- and T2-weighted (T1w, T2w) contrasts change with NBF fixation, but the effects of SSS or AFS remain unknown. We compared T1w and T2w intensities of different regions of interest (ROIs), including subcortical white matter (WM), cortical and deep gray matter (GM), in brains fixed with NBF, SSS and AFS. We scanned 20 ex situ hemispheres (NBF-immersed=7; SSS-perfused=7; AFS-perfused=6) in a 3T MRI scanner using T1w (0.7mm3) and T2w (0.64mm3) sequences overnight. Mean intensities of 29 ROIs in T1w and T2w MRIs and GM-WM ratios were calculated and compared in brains fixed with the three solutions. We found that T1w images were more affected by the fixation process, inverting the contrast of in vivo T1w and reducing the GM-WM contrast in AFS-fixed brains. T2w images resembled in vivo scans and maintained a sharp contrast in brains fixed with the three solutions, although the GM-WM intensity ratios were lowered in SSS-fixed brains. In conclusion, brains fixed with SSS and AFS from anatomy laboratories could be used for MRI studies, especially with the T2w sequence that seems more appropriate for structural analyses in different ROIs.

fMRI signals were traditionally seen as slow and sampled in the order of seconds, but recent technological advances have enabled much faster sampling rates. We hypothesized that high-frequency fMRI signals can capture spontaneous neural activity that index brain states. Using fast fMRI (TR=378ms) and simultaneous EEG in 27 humans drifting between sleep and wakefulness, we found that fMRI spectral power increased during NREM sleep (compared to wakefulness) across several frequency ranges as fast as 1Hz. This fast fMRI power was correlated with canonical arousal-linked EEG rhythms (alpha and delta), with spatiotemporal correlation patterns for each rhythm reflecting a combination of shared arousal dynamics and rhythm-specific neural signatures. Using machine learning, we found that alpha and delta EEG rhythms can be decoded from fast fMRI signals, in subjects held-out from the training set, showing that fMRI as fast as 0.9Hz (alpha) and 0.7Hz (delta) contains reliable neurally-coupled information that generalizes across individuals. Finally, we demonstrate that this fast fMRI acquisition allows for EEG rhythms to be decoded from 3.8s windows of fMRI data. These results reveal that high-frequency fMRI signals are coupled to dynamically varying brain states, and that fast fMRI sampling allows for more temporally precise quantification of spontaneous neural activity than previously thought possible.

Post-stroke epilepsy (PSE) is a major cause of acquired epilepsy in adults, yet the molecular mechanisms linking post-ischemic hypoxia to neuronal hyperexcitability remain poorly understood. The transcription factor hypoxia-inducible factor 1 (HIF1) is a central mediator of the cellular response to hypoxia and may contribute to epileptogenesis by regulating ion channel expression. Here, we identify the T-type calcium channel CaV3.2 (encoded by Cacna1h) as a direct transcriptional target of HIF1 and demonstrate its role in hypoxia-induced network hyperexcitability. Using neuronal cell lines, primary cortical neurons, and organotypic brain slice cultures (OTCs) from mouse and human tissue, we show that HIF1 activation, either through hypoxia or HIF1 overexpression, consistently increases Cacna1h expression. In NS20Y cells, overexpression of a normoxia-stable HIF1 variant increased Cacna1h promoter activity in both fluorescent and dual-luciferase reporter assays. The same effect was observed in primary cortical neurons, where HIF1 overexpression also elevated network activity measured by multielectrode array recordings. In murine and human OTCs, hypoxia led to marked increase of HIF1 and Cacna1h expression at both transcript and protein levels. Furthermore, oxygen-glucose deprivation followed by reoxygenation (OGD/R) induced a persistent increase in neuronal firing rate, which was recapitulated by HIF1 overexpression alone. Together, these results establish HIF1 as a key transcriptional regulator of CaV3.2 in neurons and reveal a conserved hypoxia-HIF1-CaV3.2 pathway that enhances neuronal excitability. This mechanism may underlie hypoxia-induced network hyperactivity and contribute to the pathogenesis of post-ischemic epileptogenesis.

Neurobehavioral disorders, ranging from depression to schizophrenia, have been found to display immune system alterations. The high incidence of comorbidity of these disorders, particularly depression, with chronic inflammatory conditions suggests shared mechanisms contributing to the manifestation of these conditions. We have previously shown that peripheral modulation of the innate immune system in mice rapidly triggers enhanced serotonin (5-HT) clearance in vivo associated with increased anxiety- and despair-like behaviors that can be suppressed by serotonergic elimination of p38 MAPK. Forebrain-projecting 5-HT synthesizing neurons of the dorsal raphe nucleus (DRN5-HT) play a key role in regulating behaviors related to mood and anxiety and whose perturbations are observed in multiple affective disorders. Here we identify molecular and circuit-level mechanisms that can translate peripheral innate immune system activation into changes in 5-HT signaling capacity. Using whole cell patch clamp recordings from acute midbrain slices, we demonstrate that the proinflammatory cytokine, IL-1{beta}, acts cell autonomously through its receptor, IL-1R1, via the p38 MAPK signaling pathway to rapidly inhibit firing of DRN5-HT neurons. In the dorsal hippocampus, we found that as with acute, peripheral lipopolysaccharide (LPS) administration, local injections of IL-1{beta} rapidly enhance 5-HT clearance as assessed by in vivo chronoamperometry. Like IL-1{beta}, TNF also acts via a serotonergic p38 MAPK dependent pathway to reduce excitability of DRN5-HT neurons. Immunocytochemical studies reveal that, IL-1R1, is nonuniformly expressed by DRN5-HT neurons and is required for LPS-induced inhibition of these cells as detected by cFos activation, with sex-dependent patterns evident. Moreover, we detected both DRN5-HT IL-1R1-dependent and -independent LPS-mediated changes in cFos changes in forbrain projection areas. Our findings support a growing appreciation that serotoninergic neurons contribute to changes in CNS physiology and behavior following peripheral immune activation. More specifically, our studies attest to a functional role of serotonergic IL-1R1 in mediating IL-1{beta} following peripheral innate immune activation, effects likely to arise both from changes in diminished 5-HT neuron excitability and elevated 5-HT clearance.

Social anxiety (SA) is associated with enhanced error monitoring, yet underlying mechanisms remain unclear. Consistent with cognitive models of SA, we propose that stronger error monitoring contributes to SA by strengthening memory encoding of errors (including relevant social cues), negatively biasing what is remembered. Supporting this hypothesis, our prior work demonstrated that high SA individuals exhibit better memory for faces presented during error (vs. correct) trials. To test whether this Memory Bias for Error Events is specific to social stimuli, 140 participants completed a Flanker task with trial-unique faces (social) or objects (non-social) as background images, followed by a surprise memory test. Results revealed that higher SA symptoms were associated with enhanced memory for faces on error (vs. correct) trials, but not for objects. These findings replicate and extend our prior work, demonstrating that SA-related memory biases for errors are specific to social stimuli, rather than reflecting general encoding biases.

The Research Domain Criteria (RDoC) framework was introduced to guide psychiatric research using biologically grounded, dimensional constructs of mental function. However, its current hierarchical domain structure remains largely unvalidated against individual-level brain imaging data. Building on our prior group-level work showing that data-driven bifactor models outperform RDoC-based models, we applied a multi-stage validation framework to Human Connectome Project (HCP) task fMRI data to test whether individual-level, empirically derived models more accurately reflect the intrinsic organization and behavioral relevance of brain activity. Using confirmatory factor analysis in two independent cohorts, we found that individual-level, data-driven bifactor models consistently outperformed RDoC-based models across multiple fit indices in both training and validation sets. The general factor derived from these models revealed a reproducible macroscale gradient spanning visual-attentional to auditory-default mode networks, aligning with canonical resting-state gradients and supporting its interpretation as a domain-general axis of large-scale brain organization. Applying community detection to subject-specific factor representations revealed four spatial motifs whose centroids corresponded to interpretable brain systems and were robustly reproduced across cohorts. Similarity to these centroids predicted individual task performance in working memory and relational reasoning, as measured by both raw accuracy and latent performance factors. To further assess organizational validity, we applied Mapper--a topological data analysis method-- to contrast maps, generating unsupervised graph representations of task-evoked brain activity. Mapper graphs annotated with data-driven centroids showed greater modularity than those annotated with RDoC domains, suggesting that the data-driven framework better captures the topological structure of individual functional brain states. Together, these findings demonstrate that individual-level, data-driven factor models provide a more accurate, interpretable, and behaviorally relevant account of brain organization than the current RDoC framework. By modeling inter-individual variability directly from neuroimaging data, this approach advances precision neuroscience and supports the empirical refinement of dimensional psychiatric frameworks such as RDoC.

In humans and non-human primates, the extrastriate visual cortex contains fine-scale columns selectively responsive to motion, disparity, and color. However, the developmental interplay between these functional modules remains poorly understood. Using high-resolution fMRI, we compared the mesoscale organization of extrastriate cortex in 16 individuals with normal vision and 15 participants with amblyopia (PwA) caused by strabismus (n=8) or anisometropia (n=7). In controls, the cortical territory occupied by disparity-selective columns exhibited a competitive relationship with that of motion- and color-selective columns. Consistent with this pattern, PwA showed a reduction in disparity-selective responses accompanied by enhanced motion- and color-selective activity, as well as expansion of the cortical territory allocated to them. Our results show that the mesoscale modules of the human visual system are rivals in development allowing intact functions to usurp those that are compromised.

Walking on uneven terrain becomes more difficult as we age, and gait becomes less automatic. Using mobile brain imaging via high-density electroencephalography (EEG) can provide insight into the neural mechanisms contributing to reduced mobility capability with aging. The objective of this study was to quantify age differences in electrocortical dynamics during uneven terrain walking, both averaged across many strides and variations within a stride. We included 31 young adults and 71 older adults for analysis. All participants walked on an uneven terrain treadmill with four levels of terrain difficulty at their self-selected speed. Compared to younger adults, older adults exhibited a greater increase in step duration variability and mediolateral sacral excursion variability as the terrain became more uneven. We identified multiple brain regions involved during walking on uneven terrain. Regardless of age group, walking on uneven terrain compared to flat terrain led to a widespread change of electrocortical dynamics in the brain, especially in the alpha (8-13Hz) and beta (13-30Hz) band power. In the parieto-occipital region, younger adults experienced a greater reduction in alpha and beta power with increasing terrain unevenness compared to older adults. We also assessed how intra-stride power fluctuations changed with terrain unevenness and age group. Greater intra-stride power spectral fluctuations in the occipital area were associated with greater terrain unevenness for younger adults, but not for older adults. In summary, older adults showed a greater increase in gait variability than younger adults as the terrain became more uneven, but exhibited a lack of modulation of parieto-occipital activity in response to terrain unevenness. The lack of task-related power modulation may suggest reduced cortical network flexibility in older adults. The absence of increased parieto-occipital activity when walking on uneven versus flat surfaces in older adults may also indicate that, unlike younger adults, older adults already heavily rely on visual processes during flat surface walking and may therefore have reduced occipital modulation range remaining to cope with the visuomotor processing demands of walking on uneven surfaces.

Wolfram-like syndrome leads to retinal ganglion cell degeneration and vision loss. Wolfram-like syndrome is primarily caused by variants in the WFS1 gene, which encodes an endoplasmic reticulum resident transmembrane protein, Wolframin. To date, the disease mechanism remains unclear, and no therapies are available. Here, we generated a mouse model carrying the pathogenic WFS1E864K allele that recapitulated key features of human Wolfram-like syndrome, including bilateral optic atrophy, retinal nerve fiber thinning and lamination of the outer plexiform layer. We demonstrated, using the Wfs1E864K mouse model, that alteration of the protein leads to impairments of retinal ganglion cell function, associated with a thinning of the inner retina layer and nerve fibers. These alterations are associated with myelin disorganization, axonal death, mitochondrial alterations in the axons, and impairment of endoplasmic reticulum-mitochondria communication in the soma. Our data showed that primary deficits are localized in the optic nerve before progressing towards the retinal ganglion cell soma. RNAseq analysis identified several altered signaling pathways such as in lipid metabolism, glia activation response, metabolic stress, organelle transport and quality control. These findings highlighted the critical role of Wolframin in optic nerve mitochondrial physiology, providing us with a pertinent model to develop novel innovative therapeutic strategies.

Alpha-synuclein (-Syn) is the primary component of Lewy bodies, the pathological hallmark of neurodegenerative synucleinopathies, including Parkinsons disease (PD) and dementia with Lewy bodies (DLB). Dysregulated expression of its encoding gene, SNCA, has been identified in association with both PD and DLB in short-read sequencing studies. However, such studies do not capture variation in transcript isoforms expressed. Here we combine for the first time SNCA-targeted long-read multiplexed arrays isoform sequencing (MAS-Iso-seq) with unbiased short-read single nucleus (sn) RNA-seq for simultaneous characterization of the SNCA transcript isoform landscape and mapping of isoform expression to specific cell types and subtypes in PD, DLB, and control sample cortical tissues. This approach enabled discovery of numerous SNCA transcript isoforms displaying novel splicing patterns and incorporating novel exons. We further identified an abundant class of transcript isoforms encoding a previously unreported -Syn protein variant (-Syn-115) and displaying increased proportional detection in excitatory neurons of PD and DLB tissues in comparison to controls. The proportion of these isoforms was found to be especially high within several specific glutamatergic neuron subtypes. In-depth characterization of the predicted structural and biochemical properties of -Syn-115 using an in silico modeling approach revealed a greater aggregative affinity compared with canonical -Syn-140, suggesting the potential for increased cytosolic -Syn-115 abundance to induce aggregation between heterogeneous -Syn isoforms, potentially driving fibril formation and disease progression. Together, our findings provide new insights into the molecular mechanisms underlying -Syn involvement in multiple synucleinopathies and have translational implications for the development of new precision medicine strategies to combat these diseases, indicating the potential for treatments targeting both specific transcript and protein isoforms, as well as disease-driving cell subtypes.

People segment ongoing information into meaningful mental representations known as events. Recent studies have found a spatio-temporal hierarchy in the event structure during movie watching and story listening. How the human brain segments stories while reading remains unclear. We examined event segmentation while reading Harry Potter using publicly available 3T fMRI data. To identify neural events, we employed a Hidden Markov Model (HMM) within six regions of interest (ROI) in the reading network. The ROIs included the inferior frontal gyrus (IFG), middle frontal gyrus (MFG), angular gyrus (AG), inferior frontal gyrus orbital (IFGorb), anterior temporal lobe (ATL), and posterior temporal lobe (PTL). These regions are also associated with DMN. The results revealed multiple timescales of events, with the IFG and AG representing shorter events, while the IFGorb, ATL, PTL and MFG represent relatively longer events. Boundaries of longer events were partially aligned within short events, suggesting a nested hierarchical event structure. Further comparisons identified associations between neural events and annotations from humans and ChatGPT (automated and less subjective segmentation) in the inferior frontal, temporal and parietal areas. Notably, the AG (a core region of the DMN and memory processing) and the IFG (relevant for language processing) exhibited stronger alignment with both sets of annotations. The findings suggest an important role of AG and IFG in event segmentation in reading. They also confirm the connection between the reading network and the DMN in event segmentation. This connection seems to be linked to the hierarchical processing of context-dependent semantic information during reading.

Understanding the molecular mechanisms by which erythropoietin (EPO) is associated with neurogenesis is essential to harness its therapeutic potential for cognitive and neuropsychiatric disorders. Here, we employed single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), combined with single-nucleus RNA sequencing (snRNA-seq), to map the epigenomic and transcriptional landscapes of adult mouse hippocampus under recombinant human EPO (rhEPO) treatment. We discovered significant lineage-specific remodelling of chromatin accessibility predominantly in newly formed pyramidal neurons, highlighting a robust EPO-driven neurogenic response. Notably, transposable elements (TEs), particularly ancient LINEs and SINEs, emerged as critical cis-regulatory elements extensively bound by key neurogenic transcription factors such as NEUROD1/2, FOXG1, and ASCL1. Integrative analyses revealed that these TE-derived regulatory elements orchestrate gene networks involved in neuronal differentiation, synaptogenesis, and synaptic plasticity. Our findings highlight a previously unrecognised role of TEs as dynamic regulators in EPO-induced hippocampal re-wiring of gene regulatory networks associated with neurogenesis, establishing a valuable epigenomic resource for advancing therapeutic strategies targeting cognitive deficits and neurodegenerative conditions.

Despite the prevalence of inner speech in everyday life, research on this has been limited, particularly when it comes to non-invasive methods. This preprint aims to fill this gap by using EEG and MEG to collect data from three different inner speech paradigms, and by conducting an initial decoding analysis. Specifically, we tested silent reading, repetitive inner speech, and generative inner speech tasks. We collect a high number of inner speech trials from a few participants. Besides comparing across recording modalities we also compare across inner speech types. Our aim is to analyse the decodability of inner speech within each task and between tasks by the use of transfer learning. We find that in both EEG and MEG, silent reading can be decoded relatively well with 30-40% accuracy across 5 words. However, the decoding performance of both types of inner speech is mostly at chance level. This prohibited further transfer learning investigations between tasks. While the inner speech results are primarily negative, we believe our exploration of data size and various decoding methods is valuable. The dataset itself is useful for the research community as it contains a much larger number of trials within one participant than any other inner speech dataset. Having multiple sessions also allows for testing across-session performance. Finally, we systematically compare silent reading decoding performance within 3 participants across four non-invasive modalities. These are EEG, 2 types of MEG machines, Elekta and CTF, and optically-pumped magnetometers (OPMs). We also compare the spatiotemporal dynamics of silent reading between these modalities. This is especially aimed at validating OPMs as a new kind of non-invasive brain recording technology. We find comparable performance to EEG, but OPM performance did not reach traditional MEG.

Organophosphate flame retardants (OPFRs) are ubiquitous flame-retardant additives with endocrine-disrupting properties. Despite increasing evidence that OPFRs impact neurodevelopment, their effects on the neuroendocrine stress response remain poorly understood. To examine their long-term impact on stress regulation, we treated pregnant C57Bl/6J dams to a mixture of tris(1,3-dichloro-2-propyl) phosphate (TDCPP), triphenyl phosphate (TPP), and tricresyl phosphate (TCP; 1 mg/kg each) from gestational day (GD) 7 through postnatal day (PND) 14. Adult offspring (8-9 weeks of age) were then challenged with acute stressors, including 1 h restraint or a 6-day acute variable stress (AVS) paradigm. Perinatal OPFR exposure produced persistent, sex-specific alterations in the hypothalamic-pituitary-adrenal (HPA) axis and stress-related neurocircuitry. Following 1 h restraint, OPFR-treated females showed heightened serum corticosterone. In addition, gene expression analysis revealed sex-dependent disruptions in key stress-regulatory pathways after OPFR treatment and 1 h restraint in the hypothalamus (Crhr1, Crhr2, Ptpn5) and pituitary (Crhr1, Pomc, Nr3c1). Females demonstrated more differences in adrenal gene expression related to steroidogenesis (Mc2r, Cyp11b2) and catecholamine biosynthesis (Dbh, Pnmt), with OPFR-treated groups having blunted responses. OPFR AVS females displayed reduced corticosterone and downregulated Pacap/Pac1r expression in the bed nucleus of the stria terminalis (BNST), accompanied by increased behavioral avoidance and immobility. In males, OPFR exposure led to increased BNST Pacap and Pac1r, expression, along with hyperactivity and avoidance behaviors. Together, these findings demonstrate that early-life OPFR exposure induces lasting, sex-specific dysregulation of the HPA axis and associated stress circuits, highlighting OPFRs as developmental neuroendocrine disruptors with implications for mood and stress-related disorders.

The major pathological hallmarks of sporadic and familial forms of Parkinsons disease (PD) are the targeted and progressive loss of midbrain dopaminergic neurons (mDA), associated with systemic iron accumulation, -synuclein (syn) accumulation and aggregation, and lipid peroxidation amongst other reactive oxygen species (ROS) generation. Therapeutic strategies aimed towards dopamine restoration, syn removal and iron chelation have provided symptomatic relief but failed to prevent or slow disease progression. This is in part due to the lack of understanding of the exact pathways leading to neuronal death in PD. In this study, we investigate ferroptosis, a unique cell death mechanism sharing multiple features with PD pathology, as a relevant pathway with implications in disease pathogenesis. We identified an enrichment of ferroptosis genes dysregulated throughout PD postmortem brain samples and several neuronal and glial PD models. Using CRISPR/Cas9 technology, we generated a rapid iPSC-derived synucleinopathy neuronal model harbouring the SNCA A53T mutation and report increased ROS generation, reduced levels of antioxidant glutathione (GSH), impaired mitophagy and a heightened vulnerability to ferroptosis-induced lipid peroxidation and cell death. Critically, inhibition of the key lipid peroxidation enzyme and driver of ferroptosis, 15-lipoxygenase (15-LO), rescued synucleinopathy associated pathologies and prevented pathological syn oligomerisation in SNCA A53T neurons. Furthermore, we report enhanced microglial ferroptosis susceptibility in models of synucleinopathy. In summary, we highlight a new mechanism by which the familial PD-associated SNCA A53T mutation causes cell death and propose 15-LO inhibition as a tractable therapeutic opportunity in PD.

The ventrolateral preoptic nucleus (VLPO) of the hypothalamus plays a major role in the induction and consolidation of non-rapid eye movement (NREM) sleep. While VLPO neurons are heterogeneous, they often display low-threshold spikes (LTS), a feature that supports rhythmic activity. Nevertheless, rhythmic bursting in these VLPO neurons has never been observed. Here, we report that [~]12% of VLPO neurons in a large database of ex vivo patch-clamp recordings display spontaneous rhythmic bursting of action potentials. This activity occurred in putative sleep-promoting neurons, identified by inhibitory responses to noradrenaline (NA), as well as wake-active neurons that were activated by NA. Unsupervised clustering of 24 neurons based on burst properties, electrophysiological, and morphological features revealed three distinct groups: one corresponding to putative sleep-promoting neurons and two wake-active neurons with fast and slow bursting dynamics. Strikingly, membrane potential oscillations persisted in the presence of tetrodotoxin (TTX), indicating that rhythmic bursting is driven by intrinsic mechanisms rather than network activity. These findings suggest that rhythmic bursting is an intrinsic and functionally relevant mode of activity in VLPO neurons, which may contribute to sleep regulation.

Women show declines in verbal memory across the menopause transition that may persist into the postmenopause. The goal of the present study was to characterize the patterns of brain activity and hippocampal functional connectivity that support verbal memory performance in midlife postmenopausal women. The study sample included 171 midlife postmenopausal women from the MsBrain I study (mean age = 59.3 years, mean education= 15.7 years, 87.7% white). All participants were cognitively normal, native English speakers, not taking menopausal hormone therapy. Participants completed neuropsychological (California Verbal Learning Test [CVLT]) and neuroimaging assessments, including an fMRI task of verbal encoding and recognition. Findings indicated that during verbal encoding, greater activation of bilateral prefrontal and medial temporal regions, as well as the precuneus, cuneus, caudate, and cerebellar regions, was associated with better performance on CVLT measures, including learning, short- and long-delay recall, and semantic clustering. Functional connectivity from both hippocampi to primarily right prefrontal regions during verbal encoding associated with better CVLT performance. In-scanner word recognition accuracy was more strongly associated with activation of parietal and occipital regions, and with functional connectivity between the right hippocampus and bilateral parietal and temporal regions. Our findings characterize the patterns underlying verbal memory abilities in midlife postmenopausal women. The patterns identified here may act as a foundation for better interpreting the effects of hormonal changes and menopausal symptoms on cognition at midlife, and for identifying neural targets for pharmacological and lifestyle interventions aimed at sustaining womens memory function.

Ants exhibit remarkable collective and social behaviors, such as alloparental care1, chemical communication2, homing3, and cooperative group hygiene4. The clonal raider ant Ooceraea biroi is especially well-suited for investigating the neuronal and genetic underpinnings of these behaviors5. Unlike most ant species, O. biroi lacks a queen caste. Instead, colonies consist entirely of regular workers and slightly larger intercaste workers6. All workers reproduce in synchrony via parthenogenesis, giving rise to age-matched cohorts of clonally identical offspring7,8. This unique life history enables precise experimental control over age, genotype, and colony composition. These features have also facilitated the introduction of genetically encoded calcium indicators into O. biroi, enabling in vivo two-photon imaging to investigate the neural basis of social behaviors9. Despite its promise as a neuroscience model, the structure of the clonal raider ant brain has not been systematically characterized, and a representative reference brain does not exist. To address this gap, we imaged the brains of 40 age-matched, genetically identical individuals with confocal microscopy and, using 3D groupwise registration, generated the first reference brain for the species. We introduce a registration pipeline to align brains to this reference, facilitating the comparison of anatomical features across labeling experiments with high spatial precision. Unexpectedly, despite homogeneity in genotype, age, and external morphology, we discovered extensive interindividual variability across our collection of brain samples. This raises the possibility that behavioral division of labor in O. biroi is linked to individual differences in brain structure. This work provides a powerful resource for the emerging clonal raider ant neuroscience community and reveals novel features of the species neurobiology that may influence social behaviors and colony function.

mRNA translational repression by eukaryotic initiation factor 4E-binding proteins (4E-BPs), plays a critical role in synaptic plasticity and the formation of long-term memory (LTM). Among the three 4E-BP paralogs, 4E-BP2 is the predominant form expressed in neurons, and its full-body deletion in mice causes memory deficits. Mice lacking 4E-BP2 in GABAergic inhibitory interneurons, but not excitatory neurons, display autistic-like behaviors and deficits in object location and recognition. The specific mRNAs translationally regulated by 4E-BP2 in GABAergic interneurons, and how they contribute to spatial and associative memory, are unknown. Here, we show that conditional knockout (cKO) mice lacking 4E-BP2 selectively in GABAergic interneurons exhibit impairments in long-term spatial and contextual fear memory formation. We further demonstrate that 4E-BP2 deletion controls the translation of selective mRNAs in interneurons without increasing general protein synthesis. One of the mRNAs is Gal, which encodes a neuropeptide that modulates memory. Our findings provide evidence that 4E-BP2 selectively controls the translation of a subset of mRNAs in inhibitory neurons that are required for LTM formation.

The medial temporal lobe (MTL) is crucial for episodic memory, whereby posterior MTL preferentially represents visuospatial information, and anterior MTL is involved in the representation of semantic or conceptual information. The neurophysiological underpinnings of content-preferential organization in the developing MTL are largely unknown. Here we utilized rare electrocorticography (ECoG) recordings from 23 pediatric epilepsy patients who completed a visual scene recognition memory task to systematically examine the neurophysiological underpinnings of memory formation along the MTL long axis. The timing of high-frequency activity (HFA, [~]70-150 Hz) differed between the posterior and anterior MTL, peaking after scene onset in the posterior MTL and around scene category response (indoor/outdoor scene categorization) in the anterior MTL. Further, in the posterior MTL, HFA was predictive of successful memory formation and positively linked to memory performance, highlighting the importance of posterior MTL HFA to memory formation. In contrast, theta frequency in the anterior MTL was linked to memory performance, and theta-HFA phase-amplitude coupling before scene category responses was predictive of successful memory formation, highlighting the importance of anterior MTL theta oscillations to memory formation. Our findings establish distinct neurophysiological features along the posterior-to-anterior axis of the developing MTL that differentially support the representation of perceptual and conceptual information during memory formation.

Emotional and cognitive processing rely on communication between the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC). The BLA regulates mPFC both directly and indirectly via the medial sub-division of the medial dorsal thalamus (MDm). Although the BLA projection to MDm has been established anatomically, less is known about the functional properties of this synapse. Here, using patch-clamp electrophysiology and optogenetics in ex vivo mouse brain slices, we found that BLA neurons make potent synaptic connections onto MDm neurons capable of evoking action potentials. The site of this BLA input overlaps with strong innervation from locus coeruleus norepinephrine (NE) axons. We found that NE acts via 2-adrenergic receptors to strongly reduce excitatory postsynaptic currents from BLA to MDm. NE also decreases the release probability of BLA axon terminals through a presynaptic mechanism. Postsynaptically, NE depolarizes MDm neurons and increases their tonic firing rates. These findings show that NE, whose levels are elevated during arousal and stress, can suppress transmission of affective information from BLA into MDm, thereby blunting this potent indirect pathway from BLA to mPFC. SIGNIFICANCE STATEMENTPrevious anatomical studies have suggested the importance of amygdala input to the limbic thalamus. Here, using ex vivo electrophysiology and optogenetics in adult mice, we characterize the excitatory input from basolateral amygdala to mediodorsal thalamus, revealing the potency and physiological characteristics of this input. Further, we show that the stress-related neuromodulator, norepinephrine, binds to the 2-adrenergic receptor to significantly dampen transmission of affective information carried by this synapse. These findings improve our understanding of key circuits involved in emotional processing and provide insight on how stress-induced neuromodulation may change circuit function, which is relevant to stress-related neuropsychiatric disorders such as depression, anxiety, schizophrenia, and PTSD.

Auditory externalization, the perception of a sound source as located outside the head, is essential for spatial hearing and auditory scene analysis. However, its neural correlates remain poorly understood. This study investigated differences in brain activation elicited by externalized versus internalized sound sources. Twenty-nine healthy participants underwent a 3T functional magnetic resonance imaging (fMRI) scan while listening to auditory stimuli presented in three spatialization conditions: reverberant externalized sounds (highest externalization), anechoic externalized sounds (intermediate externalization) and diotic anechoic sounds (internalized). Whole-brain analyses revealed greater activation for externalized compared to internalized sound sources in the left superior temporal gyrus, including the planum temporale, the cerebellum and the left posterior cingulate gyrus. Internalized sounds elicited greater relative activity in the left inferior temporal gyrus. Direct comparison between the two externalized conditions revealed stronger left superior temporal gyrus activation for reverberant sounds, while anechoic sounds preferentially activated the right middle temporal gyrus. These findings confirmed the key role of the planum temporale in auditory externalization and the involvement of higher-order brain regions, suggesting broader networks underpinning the perception of sound location.

Fragile X Syndrome (FXS) is a common inherited neurodevelopmental condition, resulting from loss of Fragile X Messenger Ribonuclear Protein (FMRP). Rodent models of FXS display cellular hyperexcitability, but it is not known to what extent this is the case in intact human neurons. Depleting FMRP in human brain slice cultures reveals cyclic-AMP-dependent cellular hyperexcitability which is corrected by phosphodiesterase 4D inhibition and may be independent of neurodevelopment.

Viewing repetitive striped patterns can induce pattern glare, experienced as visual discomfort (VD). While previous studies examined either pupillary responses or VD separately, few have investigated how they covary or evolve with repeated exposure. This study tested whether pupillary dynamics could serve as an objective "aversometer" -- a physiological marker of individual visual sensitivity beyond subjective reports. Across four experiments (preliminary: n = 97; main: n = 70 for spatial frequency, n = 46 for central field size, n = 36 for central blank, with partial overlap), we manipulated spatial frequency, central field size, and surround field size of square-wave gratings (0.5-3 s) while measuring both discomfort and pupil size. Higher spatial frequencies and larger pattern areas elicited stronger pupillary constriction and greater discomfort, whereas repeated exposures produced cumulative increases in discomfort and decreases in baseline pupil size, consistent with visual strain rather than adaptation. To assess the potential of pupillometry as an aversometer, we examined individual differences in the main spatial-frequency experiment (controlled viewing distance, n = 42). A paradoxical pattern emerged: within participants, stronger stimuli produced greater constriction, but individuals with higher overall discomfort showed weaker constriction and stronger late redilation. Similar dissociations between subjective sensitivity and pupillary responses have been noted in studies of light-induced discomfort, suggesting that related mechanisms may contribute, although their specific physiological basis remains unclear. Overall, our findings clarify how pattern-induced discomfort evolves over time and across individuals and highlight pupillometrys potential as a sensitive, objective tool for assessing visual sensitivity. HighlightsO_LIStriped patterns systematically increased discomfort and pupillary constriction C_LIO_LIRepeated exposure led to progressive discomfort and shrinking baseline pupil C_LIO_LIAmong high-sensitivity participants, weaker constriction and stronger redilation appeared C_LIO_LIThe paradox may reflect interindividual autonomic differences under visual stress C_LIO_LIPupillometry shows promise as an objective marker of visual sensitivity C_LI

Zellweger Spectrum Disorders (ZSDs) are caused by mutations in any of the different peroxin (PEX) genes, which are essential for peroxisome biogenesis and function. Clinical features of ZSDs include seizures, leukodystrophy, renal and liver dysfunction, skeletal abnormalities, and they usually result in death during infancy or early childhood. There are no treatments for ZSDs, and their rarity, the large size of the PEX genes, and the numerous different genes, has impaired therapeutic development. We previously demonstrated that ATAD1, a mitochondrial protein quality control chaperone, could correct both mitochondrial and peroxisomal phenotypes in PEX3 patient fibroblasts. In this study, we investigated whether overexpressing ATAD1 could provide similar benefits in PEX1 and PEX6 patient cell lines, which account for over 70% of ZSD cases. We used established PEX6-/- HEK293 cells, patient-derived fibroblasts with pathogenic PEX1 mutations, and newly created zebrafish mutants. Lipidomic profiling of the cell lines demonstrated widespread dysregulation, including accumulation of lysophosphatidylcholines with very-long-chain fatty acids, depletion of plasmalogens and cholesteryl esters containing polyunsaturated fatty acids, and a decrease in cardiolipins. Overexpressing ATAD1 partly corrected these imbalances, including normalizing VLCFA metabolism in PEX1 fibroblasts and restoring plasmalogens and cardiolipins in PEX6-deficient cells. Mitochondrial function analysis (Seahorse XF) showed that ATAD1 increased basal and ATP-linked respiration in both PEX1- and PEX6-deficient cells, sometimes surpassing the effects of PEX gene re-expression. ATAD1 increased peroxisome numbers in both PEX6 and PEX1 cells. Zebrafish Pex1 mutants exhibited impaired maximal respiration despite normal basal activity, confirming mitochondrial vulnerability in vivo. These findings further confirm a role for ATAD1 as a modifier that improves lipid metabolism, mitochondrial function, and peroxisome abundance that could function across multiple ZSDs.

Attention-deficit/hyperactivity disorder and anxiety disorders are highly prevalent in youth and are characterized by substantial heterogeneity and frequent co-occurrence. This transdiagnostic complexity challenges conventional diagnostic frameworks that rely on symptom-based categories, which often obscure underlying dimensional and neurobiological mechanisms and offer limited neurobiological specificity. To address these issues, we developed a deep learning-based brain-behavior modeling framework that integrates clinically salient functional connectivity with cognitive and behavioral measures to identify interpretable dimensions and biologically grounded subtypes (biotypes). We applied our model to the Adolescent Brain Cognitive Development (ABCD) dataset comprising 3,508 children aged 9-11 years and revealed two reproducible brain-behavior dimensions that captured variation in cognitive control and emotion-attention regulation. These dimensions further yielded three distinct biotypes, each exhibiting unique symptom profiles and distinct brain development. We tested the robustness and generalizability of the dimensions and corresponding biotypes in an independent cohort of 224 age-matched participants from the Healthy Brain Network (HBN) and documented their early expression before symptom onset during adolescence. These findings highlight the utility of brain-behavior dimensions for elucidating heterogeneous psychiatric presentations and advance a biologically grounded framework for early classification and potential clinical translation in youth mental health.

[11C]UCB-J is a radioligand targeting synaptic vesicle glycoprotein 2A, used to image synaptic density. For quantification, a small-volume centrum semiovale area was previously optimized as a [11C]UCB-J reference region (CS2mL); however, its high variability resulted in reduced reliability. Herin, we evaluated an alternative reference region method to assess longitudinal test-retest reliability and detection of Parkinsons disease (PD). For estimating distribution volume ratio (DVR), CS2mL and eleven white matter (WM) reference regions (range: 0.5-200 mL) were generated using the Freesurfer WM map. Same-day and longitudinal test-retest variability (TRV) were assessed (24 healthy subjects (HS); n=10 same-day and n=20 longitudinal HRRT scans, range: 7-1028 days). Each reference region was used to evaluate the substantia nigra (SN) and caudate DVRs in HS (n=25) and PD (n=20). The 10mL WM reference region yielded [11C]UCB-J DVR measurements with reduced variability in TRV (same-day: 10mL: 1.2{+/-}5.7%, same-day: CS2mL: -0.9{+/-}9.2% longitudinal: 10mL: 1.5{+/-}7.0%, CS2mL: 1.6{+/-}11.9%,) while maintaining <10% volume of distribution difference, compared to CS2mL. Further, a significant difference between PD and HS groups in SN and caudate DVRs was found using 10mL, with greater effect size (Cohens d 0.61 for SN and 0.66 for caudate) compared to CS2mL (0.38 for SN and 0.43 for caudate).

Although the autonomic sympathetic system is activated in parallel with locomotion, the underlying neural mechanisms mediating this coordination are not completely understood. Descending exercise or central command signals from hypothalamic and brainstem regions are thought to activate thoracic spinal sympathetic neurons in parallel with descending locomotor commands. In turn, subsets of thoracic sympathetic preganglionic neurons (SPNs) then increase activation of a constellation of tissues and organs that provide homeostatic and metabolic support during movement and exercise. It is known that neurons within the spinal cord (propriospinal networks) can generate well-coordinated and sustained locomotor activity but whether these propriospinal networks contribute to coordination between locomotor and autonomic systems is unknown. To investigate this, we applied neurochemicals to elicit whole-cord or lumbar-evoked locomotor activity in an in vitro spinal cord preparation, simultaneously recording lumbar ventral root (VR) activity and changes in calcium fluorescence of pre-labelled SPNs in thoracic segments. Using whole-bath drug application to elicit hindlimb locomotor activity, recorded SPN responses were increased in rostral (T4 - T7) compared to caudal (T8 - T11) segments. When locomotor-inducing neurochemicals were applied only to the lumbar region using a split-bath configuration, SPN population responses were increased in rostral (T4-7) but not caudal (T8-9) segments during both tonic and rhythmic VR activity. In both approaches, the greatest numbers of SPNs with increased fluorescence during rhythmic activity were in T6/7, whereas the greatest numbers with unchanged or decreased fluorescence were in caudal segments (T8-T11). Together these findings reveal a strong ascending lumbar to thoracic integrating communication pathway and may represent a key feature of spinal neural network function normally. Such communication pathways should be further investigated for targeted autonomic function(s) activation and therapeutic benefit after spinal cord injury.

Loneliness is globally acknowledged as a severe and burgeoning health risk, fuelling interest in helping people of all ages form meaningful social connections. One promising approach consists of intergenerational social programs. While behavioural and qualitative evidence derived from such programs promise health and wellbeing benefits, the physiological consequences of repeated intergenerational encounters remain unknown. Insight into physiological changes will shed light on the mechanisms of social connection and inform program design choices. We charted changes in interpersonal neural synchrony (INS) in 31 intergenerational (older/younger adult) and 30 same generation (younger adult) dyads across a six-session art program. At each session, dyads completed self-report measures, drew together and alone, and had their cortical activation recorded with fNIRS. In both groups, INS was greater while dyads drew together than alone. Across sessions, intergenerational dyads' INS decreased and same generation dyads' INS increased. Further findings highlight the promise of INS as a biomarker for changes in loneliness and the development of social relationships.

Loneliness is globally acknowledged as a severe and burgeoning health risk, fuelling interest in helping people of all ages form meaningful social connections. One promising approach consists of intergenerational social programs. While behavioural and qualitative evidence derived from such programs promise health and wellbeing benefits, the physiological consequences of repeated intergenerational encounters remain unknown. Insight into physiological changes will shed light on the mechanisms of social connection and inform program design choices. We charted changes in interpersonal neural synchrony (INS) in 31 intergenerational (older/younger adult) and 30 same generation (younger adult) dyads across a six-session art program. At each session, dyads completed self-report measures, drew together and alone, and had their cortical activation recorded with fNIRS. In both groups, INS was greater while dyads drew together than alone. Across sessions, intergenerational dyads' INS decreased and same generation dyads' INS increased. Further findings highlight the promise of INS as a biomarker for changes in loneliness and the development of social relationships.

Loneliness is globally acknowledged as a severe and burgeoning health risk, fuelling interest in helping people of all ages form meaningful social connections. One promising approach consists of intergenerational social programs. While behavioural and qualitative evidence derived from such programs promise health and wellbeing benefits, the physiological consequences of repeated intergenerational encounters remain unknown. Insight into physiological changes will shed light on the mechanisms of social connection and inform program design choices. We charted changes in interpersonal neural synchrony (INS) in 31 intergenerational (older/younger adult) and 30 same generation (younger adult) dyads across a six-session art program. At each session, dyads completed self-report measures, drew together and alone, and had their cortical activation recorded with fNIRS. In both groups, INS was greater while dyads drew together than alone. Across sessions, intergenerational dyads' INS decreased and same generation dyads' INS increased. Further findings highlight the promise of INS as a biomarker for changes in loneliness and the development of social relationships.

We sought to better understand the neural representation of visual motion acceleration. A straightforward estimation of acceleration would involve calculating the rate of change of velocity, which itself would be calculated from change in position over time. As it is well-established that neurons in area MT encode velocity, the brain could thus indirectly estimate acceleration by calculating the change in MTs velocity representations. An alternate mechanism, however, could operate more rapidly and directly. In this case, the brain could exploit interactions between MTs standard motion encoding and idiosyncratic temporal dynamics of neural responses. Such direct decoding would thus exploit nonlinearities usually ignored in studies of MT coding. We tested between these two theories by measuring from ensembles of MT neurons while two male awake fixating macaques viewed linearly accelerating motion stimuli. Direct decoding of acceleration from MT was possible on faster time scales, and could be done with higher fidelity, than indirect decoding. Distinct motion acceleration information could thus be efficiently read out from rich and heterogeneous MT ensemble responses, regardless of the mechanisms that give rise to various forms of motion tuning that it exhibits. A similar analysis of activity in the medial superior temporal area (MST) did not suggest this later stage of motion processing has a more refined acceleration representation. Together, these results suggest that the brain may opportunistically exploit nonlinear idiosyncrasies of neural responses to efficiently extract behaviorally relevant information on fast time scales, instead of performing explicit calculation of some variables. Significance StatementThis study aims to understand if linear acceleration information of visual motion is extracted and represented in primate visual motion areas MT and MST. By combining large-scale multi-area neuronal recordings, population-level analyses, and a rich set of moving stimuli, we showed that linear acceleration can be decoded from MT activity. Specifically, our results demonstrate that (1) motion acceleration is encoded in MT, and can be directly and quickly decoded from MT ensemble activity, and (2) area MST, despite being a later stage of motion processing, does not refine acceleration representations. These findings call for revisiting how brain areas might efficiently extract behaviorally relevant information from the environment and highlight the importance of temporal dynamics in visual motion processing.

-synuclein (-syn) aggregation is a hallmark of synucleinopathies, a class of neurodegenerative disorders such as Parkinsons disease (PD). Several lines of evidence indicate the involvement of mitochondria in the disease pathology. Despite extensive study, the link between -syn aggregation and mechanisms of mitochondrial toxicity remains not fully understood. Using high-resolution imaging with electron microscopy, we examined cells exposed to -syn fibrils vs control cells with a focus on mitochondria. We found that upon exposure to -syn fibrils, mitochondria increase in size, cristae structure gets defects, and mitochondria enhance the budding of mitochondrial-derived vesicles (MDVs). MDV formation reflects an evolutionarily conserved mechanism reminiscent of bacterial outer membrane vesicle (OMV) biogenesis. Structural proteomics analysis by mass spectrometry corroborates this microscopy observation by identifying changes in multiple proteins that regulate cristae structure, MDV formation, and trafficking. Our results provide a new link between -syn and mitochondria and identify novel pathways responding to -syn aggregates, particularly that -synuclein directly triggers MDV generation. The processes we detected could be of interest for diagnostics and potential therapeutic interventions.

Identifying cell-autonomous and non-autonomous factors that govern retinal ganglion cells (RGCs) ability to extend axons is an important step in developing therapies to achieve recovery after optic nerve injury. Here we report that the intracellular domain of the leukemia inhibitory factor receptor (LIFR/CD118) is essential for mature RGCs ability to regenerate injured axons independent of the cognate ligand (LIF) and other therapies. Overexpression of LIFR in adult RGCs induces neurite outgrowth in cultured RGCs and axon regeneration in vivo while strongly amplifying RGCs response to LIF itself and to unrelated growth factors. Conversely, in loss-of-function studies, down-regulation of LIFR eliminates the pro-regenerative effects of Pten deletion and other potent stimuli. LIFR bidirectionally regulates the constitutive activity of the MAP kinase pathway, in contrast to LIF itself, which primarily activates pSTAT3. Expression of a truncated LIFR lacking the extracellular domain is sufficient to promote axon regeneration and selectively increases the survival of particular RGC subtypes, placing the LIFR intracellular domain as an essential, cell-autonomous regulator of optic nerve regeneration.

Noninvasive neuromodulation enables brain stimulation without surgery but requires precise optimization of stimulation parameters to ensure efficacy and safety. Direct testing on human or animal subjects is costly, time intensive, and constrained by ethical and safety considerations. To address these challenges, a low-cost, versatile brain phantom was designed to emulate key biophysical properties across multiple neuromodulation modalities. The phantom was fabricated using ground beef, sodium alginate, and starch, and cast within a custom 3D printed mold. A multimodal test platform was created and validated by integrating established principles from low-intensity focused ultrasound (LIFU), transcranial direct current stimulation (tDCS), and thermal phantom design. Numerical simulations predicted a LIFU peak negative pressure of 0.631 MPa, closely matching the target Pr.3 value, with negligible temperature elevation (<0.01 {degrees}C). Consistent with prior reports, tDCS exposure did not induce lasting alterations in the phantoms physical or electrical properties. The electrical conductivity was 0.11{+/-}0.02 S/m, reflecting water saturation within the phantom matrix; the thermal conductivity averaged 0.557 W/(mK), consistent with reported values for brain tissue analogs. This study primarily evaluated LIFU and tDCS performance; future work should extend characterization to additional modalities such as deep brain stimulation and transcranial magnetic stimulation. Further assessment of the phantoms optical properties would also facilitate photobiomodulation and photoacoustic imaging studies. Overall, this inexpensive, easily fabricated phantom presents a practical and adaptable platform for multimodal neuromodulation research and parameter optimization.

Neuronal plasticity, essential for learning and memory, involves structural changes triggered by neurotrophic factors such as brain-derived neurotrophic factor (BDNF). BDNF activates its receptor, TrkB, to induce local and long-distance signaling, promoting dendritic branching. While BDNF activation of the mechanistic target of rapamycin (mTOR) pathway is well-documented in dendritic spines, its role in axons remains unclear. Using compartmentalized cultures of embryonic cortical neurons from mice, this study demonstrates that axonal BDNF triggers mTOR-dependent phosphorylation of translation regulators (4E-BP1 and S6), driving local protein synthesis. Fluorescent labeling, immunostaining, and radial microfluidic chambers were employed to isolate axonal compartments and assess local translation. Axonal BDNF increased Rab5 protein translation in a TrkB- and mTOR-dependent manner, highlighting the importance of localized protein synthesis for axonal trafficking. Furthermore, axonal protein synthesis was required for retrograde transport of internalized cargoes and CREB activation in the nucleus, linking local translation to long- distance signaling. These findings highlight the crucial role of axonal mTOR activation in regulating local proteostasis and neuronal function, offering new insights into axonal trafficking mechanisms and their implications for neuroplasticity. This work advances our understanding of how mTOR activation in axons and localized translation induced by BDNF are essential for axonal transport and efficient signaling in cortical neurons.

Internal states like hunger, pain, thirst and arousal can bias behavior by affecting sensory and memory processing. Internal states are critical to understand in the context of alcohol addiction because they influence cravings, reinstatement, and relapse. Norepinephrine plays a key role in both hunger and alcohol-induced arousal and preference, but the circuit-level mechanisms through which it modulates the influence of hunger on alcohol preference are not well understood. We sought to address this using intersectional genetic tools for manipulating neurons expressing octopamine, the invertebrate analogue of vertebrate norepinephrine. We identified a single octopamine neuron required for ethanol seeking only when Drosophila are food-deprived. Hunger increased baseline activity in this neuron, making it more responsive to an odor cue previously paired with ethanol. A combination of genetic and connectome analyses revealed that synaptic partners of this octopaminergic neuron form a functional module that acts on Drosophila memory circuitry. Thus, we show that hunger recruits a parallel circuit that drives learned ethanol preference, providing a neuronal framework through which internal state influences the expression of memory for ethanol-associated cues.

Psychedelics, particularly psilocybin, have shown therapeutic potential across several psychiatric conditions, including depression, anxiety, obsessive-compulsive disorder, and anorexia nervosa (AN). These disorders often share social deficits that may be effectively alleviated by psychedelics considering their use has been linked with emotional empathy and enhanced social cognition. However, the mechanisms through which psychedelics alter social behaviour are unclear, and mechanistic studies in animal models have largely focused on male subjects. This is problematic for understanding the therapeutic effects relevant for disorders that predominantly affect females, such as AN. Here, we used the activity-based anorexia (ABA) mouse model to examine the effects of a single psilocybin dose on social behaviour in female mice and compared outcomes to mice exposed to food restriction (FR), exercise (RW) or standard housing (Controls). Together with these metabolic stressors, we also investigated the effects of psilocybin on the circulating proinflammatory cytokine interleukin-6 (IL-6), which is implicated in AN and is suppressed by psychedelics. Psilocybin did not alter sociability in ABA, RW, or FR mice but increased preference for familiarity in Controls. Novelty-seeking behaviour was elevated in both ABA and RW groups, although with distinct social patterns. Psilocybin elevated IL-6 levels in RW mice, which was positively correlated with preference for novelty. No such relationships were found in ABA or FR groups. These findings reveal subtle, context-dependent effects of psilocybin on social behaviour and inflammation in female mice, highlighting the need to clarify its temporal, neuroplastic, and immune-related mechanisms across sexes and disease models.

Motor and declarative memory systems have been traditionally considered distinct. However, a study by Mosha and Robertson (2016) reported striking evidence of generalisation between motor and declarative learning. Specifically, learning improved if the current task (e.g. motor sequence) shared the same high-level ordinal structure as an earlier task (e.g. word list), demonstrating cross-domain transfer of unstable memories. This finding has significant implications for our understanding and conceptualisation of memory taxonomies but has not been replicated. Here, healthy adult participants (N = 125) completed a word list and motor sequence task in counterbalanced order with either a shared or distinct sequence structure. In contrast to Mosha & Robertson (2016), we found that a shared ordinal structure between the declarative and motor sequence tasks did not facilitate performance. Overall, our results challenge the robustness of cross-domain generalisation, and underscore the complexity of cross-memory interactions.

Replay activities in the hippocampus and other brain regions during sharp-wave ripples (SWRs) are thought to play important roles in learning, memory, and planning. Surprisingly, the question of how to characterize the dynamical structure of replay remains controversial. Standard methods rely on restrictive assumptions for detecting replay events with high sequentiality, and they have substantial drawbacks. To fill this gap, we develop a flexible and highly interpretable computational framework based on state-space modeling to understand the dynamics of replays. This framework is motivated by the basic idea that sequential structures can be modeled using drift-diffusion dynamics. The two parameters (i.e., drift & diffusion parameters) can be directly mapped to the speed and variability of a replay event, respectively. To capture the potentially rich neural dynamics during SWRs, our model allows the switching between several well-motivated types of dynamics. The resulting framework enables precise and unambiguous interpretations of the dynamics of SWR events. Applications of our method to population recordings from the rat hippocampus lead to insights into a number of important open questions, including: (i) whether the speed of most replay events is comparable to real-world running; (ii) whether replays follow random walk; (iii) whether "preplay" events exist. More broadly, accurate characterizations of replay dynamics may lead to a better understanding of the role of replay under normal and abnormal conditions.

Inter-brain synchronization (IBS) - reflecting inter-individual correlated neural activity during interaction - marks shared experiences like music listening. The ability of complex auditory stimuli (e.g., music) to induce IBS links to their information dynamics, notably the uncertainty they evoke, which challenges the nervous systems predictive coding. Based on mutual prediction theory (interacting individuals simultaneously process their own behavior and predict their partners; accurate mutual predictions lead to convergent neural representations and thus IBS), this study hypothesized that higher stimulus uncertainty enhances IBS (heightened uncertainty reduces independent predictability, promoting convergent representations and stronger IBS). Using information entropy to quantify uncertainty, the study conducted hyperscanning, manipulated entropy across Resting State and 6 Hz auditory stimuli (ASSR, MMN, AHER, Dream Wedding), and measured IBS via phase-locking values (PLV). Results showed frequency specificity: 6 Hz PLV increased with entropy (DW {approx} AHER > MMN {approx} ASSR > Resting State); Alpha band had highest PLV in Resting State. Critically, PLVs differed significantly between any two conditions, and each experimental conditions PLV was also significantly different from that of the Resting State. Findings confirm a 6 Hz-specific positive association between auditory uncertainty and IBS, suggesting musical elements may facilitate social interaction by modulating entropy, with entropy-IBS relations showing frequency dependence.

Inflammatory joint pain features in numerous musculoskeletal disorders that affect millions globally. The Prdm12 gene encodes a conserved zinc finger transcriptional regulator expressed selectively in the nervous system. In humans, PRDM12 mutations can cause congenital insensitivity to pain (CIP) or midface toddler excoriation syndrome (MiTES). Prdm12 is prominently expressed in developing somatosensory ganglia, where it plays a crucial role in nociceptive neuron development, its expression being maintained in mature C-LTMRs (C-low threshold mechanoreceptors) and nociceptive neurons. Despite enhanced understanding of Prdm12s role in neuronal excitability and pain behavior, the impact of Prdm12 overexpression in mature nociceptive neurons has not been explored. Here, we conducted intravenous injection of AAV-PHP.S viral vectors encoding Prdm12-GFP (Prdm12-AAV) or GFP alone (Control-AAV), observing no overt changes in mouse behavior. When examining the properties of Prdm12 overexpressing sensory neurons in vitro, we observed an increase in rheobase alongside decreased neuronal responses to capsaicin and ATP, indicating a downregulation of TRPV1 and P2X ion channels activity, respectively. We next conducted intraarticular administration of viral constructs in female mice to determine how Prdm12 overexpression in knee-innervating sensory neurons alters their excitability and influences inflammatory joint pain induced by intraarticular administration of complete Freunds adjuvant (CFA). Prdm12 overexpression in knee-innervating neurons decreased inflammation-induced changes in digging and weight bearing, prevented inflammation-induced neuronal hyperexcitability, and decreased macroscopic voltage-gated ion channel conductance. Our findings illustrate that Prdm12 overexpression strongly modulates neuronal excitability in adult animals, highlighting its importance in pain perception and its potential as an analgesic target. SummaryOverexpression of the transcriptional regulator Prdm12 in knee-innervating neurons of mice reduces inflammatory joint pain and counteracts inflammation-induced neuronal hyperexcitability.

Inflammatory joint pain features in numerous musculoskeletal disorders that affect millions globally. The Prdm12 gene encodes a conserved zinc finger transcriptional regulator expressed selectively in the nervous system. In humans, PRDM12 mutations can cause congenital insensitivity to pain (CIP) or midface toddler excoriation syndrome (MiTES). Prdm12 is prominently expressed in developing somatosensory ganglia, where it plays a crucial role in nociceptive neuron development, its expression being maintained in mature C-LTMRs (C-low threshold mechanoreceptors) and nociceptive neurons. Despite enhanced understanding of Prdm12s role in neuronal excitability and pain behavior, the impact of Prdm12 overexpression in mature nociceptive neurons has not been explored. Here, we conducted intravenous injection of AAV-PHP.S viral vectors encoding Prdm12-GFP (Prdm12-AAV) or GFP alone (Control-AAV), observing no overt changes in mouse behavior. When examining the properties of Prdm12 overexpressing sensory neurons in vitro, we observed an increase in rheobase alongside decreased neuronal responses to capsaicin and ATP, indicating a downregulation of TRPV1 and P2X ion channels activity, respectively. We next conducted intraarticular administration of viral constructs in female mice to determine how Prdm12 overexpression in knee-innervating sensory neurons alters their excitability and influences inflammatory joint pain induced by intraarticular administration of complete Freunds adjuvant (CFA). Prdm12 overexpression in knee-innervating neurons decreased inflammation-induced changes in digging and weight bearing, prevented inflammation-induced neuronal hyperexcitability, and decreased macroscopic voltage-gated ion channel conductance. Our findings illustrate that Prdm12 overexpression strongly modulates neuronal excitability in adult animals, highlighting its importance in pain perception and its potential as an analgesic target. SummaryOverexpression of the transcriptional regulator Prdm12 in knee-innervating neurons of mice reduces inflammatory joint pain and counteracts inflammation-induced neuronal hyperexcitability.

Psychedelic compounds have the ability to generate altered states of consciousness and profoundly distort perception, often resulting in visual hallucinations. While psychedelics have recently regained attention for their potential cognitive and therapeutic effects, how these drugs affect visual processing to generate visual distortions and hallucinations is not as well characterized. Furthermore, studies investigating the effect of psychedelics on visual function have all been performed using head-fixed preparations, preventing animals from engaging in the natural visual behaviors that the visual system evolved to support. To determine the impact of psychedelics on active vision, we recorded neural activity in primary visual cortex (V1) of mice during free movement, while simultaneously recording eye and head position, before and after administration of the serotonergic psychedelic DOI (2,5-dimethoxy-4-iodoamphetamine). We find that DOI increases the frequency of visual active sensing behaviors during free movement and leads to a net reduction in the visually-evoked activity that these behaviors generate in V1. The effect of DOI was highly diverse across the population of V1 neurons, driving suppression and facilitation of visual responses in a laminar specific manner. Finally, the effects of DOI were dependent upon both visual input and the statistics of the stimulus. We found a striking dissociation between impact on gaze shift responses and flashed sparse noise presented during head-fixation, which may reflect predictability of the stimulus. These findings provide insights into how psychedelics disrupt sensory processing and the neural mechanisms underlying these altered perceptual states. HighlightsO_LIWe recorded neural activity from the primary visual cortex (V1) of freely moving mice before and after administration of the psychedelic DOI. C_LIO_LIDuring free movement, DOI increased the frequency of active sampling behaviors but left the structure of these behaviors intact. C_LIO_LIThe effect of DOI on visual responses following visual active sensing behaviors during free movement was on average suppressive but highly variable on a cell by cell basis. C_LIO_LIDOI did not alter the coarse-to-fine temporal pattern of visual activity in V1 that is evoked by gaze shifts. C_LIO_LIThe effect of DOI was larger on responses to a head-fixed sparse noise stimulus than to freely-moving gaze shifts, perhaps due to its unpredictability. C_LI

Adolescence is a window of heightened vulnerability to the neurotoxic effects of binge ethanol exposure. Adolescent intermittent ethanol (AIE) exposure has been shown to induce long-lasting cognitive and behavioral impairments in patients and rodent models that increase the risk of developing alcohol use disorder (AUD). Our previous work shows that these behavioral deficits coincide with persistent dysfunction of astrocytes. Here, we aim to understand how astrocyte-synaptic structural and functional crosstalk are disrupted following AIE to provide better mechanistic understanding of why behavioral impairments persist into adulthood. Male Sprague-Dawley rats received AIE, a variety of adeno-associated viruses encoding astrocyte-specific sensors, and fiber implantation in the dorsal hippocampal (dHipp) for in vivo photometry. A subset of rats received hM3D(Gq) to chemogenetically activate astrocytes. Following AIE and a forced abstinence period that allowed growth into adulthood, rats underwent assessment in the contextual fear conditioning (CFC) task with simultaneous fiber photometry recordings. By combining immunohistochemistry (IHC), Stimulated Emission Depletion (STED) microscopy, fiber photometry, chemogenetics, and slice physiology, we show that AIE induces structural and functional decoupling of astrocytes from synapses and astrocyte dysregulation that persists into adulthood. Remarkably, stimulating astrocytic calcium signaling via chemogenetic activation attenuates heightened fear responding and restores gliotransmitter availability. These findings highlight a critical role for astrocyte-synaptic crosstalk in regulating fear learning and underscore the untapped therapeutic potential of targeting astrocytes to improve behavioral outcomes following substance use.

BACKGROUNDGenetic susceptibility is a major determinant in intracranial aneurysm (IA) formation and rupture, yet the underlying mechanisms linking genetic variation to vascular dysfunction remain largely unknown. We have identified mutations in ARHGEF17, a guanine nucleotide exchange factor that regulates RhoA activation and cytoskeletal organization, as potential risk variants for IA. Given ARHGEF17s regulatory role in endothelial barrier integrity and actin remodeling, we hypothesized that ARHGEF17 deficiency promotes IA pathogenesis through dysregulation of the RhoA/ROCK2/MLC signaling axis, leading to endothelial dysfunction and vascular wall instability. METHODSCRISPR-Cas9-mediated ARHGEF17 knockout (ARHGEF17-/-) mice and morpholino-based ARHGEF17-deficient zebrafish were established to assess the in vivo vascular effects of ARHGEF17 loss. An intracranial aneurysm model combining elastase injection and deoxycorticosterone acetate (DOCA)-induced hypertension was used to evaluate aneurysm incidence, rupture rate, and survival. Structural remodeling of the Circle of Willis (CoW) was assessed by Victoria Blue, EVG, and Picrosirius Red staining, as well as immunofluorescence for -SMA, OPN, CD31, and inflammatory markers. Complementary in vitro studies were performed in HUVECs using lentiviral ARHGEF17 silencing (three shRNAs of varying efficiency) to examine endothelial proliferation, migration, tube formation, and barrier function (TEER). Activation of RhoA/ROCK2/MLC signaling was quantified by G-LISA and Western blotting. The ROCK inhibitor Y-27632 (10 M) was applied to determine pathway dependence. RESULTSARHGEF17-/- mice exhibited a significantly higher incidence and rupture rate of intracranial aneurysms, accompanied by fragmentation of elastic fibers, loss of collagen organization, vascular smooth muscle cell dedifferentiation, and robust inflammatory activation in the CoW. Zebrafish lacking ARHGEF17 showed frequent intracranial hemorrhage and compromised vascular wall integrity, further confirming ARHGEF17s role in cerebrovascular stability. In ECs, ARHGEF17 knockdown impaired proliferation, migration, tube formation, and barrier integrity in a silencing-efficiency-dependent manner. Mechanistically, ARHGEF17 deficiency activated the RhoA/ROCK2/MLC pathway, leading to increased phosphorylation of MLC and MYPT1 and disorganization of F-actin and junctional proteins. Pharmacological inhibition with Y-27632 restored endothelial function, normalized cytoskeletal structure, and re-established junctional continuity, indicating a ROCK2-dependent mechanism. CONCLUSIONSOur findings establish ARHGEF17 as a critical regulator of cerebrovascular integrity and identify RhoA/ROCK2/MLC mediated cytoskeletal remodeling as the mechanistic link between ARHGEF17 deficiency and aneurysm pathogenesis. Loss of ARHGEF17 compromises endothelial barrier function, triggers vascular inflammation, and promotes aneurysm formation and rupture. Importantly, ROCK inhibition rescues endothelial dysfunction, highlighting the RhoA/ROCK2/MLC axis as a promising therapeutic target for ARHGEF17 mutation-associated intracranial aneurysms.

Notch filters can alter color contrasts by selectively filtering different spectral bands of the stimulus and have been developed to enhance reddish-greenish contrasts for color-deficient observers with anomalous trichromacy. We examined the effects of such filters on color salience for normal trichromats, using a visual search paradigm where the task was to locate a color target superimposed on a variegated chromatic background, similar to foraging for fruits among foliage. Background colors varied along a bluish-yellowish or purpliish to yellow-green (short-wave cone isolating) axis, roughly spanning the range of dominant color variations in arid or lush environments. Target colors sampled a wide range of hue angles and contrasts. Testing was conducted on a computer monitor, with the filter effects simulated by calculating corresponding chromaticities with or without the filter for naturalistic (Munsell) reflectances. The filter evaluated (Enchroma SuperX(R) glasses) was designed to increase color contrast along a magenta-green axis. Consistent with this, search times for targets on the blue-yellow background were significantly faster for the filter condition, because the filter increased the target-background color difference. Alternatively, overall differences in search times were not observed for the S-cone background. The differences on the two backgrounds could be qualitatively accounted for by the relative salience of the stimuli predicted by a perceptual color space (CIELAB). Our results demonstrate the efficacy of the filters for enhancing visual performance for normal trichromats and naturalistic tasks, and illustrate how these effects depend on the potential color characteristics of the environment.

Tauopathies are a group of neurodegenerative disorders, including Alzheimers disease, frontotemporal dementia, and progressive supranuclear palsy, characterized by the pathological accumulation of tau protein. While tau reduction has emerged as a promising disease-modifying strategy, most preclinical studies have focused on preventive approaches, and the therapeutic potential after clinical onset remains largely unexplored. This limitation is critical, as patients are typically diagnosed after symptoms emerge. Furthermore, global tau suppression may disrupt physiological tau functions and lead to adverse effects, underscoring the need for targeted interventions. RNA-based therapies, particularly microRNA (miRNA)-mediated silencing, offer high specificity, versatility, and sustained target knockdown. Here, we developed artificial microRNAs (Tau-miRNAs) designed for site-directed expression to selectively reduce tau levels in vulnerable brain regions, thereby minimizing off-target effects. We tested the efficacy of Tau-miRNAs in a tauopathy mouse model at advanced disease stages, delivering them into the prefrontal cortex after cognitive and electrophysiological deficits had developed. This post-symptomatic intervention led to long-term improvements in memory, restoration of neuronal firing properties, and reduced pathological tau at synapses. Our findings highlight the therapeutic potential of spatially targeted RNA-based tau-lowering strategies for late-stage intervention in tauopathies, addressing a critical unmet need in the treatment of these devastating disorders.

Cortico-thalamo-cortical oscillations are central to both normal and pathological brain activities and emerge from complex cortical and thalamic interactions. However, the specific activity of identified cortical neurons during the paroxysmal oscillations associated with absence seizures (ASs) in awake animals remains underexplored. The dominant narrative suggests that seizures indiscriminately disrupt cortical activity through generalized hyperexcitability, but direct evidence supporting this view is lacking. Here, we recorded single units from pyramidal neurons and different interneuron subtypes in the neocortex of two validated rodent models of absence epilepsy under awake, behaving conditions. We find that neurons maintain their firing rank order across interictal and ictal states, regardless of whether their ictal firing rate increases, decreases, or remains stable compared to the interictal phase. Rather than a random cortical takeover, ictal activity represents a scalable modulation of pre-existing network states. These results challenge the generalized hyperexcitability model and highlight the structured, heterogeneous nature of cortical activity during ASs, with implications for mechanistic understanding and targeted therapies.

Mind blanking (MB) is a mental state of seemingly no reportable thought content. The question of how we can entertain no thoughts while awake is challenging for the study of spontaneous thinking. By combining EEG-fMRI with experience sampling during task performance, we categorised changes in mental content and self-reported vigilance to map the neurophysiological signatures of MB. We demonstrate that fMRI connectivity around MB reports is characterised by a "rich" pattern of long and short-range signal anticorrelations. At the same time, sleepiness reports are linked to a "simpler" hyperconnected fMRI pattern, characterised by overall positive connectivity. Put together, an interaction appears: when people report being alert, connectomes around MB reports resemble the hyperconnected pattern, indicating that the neuronal correlates of MB depend on self-rated vigilance. The hyperconnected pattern also correlated with EEG slow-wave activity, tying MBs topology to sleep-like electrophysiology during wakefulness. Collectively, we show that distinct cortical events underlie the shared phenomenology of a thought-free mind. We conclude that MBs neurophysiological correlates vary across perceived vigilance levels and that more refined characterisation of the neuronal correlates of thought-less mental states exist. Our findings build on the quest to bridge mental content and its absence with measurable brain activity and provide insights into how ongoing thinking is maintained during wakefulness.

Determining if repeat associated non-AUG (RAN) proteins contribute to the CAG polyGln-encoding spinocerebellar ataxias (CAG-SCAs) is critical for understanding mechanisms and developing therapies for these diseases. Immunohistochemistry using antibodies against polySer and polyLeu repeats and locus specific C-terminal regions show sense polySer (AGC frame) and antisense polyLeu (CUG frame) RAN proteins accumulate in affected grey and white-matter brain regions, throughout the cerebellum and pons, in SCA1, SCA2, SCA3, SCA6, and SCA7 autopsy brains. Cerebellar white matter regions with prominent polySer and polyLeu but minimal polyGln aggregates show demyelination, white matter loss, and activated microglia. In SCA3 mice, RAN proteins accumulate in an age-dependent manner. In neural cells, polySer and polyLeu RAN proteins are toxic and cause autophagic dysfunction. In cells, the FDA-approved drug metformin decreases RAN protein levels and reduces toxicity. Taken together, these data identify sense and antisense RAN proteins as a common molecular mechanism shared by the CAG-SCAs.

Each stage of neuronal development (i.e., proliferation, differentiation, migration, neurite outgrowth and synapse formation) requires functional and highly coordinated metabolic activity to ultimately ensure proper sculpting of complex neural networks. Energy deficits underlie many neurodevelopmental, neuropsychiatric and neurodegenerative diseases implicating mitochondria as a potential therapeutic target. Iron is necessary for neuronal energy output through its direct role in mitochondrial oxidative phosphorylation. Iron deficiency (ID) reduces mitochondrial respiratory and energy capacity in developing hippocampal neurons, causing permanently simplified dendritic arbors and impaired learning and memory. However, the effect of ID on early axonogenesis has not been explored. We used an embryonic mixed-sex primary mouse hippocampal neuron culture model of developmental ID to evaluate mitochondrial respiration and dynamics and effects on axonal morphology. At 7 days in vitro (DIV), ID impaired mitochondrial oxidative phosphorylation capacity and stunted growth of both the primary axon and branches, without affecting branch number. Mitochondrial motility was not altered by ID, suggesting that mitochondrial energy production --- not trafficking --- underlie the axon morphological deficits. These findings provide the first link between iron-dependent neuronal energy production and early axon structural development and emphasize the importance of maintaining sufficient iron during gestation to prevent the negative consequences of ID on brain health across the lifespan. Significance StatementThis study used a primary mouse hippocampal neuron culture model of iron deficiency to address an important gap in knowledge of how disruption of iron-regulated mitochondrial activities affects axonal development. After axon initiation but prior to rapid dendrite outgrowth, iron chelation reduced mitochondrial oxidative phosphorylation capacity and stunted the growth of the primary axon and branches but without affecting branch number. Mitochondrial motility was not altered in iron-deficient axons, indicating that reduced neuronal energetic capacity and not impaired axonal mitochondrial trafficking may underlie these morphological deficits. Both iron and mitochondrial dyshomeostasis underlies many neurodevelopmental, neuropsychiatric, and neurodegenerative disorders, which can have origins during the period of fetal-neonatal development when rapid axon growth/branching occurs. This study highlights the importance of advancing knowledge on the effects of mitochondrial deficits in early life as it pertains to optimizing brain health throughout the lifespan.

It is widely believed that the gliogenic switch during rodent embryonic development is governed by the orchestrated crosstalk between a cohort of genes and extracellular cues. Here we report that ectopic expression of the single bHLH factor, pancreas transcription factor 1 (PTF1A), is sufficient to drive radial glial progenitors (RGPs)-regardless of progenitor heterogeneity and developmental stage-to differentiate into glial cells. Ptf1a- expressing RGPs exhibit progenitor behaviors indicative of a neurogenic-to-gliogenic fate transition, resembling endogenous progenitors at the late stages of embryonic development, and preferentially produce OLIG2+ oligodendrocytes in vivo, some of which are positive for PDGFR or CC1. This robust gliogenic competency depends on the dosage of stable Ptf1a expression in RGPs. RNAseq reveals the glial transcriptome, including upregulated expression of several notch signaling components and the endothelin receptors in Ptf1a RGPs. We further identify Ednrb as one of the downstream targets of Ptf1a that directs RGPs toward gliogenesis via the ERK1/2 signaling pathway. In summary, our study uncovers a novel and robust role for Ptf1a in glial fate specification, offering a potential strategy for generating human oligodendrocytes in vitro.

Long-term potentiation (LTP), the best-characterized form of Hebbian synaptic plasticity, is well known to be under strong circadian regulation. In mice and rats, both nocturnal species, most studies indicate that LTP in the hippocampal CA1 region is more robust when induced during the dark phase. Our examination of the underlying mechanisms at the CA3 to CA1 synapse provides evidence that the capacity to express LTP does not differ between the light and dark cycles of the 24-hour day. Instead, the magnitude of theta-burst stimulation-induced LTP (TBS-LTP) correlates with daily fluctuations in the ratio of synaptic excitation to inhibition (E/I ratio): both the E/I ratio and TBS-LTP are higher during the dark phase. Consistent with a causal relationship, blockade of inhibition abolishes the light-dark difference in TBS-LTP induction, likewise, pairing-induced LTP, which is less constrained by inhibitory recruitment, does not differ between cycles. Supporting this model, using the APP/PS1 model of AD we observed that neither the E/I ratio nor TBS-LTP change during the light cycle. Finally, we made the intriguing observation that these daily oscillations reverse direction after puberty in WT mice, shifting from being larger in the dark cycle of 2-month-old mice to being larger in the light cycle in 8-month-old mice. This developmental switch may reflect an age-dependent reorganization of circadian control over hippocampal plasticity.

Detecting salient visual objects and orienting toward them are commonplace tasks for animals, yet the underlying neural circuit mechanisms remain poorly understood. The fruit fly is an ideal model for a comprehensive analysis of feature detection mechanisms given its complete synaptic wiring diagrams, robust behavioral assays, and cell-type-specific gene expression datasets. We previously showed that columnar visual neurons T3 are required for saccadic orientation toward landscape features during flight. Here, we examine how signals downstream of T3 are processed in the central brain. We identify the LC17 type of visual projection neurons as key postsynaptic targets: they receive strong excitatory input from T3, project to premotor brain regions, and are thus positioned to support visual approach. Using in vivo optical physiology and virtual reality behavior, we demonstrate that LC17 neurons are indeed necessary for object tracking during flight. Furthermore, we find that electrical synapses in LC17 are also required for tracking behavior. Accordingly, we show that the innexin Shaking B (shakB) is highly expressed in LC17 dendrites, and genetic perturbations confirm an essential role for gap junctional coupling in this circuit. Our findings reveal mechanisms underlying visual approach, and highlight the interplay between electrical and chemical neurotransmission for rapid object detection and action selection.

Glioblastoma (GBM) is a highly heterogenous and malignant brain tumor, in part because it disrupts normal brain circuits to fuel its own growth and invasion. Thus, there is a need to identify the molecular features of invasive GBM cells and their regulators in the neural microenvironment. To address this in a fully human model, we engrafted patient-derived GBM cells (total n=15 independent samples) from three sources-- fresh neurosurgical resections, cell lines, and whole GBM organoids--into human induced pluripotent stem cell-derived organoids patterned to forebrain, midbrain, and spinal cord identities. GBM cells from all sources infiltrated brain organoids within 2 days post-engraftment, reaching maximal invasion by day 14. Across organoids of distinct spatial and maturational milieu, GBM cells showed a consistent reduction in astrocyte-like states and an enrichment in neuron/glia progenitor-like (NPC-like) states. These NPC-like GBM cells expressed neuronal and synaptic machinery, and tumors enriched in this transcriptomic state prior to engraftment achieved greater organoid coverage, suggesting enhanced infiltration and synaptic integration of this GBM cell type. Although GBM cell states converged across organoid types after engraftment, infiltration was greater in the forebrain than spinal cord. This is likely reflective of synaptic input from deep-layer TBR1 excitatory neurons in the forebrain, as demonstrated by a combination of rabies-based monosynaptic tracing and single-cell transcriptomics. In contrast, inhibitory neurons were the predominant synaptic partners of GBM in the spinal cord. Together, this fully human model of the neural-GBM connectome reveals how neuron-like GBM states and regionally distinct synaptic inputs cooperatively shape tumor invasion.

Relapse vulnerability in substance use disorder (SUD) is primarily driven by cue-induced activation of neurons within the nucleus accumbens core (NAcore), among other contributing factors. Neuronal ensembles within the NAcore, defined here as selectively co-activated neurons during specific behavioral experiences, are essential during cocaine sensitization and recall. While transient synaptic plasticity (t-SP) has been widely observed in general neuronal populations within the NAcore during reinstatement, its ensemble-specific dynamics remain unclear. Here, we used c-Fos-TRAP2-based tagging to identify cocaine-seeking ensembles in mice following cocaine intravenous self-administration, extinction, and cue-induced reinstatement. Structural spine plasticity was assessed via confocal microscopy, and functional changes were measured using whole-cell electrophysiology across multiple reinstatement time points. Ensemble neurons exhibited enhanced dendritic spine head diameter (dh) and AMPA/NMDA (A/N) ratios following cue exposure, consistent with t-SP. Notably, spine classification revealed a reduction in mature spines during reinstatement, suggesting morphological remodeling rather than new spine formation in both ensemble and non-ensemble cells. Non-ensemble neurons exhibited classical functional transient synaptic plasticity, characterized by increased A/N ratios but no significant changes in dh. To begin assessing if presynaptic vesicle release impacts t-SP, paired-pulse ratio analysis indicated no differences in population or time point. Importantly, ensemble neurons displayed elevated A/N ratio following cocaine exposure, suggesting prior silent synapse maturation. These findings demonstrate that t-SP is not uniformly distributed across NAcore neurons but differs significantly between ensemble and non-ensemble neurons. By linking ensemble identity to both structural and functional plasticity, this study refines our understanding of cue-induced relapse mechanisms. Significance StatementRelapse in substance use disorder is strongly driven by cue-induced reactivation of neuronal ensembles in the nucleus accumbens core. While transient synaptic potentiation has been widely described in bulk neuronal populations within the nucleus accumbens core, its ensemble-specific expression has remained unclear. Here, we combined c-Fos-TRAP2 tagging, confocal imaging, and slice electrophysiology to show that transient synaptic potentiation is selectively expressed in behaviorally relevant ensembles. By linking ensemble identity with structural and functional plasticity during cue-induced cocaine seeking, these findings refine current models of relapse and identify ensemble-specific plasticity as a potential target for therapeutic intervention.

BackgroundMultivariate pattern analysis (MVPA) has become an increasingly important method for decoding distributed brain activity from neural electrophysiological recordings by leveraging both temporal and spatial features. These multivariate approaches have proven important for both cognitive neuroscience and brain-computer interfaces. MVPA might benefit from magnetoencephalography (MEG) systems based on optically pumped magnetometers (OPMs), as these sensors can be placed closer to the scalp, providing higher spatial resolution compared to conventional MEG systems that rely on superconducting quantum interference devices (SQUIDs). As OPM-based MEG systems become available at more institutions, it is essential to experimentally compare their performance with traditional SQUID-based systems using MVPA. MethodsWe adapted a visual object-word paradigm from a previous study, originally implemented on a TRIUX MEGIN SQUID system, to the FieldLine HEDscan OPM system. Participants were recruited and we recorded their ingoing brain activity while did the same task in both systems. Visual stimuli of different objects were presented alternately in two modalities: pictures and the corresponding written words. For each modality, MVPA was used to classify the objects from OPM and SQUID magnetometers data respectively. To further investigate the advantages of OPM, we evaluated the effect classification accuracy of two spatial factors by controlling the number of sensors included and the spatial frequency content of the sensor data. ResultsWe found higher time-resolved decoding accuracy for the OPM compared to the SQUID data. Moreover, OPMs show higher classification performance compared to SQUIDs when controlling for the same number of sensors; consistently, the OPM system required fewer sensors to reach the performance limit of the SQUID system. Our analysis considering the spatial frequency content of the signal revealed that decoding accuracy plateaued for the SQUID system at lower spatial frequencies while the performance of the OPM system continued to improve when higher-order spatial components were included. ConclusionOur OPM-MEG system outperformed the SQUID-MEG system on MVPA on decoding of visual processing. This advantage of OPM is driven by its higher spatial resolution, resulting from the sensors being positioned closer to the head and thus able to capture higher spatial frequency components of the brain signal. OPM may facilitate cognitive neuroscience research as well as brain-computer interfaces by providing higher sensitivity when employing paradigms using multi-variate data analysis.

Quantal synaptic transmission in vestibular end-organs is glutamatergic. Although genetic deletion of Slc17a8 (termed Vglut3) leads to deafness in mice, the dependence of vestibular function on VGLUT3-mediated quantal transmission is unknown. Here, we investigated the vestibular phenotype of Vglut3-/- mice at the cellular, systems, and behavioral levels. The type-II vestibular hair cells (VHCs) in Vglut3+/+mice were strongly immunoreactive for VGLUT3, while type-I VHCs showed poor immunoreactivity. In Vglut3-/- mice quantal synaptic transmission in utricular calyces was reduced in rate and amplitude by > 95%. In vivo recordings of spontaneous activity in the vestibular nerve revealed similar action potential rates and regularity in Vglut3+/+and Vglut3-/- mice, suggesting a divergent underlying mechanism compared to the silent Vglut3-/- auditory nerve. In behavioral studies, Vglut3-/- mice did not exhibit considerable sensorimotor or balance deficits. Collectively, these data support the view that non-quantal transmission is the predominant mode of neurotransmission between type I VHCs and vestibular calyceal afferent neurons. We propose that non-quantal transmission alone underlies the apparently normal vestibular nerve physiology and behavioral function in Vglut3-/- mice.

BackgroundHuntingtons disease (HD) is a hereditary life-threatening disease marked by progressive neuronal loss and atrophy of grey matter structures, particularly the caudate putamen. Brain imaging studies have revealed that the degradation of the white matter occurs many years prior to symptomatic onset and neuronal loss, suggesting that the decay of brain white matter is an active contributor to the disease progression. However, the mechanisms by which the HD mutation triggers white matter loss is not well understood. MethodsWestern blot, immunohistochemistry, and electron microscopy were conducted to assess white matter pathology and explore the relevant mechanisms in CAG140 knock-in mice, which express the HD protein in the same way as patients suffering from HD and thus biologically replicate HD in human. ResultsWestern blot analysis of proteins localized at different layers of the myelin coat revealed that the myelin-associated glycoprotein (MAG), which is localized at the innermost layer of the myelin coat and essential for maintaining the periaxonal space and the integrity of the myelin sheath, manifested as an early and progressive decline in HD mouse caudate putamen. The loss of MAG was detected at myelinated axons and in fiber bundles in HD mouse brains at an age when the abundance of myelinated axons was normal. Fluorescence immunohistochemical studies found that MAG labeling was concentrated in the soma of a subset of oligodendrocytes, which expressed breast carcinoma amplified sequence 1, a marker for new oligodendrocytes. While their abundance was normal, new oligodendrocytes in HD mouse caudate appeared to be impeded in acquiring the expression of MAG and in targeting MAG away from perinuclear punctate structures to processes, signs of impaired maturation. Compared with those in wildtype mouse brains, oligodendrocytes in HD mouse brains had a reduced abundance of small vesicles whereas an increased abundance of large punctate structures in the perinuclear region, implying defective generation of small vesicles transporting MAG from large punctate structures in the soma to processes. The MAG-containing perinuclear punctate structures were negative for proteins specifying trans-Golgi networks, early endosomes, or exosomes but had a minor portion labeled with lysosome-associated membrane protein 1, indicating that the structures where MAG accumulates in the soma are derived from the late endosomal lysosomal compartment. ConclusionsOur study suggests that the decay of the brain white matter in Huntingtons disease involves a deficit in trafficking of myelin-associated glycoprotein, preventing its proper delivery from the soma of oligodendrocytes to myelin-forming processes.

Imbalance of reduction/oxidation (redox) in the brain is associated with numerous diseases including Alzheimers disease (AD), substance abuse disorders, and stroke. Moreover, cognitive decline can be caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. {Delta}FOSB is a neuronally enriched transcription factor critical for orchestrating gene expression underlying memory, mood, and motivated behaviors. It is dysregulated in many conditions including AD. We showed recently that {Delta}FOSB forms a redox-sensitive disulfide bond between cysteine 172 (C172) of {Delta}FOSB and C279 of its preferred binding partner JUND. This bond works as a redox switch to control DNA-binding, based on studies of recombinant proteins in vitro. Here, we show that this redox control of {Delta}FOSB function in vitro is conserved in vivo. We show that {Delta}FOSB C172 forms a redox-sensitive disulfide bond with JUND that regulates the stability of this AP1-transcription factor complex and its binding to DNA in cells. We also validate the formation of {Delta}FOSB-containing complexes held together via disulfide bonds in mouse brain in vivo. We show that exogenous oxidative stress reduces {Delta}FOSB binding to gene targets in mouse brain and that Fosb C172S knock-in mice, which lack a functional {Delta}FOSB redox switch, are insensitive to this oxidation-dependent reduction in target gene binding, demonstrating that {Delta}FOSB is regulated by a redox switch that modulates binding to target genes in the hippocampus. Finally, we demonstrate that FosB C172S knock-in mice are less sensitive to cognitive dysfunction induced by oxidative stress. This evidence supports {Delta}FOSB as an important mediator of oxidative stress-driven changes in gene expression and cognition and implicates {Delta}FOSB as a possible therapeutic target for diseases associated with oxidative stress in the brain, including AD.

Voluntary reaching movements are often made with incomplete information about the movement goal, which may require the brain to flexibly adjust motor plans and ongoing movements. To examine how uncertainty about a reach target influences neural preparation and execution, we recorded activity from dorsal premotor (PMd) and primary motor (M1) cortices of a rhesus macaque trained to reach to one of two potential targets. In the task, a timing cue flashed three times in succession. Potential targets were displayed at the time of the first flash and the monkey needed to initiate the movement almost simultaneously with the third flash. Colorings of potential targets indicated the probability that the target would be at one location or the other, thereby inducing varying levels of uncertainty about the final target location. On half the trials, the final target was displayed so late that the monkey had to guess the target location, based on cues provided by the potential targets. While the monkey performed this task, we recorded 165 neurons from PMd and 37 from M1. Population neural trajectories in the preparatory subspace of PMd (but not M1) were progressively less expansive with higher levels of uncertainty. Despite differences in preparatory states associated with uncertainty, the movements produced were the same. The narrower separation between states suggested a neural-based explanation for more rapid movement re-preparation with higher uncertainty. Furthermore, we found a dimension in neural state-space representing the level of uncertainty during movement preparation and execution. SIGNIFICANCE STATEMENTThe dorsal premotor cortex (PMd) in primates plays a critical role in organizing preparatory states needed for the execution of target-directed movements mediated downstream by the primary motor cortex (M1). But what if the location of the target is uncertain - as often occurs in our daily lives, such as reaching for a pair of glasses in the dark that have fallen to the floor. We found that different levels of uncertainty are clearly represented in population neural activity during preparation for movement in monkey PMd but not M1. Furthermore, these different neural states related to uncertainty were not associated with changes in the movements produced. These findings provide further insight (and questions) about the operations of the motor cortex.

Parabens, particularly methylparaben (MP) and ethylparaben (EP), are extensively used preservatives in cosmetics, foods, and pharmaceuticals. Although considered safe at low concentrations, recent evidence questions their biological inertness under chronic exposure. This study evaluated the developmental, biochemical, and behavioral effects of continuous dietary MP and EP exposure in Drosophila melanogaster, an established in vivo model for toxicological screening. Flies were chronically exposed to MP (0.5-2%) or EP (0.5-1.5%) throughout development and adulthood. Developmental timing, lifespan, oxidative-stress markers (MDA, FRAP, total protein), and locomotor performance (negative geotaxis in adults, crawling in larvae) were quantified. Paraben exposure significantly delayed development ([~]15% increase in eclosion time), reduced median lifespan (up to 50% decrease at 2% MP), and elevated oxidative damage ({uparrow}MDA, {downarrow}FRAP) in a dose-dependent manner. Protein content declined more rapidly with age, suggesting oxidative degradation or proteolysis. Both adult climbing and larval crawling performances were impaired, linking biochemical stress to neuromuscular dysfunction. MP produced stronger oxidative and behavioral effects than EP. Feeding controls confirmed that observed deficits were not due to nutritional differences. Chronic MP and EP exposure induces systemic toxicity in D. melanogaster, integrating endocrine disruption and redox imbalance as plausible mechanisms. Given conserved stress and hormonal pathways, these findings reinforce the need to re-evaluate low-dose paraben safety limits and highlight Drosophila as a rapid, ethically viable platform for screening environmental preservatives and safer substitutes.

Our inability to obtain nerve samples from the vast majority of neuropathic pain patients impedes our ability to understand the disease, creates challenges in understanding mechanisms in specific patient populations, and limits our ability to make treatment decisions based on quantifiable molecular data. Fields like oncology have overcome these problems to take advantage of the insight that sequencing offers for understanding mechanisms of disease and have leveraged these molecular insights to dramatically change the treatment landscape in the past decade. Here we tested the hypothesis that skin biopsies could be used to gain insight into neuronal transcriptomic changes in patients with paclitaxel-induced peripheral neuropathy (PIPN). Our analysis reveals that hundreds of differentially expressed genes (DEGs) found through bulk RNA sequencing in these skin biopsies are likely contributed by dorsal root ganglion (DRG) neuronal axons and/or terminals. Up-regulated genes were representative of broad class of nociceptors whereas down-regulated genes were associated with putative injured DRG neurons expressing the PDIA2 gene. DEGs that could be confidently associated with specific subsets of skin cells were mostly expressed by keratinocytes supporting a growing literature tying keratinocyte-neuron communication abnormalities to pain in PIPN. Our findings warrant further assessment of skin biopsies in additional neuropathic pain populations to gain insight into DRG neuron changes that have previously been thought to be inaccessible in routine clinical or scientific assessment in most patients.

Object handovers - while representing one of the simplest forms of physical interaction between two agents - involve a complex interplay of predictive and reactive control mechanisms in both agents. As human-human pairs have unrivaled skills in physical collaboration tasks, we take the approach of understanding and applying biomimetic concepts to human-robot interaction. Here, we apply the concept of passer movement cues, that is, slower movement for heavy objects and faster movements for lighter objects, to robot-human handovers. We first show that when a simulated passing agents movement is scaled with object mass, participants as receivers adapt their anticipatory grip forces according to mass in a virtual environment. We then apply the same concept to a physical robot-human handover and show that our approach generalizes to the real-world. The predictive scaling of grip forces is learned iteratively upon repeated presentations of trajectory-mass pairings, whether the masses are presented in a random or blocked order. Overall we demonstrate that the presentation of robotic kinematic cues can provide intuitive and naturalistic human predictive control in object handover. This extends the use of non-verbal cues in robot-human handover tasks and facilitates more legible and efficient physical robot-human interactions.

Age-related cognitive decline affects millions of individuals worldwide, but the cellular mechanisms underlying this decline remain incompletely understood. Microglia undergo significant changes with aging, including alterations in morphology, that may reflect or contribute to cognitive dysfunction. However, the relationship between specific microglial morphologies and cognitive performance in relevant brain regions remains poorly understood. To address this, we evaluated the relationship between morphology-based microglial phenotypes and cognitive performance across domains affected by aging. Microglial morphology was analyzed in four cognitive brain regions of male and female 3-, 9-, and 15-month-old rats and features were subjected to hierarchical clustering on principal components to identify microglial subtypes. Rats underwent cognitive testing using a radial arm water maze and a T-maze set-shifting task to assess spatial working and reference memory, striatal-based learning, and cognitive flexibility. We observed age-related cognitive impairments alongside region-specific changes in microglial morphotype abundance. Importantly, the relative abundance of distinct microglial clusters correlated with cognitive performance in functionally relevant brain regions including the prefrontal cortex, the orbitofrontal cortex, and the hippocampus. Taken together, these findings highlight the utility of morphological profiling in capturing microglial heterogeneity and suggest that morphological changes may reflect or contribute to cognitive decline during aging.

Higher brain functions and cognition undergo a critical period of development during adolescence, when psychiatric disorders such as schizophrenia typically onset. Understanding how developmental processes during adolescence interact with schizophrenia pathophysiology and risk remains a central goal in psychiatry. Here we show that a well-established biomarker of schizophrenia, mismatch negativity, matures during adolescence in mouse primary visual cortex, along with a strengthening of fronto-visual functional connectivity. Because microglia are implicated in schizophrenia risk and disease states, we further investigated what role microglia may play in the development of mismatch responses under physiological conditions. We found that microglial depletion with PLX5622 in adolescence arrests the development of resting oscillations in frontal areas, but does not affect the development of deviance detection, other signatures of visual context processing, or prefrontal-visual functional connectivity. Our findings suggest (a) a key component of mismatch negativity develops in adolescence, a period of vulnerability to schizophrenia, and (b) the development underlying this component does not require robust microglia activity, clarifying the developmental role of microglia in higher order visual processing.

Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor-dominant phenotype. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding Mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 are known to affect mitochondrial dynamics. We previously demonstrated that the mutated MFN2Arg94Gln further disrupts contacts between the ER and the mitochondria, leading to progressive axonal degeneration. There is no effective therapeutic approach to slow or reverse the progression of CMT2A, and treatments currently under development primarily focus on restoring mitochondrial function. Here, we provide proof-of-concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice carrying the mutated MFN2Arg94Gln. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved following vector injection after the onset of symptoms, rescuing the molecular hallmarks of CMT2A pathology and reversing locomotor. Notably, AAV administration was well tolerated, with no evidence neither of hepatotoxicity nor dorsal root ganglion inflammation. These results establish that boosting MFN2 levels using gene therapy is a promising therapeutic avenue for CMT2A

Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor-dominant phenotype. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding Mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 are known to affect mitochondrial dynamics. We previously demonstrated that the mutated MFN2Arg94Gln further disrupts contacts between the ER and the mitochondria, leading to progressive axonal degeneration. There is no effective therapeutic approach to slow or reverse the progression of CMT2A, and treatments currently under development primarily focus on restoring mitochondrial function. Here, we provide proof-of-concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice carrying the mutated MFN2Arg94Gln. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved following vector injection after the onset of symptoms, rescuing the molecular hallmarks of CMT2A pathology and reversing locomotor. Notably, AAV administration was well tolerated, with no evidence neither of hepatotoxicity nor dorsal root ganglion inflammation. These results establish that boosting MFN2 levels using gene therapy is a promising therapeutic avenue for CMT2A

Representational competition occurs when a task-relevant target stimulus and a distractor overlap in space and time. Given limited neural resources, it is expected that stronger representations of the distractor will result in weaker representations of the target, leading to poorer behavioral performance. We tested this hypothesis by recording fMRI while participants (n = 27) viewed a compound stimulus consisting of randomly moving dots (the target) superimposed on IAPS affective pictures (the distractor). Each trial lasted [~]12 seconds, during which the moving dots and the IAPS pictures were flickered at 4.29 Hz and 6 Hz, respectively. The task was to detect and report brief episodes of coherent motion in the moving dots. Depending on the emotion category of the IAPS pictures, the trials were classified as pleasant, neutral and unpleasant. Focusing on three ROIs: middle temporal cortex (MT), ventral visual cortex (VVC), as well as the primary visual cortex (V1), we performed MVPA analysis to decode the distractor categories in each ROI, and correlated the decoding accuracy, taken to index the strength of distractor representation, with the accuracy in detecting the episodes of coherent motion. The following results were found: (1) the decoding accuracy was above chance level in all ROIs, and (2) in MT and VVC but not in V1, the higher the decoding accuracy, the worse the behavioral performance. These results suggested that distractor information was represented in V1 as well as in the two motion-processing areas, and in the motion-processing areas, stronger representations of the distractor led to poorer ability to process attended information, leading to worse behavioral performance. The hypothesis was thus supported and trade-offs in the fidelity of stimulus representations prompted by neural competition demonstrated.

Focal stroke leads to complex changes in the cerebral microcirculation in surviving brain tissues that strongly influence recovery. Plasminogen activator inhibitor-1 (PAI-1; encoded by Serpine1) is highly upregulated in endothelial cells after stroke. Since the primary function of PAI-1 is to inhibit fibrin clot breakdown, we hypothesized that blocking this pathway would be beneficial for recovery since it is expected to increase capillary blood flow after stroke. Using longitudinal in vivo imaging in mice subjected to ischemic stroke, we unexpectedly found that knockdown of Serpine1 in brain endothelial cells leads to a long-lasting reduction in peri-infarct capillary width, red blood cell velocity and flux. Conversely, stimulating this pathway in naive mice increased capillary width and blood flow. Lowered peri-infarct blood flow in Serpine1 knockdown mice attenuated deleterious blood brain barrier disruption and pro-inflammatory gene expression. Serpine1 knockdown improved the progressive recovery of sensory evoked cortical responses, as well as cognitive and sensorimotor function. These findings challenge the assumption that increased blood flow after stroke is better for recovery and reveal that carefully tuning flow, rather than maximizing it, may be optimal. Further our data highlight the therapeutic potential of targeting endothelial Serpine1/PAI-1 signalling in promoting stroke recovery.

In neuroscience, methods from information geometry (IG) have been successfully applied in the modelling of binary vectors from spike train data, using the orthogonal decomposition of the Kullback-Leibler divergence and mutual information to isolate different orders of interaction between neurons. While spike train data is well-approximated with a binary model, here we apply these IG methods to data from electroencephalography (EEG), a continuous signal requiring appropriate discretization strategies. We developed and compared three different binarization methods and used them to identify third-order interactions in an experiment involving imagined motor movements. The statistical significance of these interactions was assessed using phase-randomized surrogate data that eliminated higher-order dependencies while preserving the spectral characteristics of the original signals. We validated our approach by implementing known second- and third-order dependencies in a forward model and quantified information attenuation at different steps of the analysis. This revealed that the greatest loss in information occurred when going from the idealized binary case to enforcing these dependencies using oscillatory signals. When applied to the real EEG dataset, our analysis detected statistically significant third-order interactions during the task condition despite the relatively sparse data (45 trials per condition). This work demonstrates that IG methods can successfully extract genuine higher-order dependencies from continuous neural recordings when paired with appropriate binarization schemes.

The hippocampus supports episodic memory by binding spatial and semantic information, yet how this information is simultaneously organized along its long axis remains debated. Gradient accounts propose a continuous shift in representational scale, from coarse coding in anterior to fine coding in posterior regions, whereas modular accounts posit discrete subregions specialized for distinct functions. Using high-resolution fMRI together with eye tracking as a readout of spatial and semantic memory during sequence learning, we directly tested these competing models. During predictable sequences, hippocampal activity continuously varied along the long axis. In contrast, modular organization emerged when sequences mismatched memory. Subregions in the anterior and posterior hippocampus were sensitive to semantic and spatial mismatches, respectively. Notably, the intermediate hippocampus was specifically sensitive to concurrent mismatches in both dimensions, but not to mismatches in either dimension alone. These content-sensitive subregions were embedded within distinct cortical networks that reorganized according to memory demands. Together, our findings show the hippocampus flexibly combines gradient and modular dynamics to simultaneously represent the spatial and semantic content that defines episodic memory.

Sleep is essential for adaptation and survival across the lifespan, yet the ecological pressures shaping sleep ontogeny remain poorly understood. We investigated sleep across early developmental stages in Drosophila mojavensis, a stress-resilient desert-adapted species. While adult D.mojavensis exhibit prolonged and consolidated sleep, along with enhanced starvation tolerance and survival compared to Drosophila melanogaster, the developmental trajectory underlying these adaptation strategies for surviving in harsh environments is unknown. Moreover, during developmental (larval) periods, animals do not encounter the same environmental stressors experienced by adults (e.g., food scarcity, extreme temperatures). We find that in contrast to adults, D.mojavensis larvae exhibit reduced and fragmented sleep relative to D.melanogaster. D.mojavensis larval sleep is also deeper, reflecting a shift toward increased sleep efficiency rather than simple sleep loss. D.mojavensis larvae consume more food than D.melanogaster and survive longer under starvation, suggesting a strategic tradeoff by suppressing sleep to prioritize nutrient intake and energy storage early in life while resources are more abundant. Metabolic analyses reveal elevated triglyceride accumulation in D.mojavensis across their lifespan, indicating enhanced energy storage capacity. These findings provide an example of how, within a fixed genetic background, an animal can reallocate sleep in opposing manners to maximize survival and energetics depending upon ecological pressures unique to each phase of life.

Autistic individuals often show difficulties in empathy, but the underlying neural mechanisms of empathy in naturalistic contexts of pain have been less examined. This study employed a kinetic pain empathy paradigm, manipulating the congruence between pain expressions, i.e., body gestures and facial expressions based on a predictive coding framework. We collected EEG data from 51 autistic and 58 neurotypical adults during a pain observation task. Results indicated that autistic and neurotypical adults share a similar neural architecture for empathy processing and conflict resolution, involving an early stage of sensory arousal (i.e., N2 and theta) and a later stage of cognitive reappraisal (i.e., P3). However, the multivariate pattern analysis (MVPA) revealed nuanced but significant between-group differences in neural patterns. Compared to neurotypical peers, autistic adults demonstrated atypical processes in both empathy and conflict resolution. Specifically, they exhibited heightened early emotional arousal but expended greater cognitive effort to evaluate others pain. Autistic adults also showed increased alertness to unexpected sensory input and allocated more cognitive resources to resolve prediction errors from incongruent pairings. In contrast, neurotypical adults suppressed unnecessary cognitive efforts for meaningless errors. In summary, autistic adults may experience challenges in efficiently adjusting predictions to the external context, with their neural processing heavily depending on sensory input and less efficient in adapting cognitive resources to evaluate and respond to varied contextual demands.

Immunohistochemistry for amyloid-{beta} (A{beta}) peptide is an indispensable method for Alzheimers disease (AD) research. Despite a wide variety of available antibodies against the peptides, the difference of immunohistochemical reactivity is not fully described among anti-A{beta} antibodies. Immunohistochemical reactivity of Abs against A{beta} peptides is critical for accurate and reliable evaluation of A{beta} burden in patients as well as models of AD. Here, we examined immunohistochemical reactivity of two mouse and one rabbit monoclonal antibodies against A{beta} N-terminal regions using two AD mouse models, AppNL-F and AppNL-G-F. 6E10, 82E1 and D54D2 A{beta} antibodies were used in this study. We found significant differences in the immunohistochemical reactivity in both AppNL-F and AppNL-G-F models. While 6E10 immunoreactivity was mainly localized to A{beta} plaques, D54D2 and 82E1 antibodies stained much more broadly beyond plaques. Interestingly, the latter two Abs showed blurred filamentous immunoreactivity beyond amyloid plaque cores. Double immunostaining using a tyramide signal amplification method, Fluorochromized Tyramide-Glucose Oxidase (FT-GO), suggested that the differential immunohistochemical outcomes were only partially attributable to their sensitivity. Moreover, heat induced epitope retrieval (HIER) did not affect the differential immunohistochemical outcomes. Our analysis indicates that outcomes of A{beta} immunohistochemistry highly depends on the antibody used in the study.

Immunohistochemistry for amyloid-{beta} (A{beta}) peptide is an indispensable method for Alzheimers disease (AD) research. Despite a wide variety of available antibodies against the peptides, the difference of immunohistochemical reactivity is not fully described among anti-A{beta} antibodies. Immunohistochemical reactivity of Abs against A{beta} peptides is critical for accurate and reliable evaluation of A{beta} burden in patients as well as models of AD. Here, we examined immunohistochemical reactivity of two mouse and one rabbit monoclonal antibodies against A{beta} N-terminal regions using two AD mouse models, AppNL-F and AppNL-G-F. 6E10, 82E1 and D54D2 A{beta} antibodies were used in this study. We found significant differences in the immunohistochemical reactivity in both AppNL-F and AppNL-G-F models. While 6E10 immunoreactivity was mainly localized to A{beta} plaques, D54D2 and 82E1 antibodies stained much more broadly beyond plaques. Interestingly, the latter two Abs showed blurred filamentous immunoreactivity beyond amyloid plaque cores. Double immunostaining using a tyramide signal amplification method, Fluorochromized Tyramide-Glucose Oxidase (FT-GO), suggested that the differential immunohistochemical outcomes were only partially attributable to their sensitivity. Moreover, heat induced epitope retrieval (HIER) did not affect the differential immunohistochemical outcomes. Our analysis indicates that outcomes of A{beta} immunohistochemistry highly depends on the antibody used in the study.

Alzheimers disease (AD) is a progressive and debilitating neurodegenerative disease of the central nervous system, characterized by deterioration in cognitive function including extensive memory impairment. The hippocampus, a medial temporal lobe region, is a key orchestrator in the encoding and retrieval of memory and is believed to be one of the first regions to deteriorate in AD. In this work we examined hippocampal macrostructure (specifically gyrification and thickness) and microstructure in Alzheimers disease (AD) and mild cognitive impairment (MCI) relative to healthy aged controls in the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset. We first utilized an iterative training paradigm to adapt an existing deep learning approach for capturing hippocampal topology to elderly individuals as well as individuals with potential hippocampal degeneration. Using this new model, we found notable decreases in both thickness and gyrification in AD and MCI across both the subfields and anterior-posterior axis. Using the diffusion tensor representation derived from diffusion MRI data, we found significant increases in the mean diffusivity across the extent of the hippocampus in AD and MCI, which may be related to a number of changes such as loss of neuronal cells, decreased fiber density, demyelination, and increased presence of CSF. Examining the primary direction of diffusion relative to canonical hippocampal axes, we found distinct diffusion orientation shifts in AD and MCI throughout the anterior-posterior extent of the subiculum and CA1. Specifically, we found a decrease in diffusion oriented tangentially, and an increase in diffusion oriented along the long-axis. This could potentially be related to the known degeneration of the perforant path, which is greatly affected in AD and is a largely tangential oriented pathway. The AD-related changes in diffusion orientations were found to not have significant spatial overlap with AD-related changes in mean diffusivity, suggesting that they may be capturing distinct spatially-localized disease processes. Finally, we showed that the macro- and microstructure of the hippocampus in AD changed less across age relative to MCI and controls. As well, the age-related hippocampal macrostructure changes in MCI appeared indistinguishable from healthy aging.

RE1 Silencing Transcription Factor (REST) is a repressor of transcriptional initiation of genes involved in neurogenesis. Here, we show that conditional REST elevation in cerebellar granule cell progenitors (CGNPs) of RESTTG mice perturbed foliation, increased cell migration, and sustained C-X-C motif receptor 4 (Cxcr4) signaling, a pathway key to postnatal CGNP migration. Mechanistic studies uncovered a novel role for REST in controlling transcript diversity and exon skipping in CGNPs. Alternative transcript expression was detected in known Cxcr4 signaling regulator, G-protein-coupled receptor kinase-6 (Grk6). Further analysis of Grk6s isoform expression revealed an upregulation of a transcript lacking exon 10a (Grk6-207) in RESTTG CGNPs. Grk6-207 expression in wildtype CGNPs hyperactivated Cxcr4 signaling and increased chemotaxis. Structural modeling of Grk6-207 predicted changes in active site conformation and interactions with Cxcr4 and {beta}-Arrestin-1, supporting impairment of Cxcr4 signaling desensitization. Interestingly, REST elevation promoted increased chromatin accessibility at the exon10a-10b junction and exon 10a exclusion. Integrated multiomic analyses identified the enhancer of zeste (Ezh2) as a potential mediator of alternative transcript generation which demonstrated increased occupancy at the exon10a-10b locus in RESTTG CGNPs. Pharmacological inhibition of Ezh2 downregulated Grk6-207, confirming a role for Ezh2 in Grk6 exon10a exclusion and the increased migration in RESTTG CGNPs. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/682654v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@14bdc18org.highwire.dtl.DTLVardef@15eb8a1org.highwire.dtl.DTLVardef@1ab7494org.highwire.dtl.DTLVardef@172e207_HPS_FORMAT_FIGEXP M_FIG C_FIG

Resting-state functional connectivity (RSFC) holds promise for the detection and characterisation of dementia. The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) Study, by the Canadian Consortium on Neurodegeneration in Aging (CCNA), provides a unique resource to study deeply phenotyped neurodegenerative conditions. We present RSFC derivatives for 784 participants (data release 7 of the cohort) who were either cognitively unimpaired or diagnosed primarily with Alzheimers disease (AD), mixed dementia (AD with a vascular component), mild cognitive impairment (MCI), vascular MCI, frontotemporal dementia, Parkinsons disease with or without MCI or dementia, Lewy body disease or subjective cognitive impairment. Functional MRI scans were preprocessed using fMRIPrep, and time-series and whole-brain connectomes generated using three atlases at multiple resolutions, denoised using seven different techniques. High-motion artifacts were managed using a liberal quality control threshold appropriate for an older clinical population, resulting in data from 680 participants. These derivatives are made available to the research community to accelerate research on RSFC biomarkers of neurodegenerative disease, reducing duplication of effort, saving computational resources, and improving standardisation across studies.

Colour constancy refers to our ability to distinguish changes in surface properties from changes in the properties of light illuminating the scene. The apparent ease with which we can tell that objects do not change colour, for example, when moving from sunlight to the shade, belies the complexity of solving this ill-constrained problem. Although there is a substantial body of work testing which image cues might be used to accomplish this, there is surprisingly little known of how the brain performs this computation. Here, we tested a fundamental aspect of this perceptual process: whether it requires attention. We measured visual search times for both surface colour (requiring separation of surface and illuminant properties) and raw, colorimetric colour (which does not). We found a clear difference between the two: visual search for colorimetric colour was fast and near-parallel, while search for surface colour was slow and consistent with the serial deployment of attention. That is, search times suggest that the perceptual separation of surface and illuminant properties in colour constancy may require an attention-based process analogous to perceiving conjunctions of simple features in feature binding. Colour discrimination thresholds suggested that while colorimetric colour detection is fast and parallel, once attention was directed to these stimuli and perceptual scission occurs, colorimetric colour information was discarded by the visual system. These results offer important new insights into the sequence of processes the brain uses to accomplish colour constancy. Public Significance StatementThis work sheds new light on how the human visual system recognises the colour properties of different materials under varying lighting conditions. We find evidence that although material and lighting properties are perceptually separated automatically when attended, that this process requires attention.

Affective blindsight, the capacity to discriminate emotional stimuli despite bilateral damage to the primary visual cortex (V1) and without conscious awareness, offers a unique model of non-conscious visual processing. Subcortical pathways involving the pulvinar and amygdala have been proposed, but putative cortical contributions remain unclear. We examined 182 patients, including 31 with bilateral V1 lesions. Among these, 15 had cortical visual loss and 7 showed affective blindsight. Using behavioral testing, lesion symptom mapping, and tractography, we found that preserved pulvinar connectivity with both the posterior superior temporal sulcus (STS) and the amygdala is necessary for affective blindsight. These findings provide causal evidence for a multi-route architecture, identifying the pulvinar-STS pathway, alongside the pulvinar-amygdala pathway, as a critical substrate for non-conscious affective processing.

Affective blindsight, the capacity to discriminate emotional stimuli despite bilateral damage to the primary visual cortex (V1) and without conscious awareness, offers a unique model of non-conscious visual processing. Subcortical pathways involving the pulvinar and amygdala have been proposed, but putative cortical contributions remain unclear. We examined 182 patients, including 31 with bilateral V1 lesions. Among these, 15 had cortical visual loss and 7 showed affective blindsight. Using behavioral testing, lesion symptom mapping, and tractography, we found that preserved pulvinar connectivity with both the posterior superior temporal sulcus (STS) and the amygdala is necessary for affective blindsight. These findings provide causal evidence for a multi-route architecture, identifying the pulvinar-STS pathway, alongside the pulvinar-amygdala pathway, as a critical substrate for non-conscious affective processing.

The heart continuously shapes neural processing and behavior through cardiac-brain interactions. While cortical excitability fluctuations and their role in cardiac-dependent cognitive and sensorimotor phenomena have been extensively studied, the temporal dynamics and contribution of spinal excitability oscillations across the cardiac cycle remain poorly characterized. In this study, we examine whether motor evoked potentials elicited by magnetic stimulation of the spinal cord are modulated by the cardiac cycle phase in healthy participants. Real-time adapting ECG-triggered stimulation enabled precise targeting of five phases across the cardiac cycle. Spinal excitability was significantly phase-dependent, with MEPs peaking during late diastole. MEPs amplitude was also found to be modulated by preceding cardiac intervals, where shorter intervals predict stronger diastolic facilitation. These findings establish that spinal excitability is rhythmically modulated by the cardiac cycle, potentially through blood pressure-mediated mechanisms. Notably, the diastolic facilitation observed here contrasts with previously reported motor cortex excitability profiles, indicating a non-synchronous cardiac modulation of spinal versus cortical excitability. These results may benefit neuromodulation approaches for motor and psychiatric disorder treatment and emphasize the critical importance of including spinal measures in future heart-brain interaction studies.

While the brain performs specialized functions across distinct regions, the spatial organization of the human brain proteome remains largely uncharted. Here we present a comprehensive spatially-resolved proteome atlas of the human brain, analyzing over two thousand MRI-guided locations across four individuals. Proteome analysis integrated with transcriptomics reveals extensive post-transcriptional regulation, with cortical regions showing markedly higher protein diversity than transcript. Unsupervised molecular clustering defines distinct brain territories that transcend anatomical boundaries, instead reflecting metabolic demands and functional specialization patterns. Application to epilepsy brain tissue uncovered disrupted astrocyte metabolism, protein homeostasis and therapeutic targets including the seizure-associated purinergic receptor P2RX7. This resource bridges molecular and systems neuroscience to accelerate neurological drug discovery.

While the brain performs specialized functions across distinct regions, the spatial organization of the human brain proteome remains largely uncharted. Here we present a comprehensive spatially-resolved proteome atlas of the human brain, analyzing over two thousand MRI-guided locations across four individuals. Proteome analysis integrated with transcriptomics reveals extensive post-transcriptional regulation, with cortical regions showing markedly higher protein diversity than transcript. Unsupervised molecular clustering defines distinct brain territories that transcend anatomical boundaries, instead reflecting metabolic demands and functional specialization patterns. Application to epilepsy brain tissue uncovered disrupted astrocyte metabolism, protein homeostasis and therapeutic targets including the seizure-associated purinergic receptor P2RX7. This resource bridges molecular and systems neuroscience to accelerate neurological drug discovery.

Spinocerebellar ataxia type 34 (SCA34) is an autosomal dominant neurodegenerative disease primarily characterized by progressive cerebellar atrophy and ataxia, frequently accompanied by cognitive dysfunction and erythrokeratodermia variabilis. In 2014, missense mutations in the gene encoding elongation of very long chain fatty acids protein 4 (ELOVL4) were identified as the causative gene for SCA34. ELOVL4, which is involved in the synthesis of very long chain fatty acids, is highly expressed in the cerebellum compared to other brain regions, with predominant expression in neurons. We attempted to establish a mouse model of SCA34 by expressing mutant ELOVL4 in cerebellar neurons using adeno-associated virus (AAV) vectors and to elucidate the underlying pathogenic mechanisms. Expression of W246G mutant ELOVL4 successfully induced progressive motor dysfunction beginning at two weeks post-AAV vector injection. Immunohistochemical analyses revealed that the degeneration of cerebellar Purkinje cells and neurons in the deep cerebellar nuclei (DCN) paralleled the observed motor decline. Importantly, microglial activation was detected in the molecular layer of the cerebellar cortices and the DCN prior to the onset of both neurodegeneration and motor dysfunction. Furthermore, after the onset of motor symptoms, the SCA34 model mice exhibited decreased synaptic inputs from climbing fibers to Purkinje cells, as well as reduced inputs from Purkinje cells to DCN neurons. These findings suggest that early microglial activation and the resulting synaptic disturbance are critical preceding events that lead to the progressive cerebellar neurodegeneration and motor dysfunction observed in this SCA34 mouse model.

Mutation in paired-like homeobox 2B (PHOX2B) is used as the diagnostic marker of Haddad syndrome (HS). The mutant gene/protein afflict neural crest cells during embryonic development which leads to congenital central hypoventilation syndrome (CCHS) and Hirschsprung's disease (HSCR). Previous studies on HS and CCHS have mainly focused on the conformational dynamics of the mutant protein and have remained controversial. Here we performed RNA-sequencing on the patient derived neuroepithelial stem cells (NESCs), pertinent to the neurodevelopmental phenotype in HS, and found that the PHOX2B-PARM has a profound impact on the transcriptional profile of the cells. The single copy of PHOX2B-PARM in heterozygote cells were leading to >10 fold differentially expressed genes. In the patient cells there was a significant enrichment of genes related to neuronal development and synapse organization mainly driven by L1CAM interactions and synaptogenesis signaling pathway. Our result not only highlight the use of a suitable model of HS but also provide a clear path for future experimental validation and downstream targets with potential therapeutic values.

Experience is thought to modify neural connections to adapt the network to be more optimal for the environment. Given the brains complexity, multiple network changes could each move the system toward optimality. Standard methods ignore this multiplicity and examine each connection independently; these studies have often shown considerable inter-individual variability and modest effects (1). Here, we take a different strategy, determining how a whole-brain connection pattern differs from the typical pattern, that is, how idiosyncratic the pattern is. We examined how the idiosyncrasy of whole brain connection patterns varies with frequency of the use of that part of cortex for attention-demanding tasks, focusing on central versus peripheral vision in healthy individuals (where individuals use central vision more frequently for attention-demanding tasks). We found that the whole-brain pattern of functional connections to the cortical representations of central vision is idiosyncratic, whereas patterns of connections to representations of peripheral vision were very similar person-to-person. In a second set of analyses, we examined the brains of people with central vision loss who use a portion of peripheral vision (called the preferred retinal locus) more frequently for attention-demanding tasks in their daily lives. The cortical representation of the preferred retinal locus exhibits more idiosyncratic connections, compared to a control brain region, or compared to the same brain region in matched control participants with healthy vision. These results are consistent with the hypothesis that increased attentive use of a brain area results in idiosyncratic patterns of whole brain connections. Significance StatementWe found that increased attentive use of a brain region results in more idiosyncratic patterns of connections of that region to the rest of the brain. Our findings support the view that V1 retains the capacity for plasticity well beyond the critical period and that these adaptations are idiosyncratic to the individuals experiences. This approach suggests that tailoring personalized rehabilitation plans for individuals with retinal diseases may be more effective than a one size fits all approach. More generally, it offers a promising framework for investigating brain plasticity in both typical and clinical populations, especially in the context of sensory loss and compensatory adaptation.

The flexible deployment of cognitive control is essential for adaptive functioning in dynamic environments given limited cognitive resources. That flexibility depends on rapid detection and resolution of control- prediction errors (CPEs) when current demands diverge from the control plan. Deficits in control and control flexibility are common in psychiatric disorders, yet targeted interventions are limited by incomplete circuit- level understanding and limited means for modulating control circuits . We analyzed two intracranial electroencephalography datasets (one with brief internal capsule stimulation, ICS) to identify a human neurocomputational mechanism for CPE resolution and to test its modifiability. A third dataset of patients receiving internal capsule deep brain stimulation (IC DBS) assessed clinical relevance of modifying CPE-related processes. Phase-amplitude coupling (PAC) anchored to the {theta} phase of right rostral anterior cingulate cortex (rACC-R), especially {theta}-{gamma} coupling between rACC-R and nodes of the cognitive control network (dorsolateral prefrontal cortex, dlPFC; dorsal ACC, dACC), was associated with faster CPE resolution. An adaptive drift-diffusion model indicated that ICS improves control flexibility specifically under high CPE, and mediation analyses showed that this behavioral improvement is mediated by CPE-dependent increases in rACC-R {theta}-centered PAC. In a psychiatric cohort (N=14; primarily treatment-resistant depression, TRD) with IC DBS, enhanced control flexibility, rather than CPE-independent general cognitive control, was strongly associated with clinical response (AUC = 0.90), suggesting both a behavioral flexibility index and rACC-R PAC as candidate biomarkers for DBS optimization. These findings identify a rACC-centered, {theta} phase-based coordination of the cognitive control network as a neurocomputational substrate of flexible control. They demonstrate that capsule stimulation selectively augments this substrate when flexibility is required, and establish flexibility, rather than general control, as the feature that tracks therapeutic benefit in TRD. Together, they suggest actionable biomarkers to guide, personalize, and potentially enable closed-loop neuromodulation for disorders marked by cognitive rigidity.

Unimanual actions can interfere with or facilitate similar actions performed with the opposite hand, especially when in close temporal proximity. Across three sequential button-press experiments, we tested how effector homology - anatomical similarity between fingers - and temporal delays between actions shape these effects. Specifically, we examined whether a priming action altered the reaction time (RT) of a subsequent action. Compared with unimanual RTs, we indexed slowing of the second actions RT as interference, and quickening as facilitation. Priming with homologous actions (e.g., index finger-index finger) produced interference at short intervals ([≤]200ms) but transitioned to facilitation at longer intervals ([≥]400ms). Priming with non-homologous actions (e.g., little finger-index finger) also produced interference at short intervals, but never resulted in facilitation. Critically, these patterns emerged whether the priming actions were performed with the opposite or the same hand, indicating that interference and facilitation do not depend on interhemispheric dynamics. Our results reveal a previously undocumented time-dependent shift from interference to facilitation that is specific to homologous actions, challenging models that explain the interference between parallel actions solely by competitive interhemispheric dynamics or central bottleneck processes. We propose that facilitation and interference flexibly coexist, and are shaped by effector homology and timing. These findings extend current models of bimanual coordination and highlight new opportunities for enhancing motor performance and neurorehabilitation. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/682693v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@1c24967org.highwire.dtl.DTLVardef@6129e4org.highwire.dtl.DTLVardef@1056f52org.highwire.dtl.DTLVardef@1cfa13a_HPS_FORMAT_FIGEXP M_FIG A left-hand index finger press primed a subsequent right-hand index (homologous) or right-hand little finger (non-homologous) response at variable delays. For homologous actions (index-index), reaction times (RTs) quickened relative to unimanual single-press baseline for delays [≥]400ms, whereas for non-homologous actions (index-little), RTs slowed and gradually returned to baseline by ~600ms. This dissociation indicates that effector homology and timing dictate whether a preceding action facilitates or interferes with the execution of a subsequent one. C_FIG

The calyx of Held is a giant axo-somatic synapse classically confined to the auditory brainstem. We recently identified morphologically similar calyx-like terminals in the extended amygdala (EA) that arise from the ventrolateral parabrachial complex and co-express PACAP, CGRP, VAChT, VGluT1, and VGluT2, targeting PKC{delta}+/GluD1+ EA neurons. Here we asked whether this parabrachial-EA pathway participates in compensation during acute hypotension. In rats given hydralazine (10 mg/kg, i.p.), we quantified Fos protein during an early phase (60 min) and a late phase (120 min). Early after hypotension, Fos surged in a discrete subpopulation of the parabrachial Kolliker-Fuse (KF) region and in the EA, whereas magnocellular neurons of the supraoptic and paraventricular nuclei (SON/PVN) remained largely silent. By 120 min, magnocellular SON/PVN neurons were robustly Fos-positive. Confocal immunohistochemistry showed that most Fos+ PKC{delta}/GluD1 EA neurons were encircled by PACAP+ perisomatic terminals (80.8%), of which the majority co-expressed VGluT1 (88.1%). RNAscope in situ hybridization further identified a selective KF population co-expressing Adcyap1 (PACAP) and Slc17a7 (VGluT1) that became Fos-positive during the early phase. Together these data indicate that a KFPACAP/VGluT1 projection forms calyceal terminals around PKC{delta}/GluD1 EA neurons, providing a high-fidelity route for rapid autonomic rebound to falling blood pressure, while slower endocrine support is subsequently recruited via vasopressinergic magnocellular activation. This work links multimodal parabrachial output to temporally layered autonomic-neuroendocrine control. Short abstractAcute hypotension triggers rapid autonomic compensation followed by slower endocrine support. We identify a Kolliker-Fuse (KF) PACAP/VGluT1 pathway to the extended amygdala (EA) that initiates the fast limb. In hydralazine-treated rats, Fos rose at 60 min in KF and EA but not in magnocellular SON/PVN; by 120 min SON/PVN were strongly Fos-positive. Confocal microscopy showed that [~]81% of Fos+ PKC{delta}/GluD1 EA neurons were surrounded by PACAP+ calyceal terminals, [~]88% of which co-expressed VGluT1. RNAscope revealed a selective KF Adcyap1/Slc17a7 population that became Fos-positive early. We conclude that KF PACAP/VGluT1 calyces onto PKC{delta}/GluD1 EA neurons provide a high-fidelity autonomic pathway that precedes vasopressin-mediated endocrine compensation.

The calyx of Held is a giant axo-somatic synapse classically confined to the auditory brainstem. We recently identified morphologically similar calyx-like terminals in the extended amygdala (EA) that arise from the ventrolateral parabrachial complex and co-express PACAP, CGRP, VAChT, VGluT1, and VGluT2, targeting PKC{delta}+/GluD1+ EA neurons. Here we asked whether this parabrachial-EA pathway participates in compensation during acute hypotension. In rats given hydralazine (10 mg/kg, i.p.), we quantified Fos protein during an early phase (60 min) and a late phase (120 min). Early after hypotension, Fos surged in a discrete subpopulation of the parabrachial Kolliker-Fuse (KF) region and in the EA, whereas magnocellular neurons of the supraoptic and paraventricular nuclei (SON/PVN) remained largely silent. By 120 min, magnocellular SON/PVN neurons were robustly Fos-positive. Confocal immunohistochemistry showed that most Fos+ PKC{delta}/GluD1 EA neurons were encircled by PACAP+ perisomatic terminals (80.8%), of which the majority co-expressed VGluT1 (88.1%). RNAscope in situ hybridization further identified a selective KF population co-expressing Adcyap1 (PACAP) and Slc17a7 (VGluT1) that became Fos-positive during the early phase. Together these data indicate that a KFPACAP/VGluT1 projection forms calyceal terminals around PKC{delta}/GluD1 EA neurons, providing a high-fidelity route for rapid autonomic rebound to falling blood pressure, while slower endocrine support is subsequently recruited via vasopressinergic magnocellular activation. This work links multimodal parabrachial output to temporally layered autonomic-neuroendocrine control. Short abstractAcute hypotension triggers rapid autonomic compensation followed by slower endocrine support. We identify a Kolliker-Fuse (KF) PACAP/VGluT1 pathway to the extended amygdala (EA) that initiates the fast limb. In hydralazine-treated rats, Fos rose at 60 min in KF and EA but not in magnocellular SON/PVN; by 120 min SON/PVN were strongly Fos-positive. Confocal microscopy showed that [~]81% of Fos+ PKC{delta}/GluD1 EA neurons were surrounded by PACAP+ calyceal terminals, [~]88% of which co-expressed VGluT1. RNAscope revealed a selective KF Adcyap1/Slc17a7 population that became Fos-positive early. We conclude that KF PACAP/VGluT1 calyces onto PKC{delta}/GluD1 EA neurons provide a high-fidelity autonomic pathway that precedes vasopressin-mediated endocrine compensation.

Social interaction is inherently asymmetric, requiring coordinated activity between non-homologous brain regions across individuals. However, the brain-wide dynamics underlying such inter-brain coordination remain poorly understood. We used multi-fiber photometry to simultaneously record from 24 brain regions in pairs of freely interacting mice, including a model of autism. Social interactions evoked widespread, dynamic activity across brains, with inter-brain synchrony, especially between non-homologous areas, exceeding intra-brain synchrony, particularly in dominant mice. Network analysis revealed three subnetworks: (1) Emotional, intra-brain enhanced in subordinates; (2) Sensory, spanning both mice; (3) Decision/consolidation, linking dominant prefrontal cortex to subordinate hippocampus. These subnetworks encoded dominance, identity, and interaction roles, and followed a clear temporal sequence around social events. In an autism model, socially evoked activity was hyperactive displaying mostly within brain synchrony but lacked inter-brain synchrony. Our results uncover dynamic inter-brain circuits as a hallmark of social behavior and reveal their disruption in autism.

Recent theory on the neural basis of working memory (WM) has attributed an important role to "activity-silent" mechanisms, suggesting that sustained neural activity might not be essential in the retention of information. This idea has been challenged by reports of ongoing neural activity in the alpha band during WM maintenance, however. The precise role of these alpha oscillations is unclear: Do they reflect attentional prioritization of stored information, or do they serve as a general maintenance mechanism, for instance to periodically refresh synaptic traces? To address this, we designed a visual WM task involving two memory items, one of which was prioritized for recall. The task included both a short (1 s) and a long (3 s) delay intervals between encoding and retrieval. The long delay was implemented to provide a more decisive test of WM maintenance, providing a point in time when any initially silent synaptic traces would likely need to be refreshed as well. Time-resolved decoding analyses revealed that both prioritized and deprioritized items were initially decodable following stimulus presentation. However, only the prioritized item exhibited sustained decodability throughout the delay, particularly in the long delay condition, where it transitioned into a stable coding scheme. This prolonged representation was selectively supported by induced alpha power, which reliably tracked the prioritized item, but not the deprioritized one. Impulse-based decoding further confirmed this asymmetry, highlighting a selective reactivation of the deprioritized item only upon contextual relevance. Together, these findings suggest that sustained alpha-band activity reflects attentional prioritization, rather than general memory maintenance. Unattended, non-prioritized items appear to transition into an activity-silent state, consistent with models of synaptic storage in WM.

Immunohistochemistry (IHC) is one of the most widely used techniques across basic, translational, and clinical sciences. Key considerations need to be made to achieve reliable and robust IHC staining, however what has been understudied is the stability of IHC signal intensity over time. Changes in signal intensity over time have significant implications for data analysis and interpretation and ultimately impact scientific conclusions. In order to explore changes in IHC signal, the stability of fluorescence intensity was assessed over the course of six weeks using widefield or confocal microscopy. Results indicate that fluorescence intensity can decrease over this time course and that whether this decrease occurs and to what extent is influenced by the selection of the primary antibody as well as that of the secondary antibody, primary-secondary antibody combination, and utilization of chemical staining versus IHC staining. This investigation reinforces best practices for imaging fluorescent staining to ensure accurate and reliable data collection, be it for cell counting, assessing protein expression levels, or marker colocalization.

The hippocampal-entorhinal system supports spatial navigation and memory by orchestrating the interaction between grid cells and place cells. While various models have reproduced these patterns, many rely on predefined connectivity or fixed weights and lack mechanisms for learning or biologically realistic temporal dynamics. The Tolman-Eichenbaum Machine (TEM) has recently gained attention as a unified generative model that explains the emergence of both grid and place cells through learning. However, existing TEM implementations rely on rate-based units and simplified architectures, which limit their biological plausibility. Here, we introduce the Spiking Tolman-Eichenbaum Machine (Spiking TEM)--a spiking neural network model that extends the original TEM with spike-based computation and an anatomically inspired hippocampal-entorhinal architecture. Our model learns grid-like codes in the entorhinal module and context-specific place codes in the hippocampal module, while also exhibiting key temporal coding phenomena observed in electrophysiological recordings, including phase locking of spikes to theta oscillations and phase precession. Furthermore, the model gives rise to predictive grid cells in layer III of the entorhinal cortex, which prospectively encode upcoming spatial positions. These results demonstrate that structured spatial representations and temporally precise coding schemes can emerge from biologically plausible spike-based learning and dynamics, offering a unified framework for understanding spatial and temporal coding in the hippocampal-entorhinal circuit.

Perception is increasingly understood as an inferential process, whereby what we perceive results from the integration of sensory inputs with expectations derived from prior knowledge. Top-down predictions have been shown to alter the encoding of sensory information, from early to late stages of processing. Yet, how such predictions shape neural representations in sensory cortices remains debated. Competing accounts suggest that predictions either sharpen neural representations by enhancing selectivity or dampen activity by broadly suppressing stimulus-driven responses. In a preregistered fMRI study, we tested whether these effects depend on the level of attentional engagement and explicit knowledge of predictive associations. Using a multisensory fMRI paradigm with concurrent but independent visual and auditory probabilistic associations (75% validity) and manipulated attention, we investigated predictive effects in human early visual cortex. Consistent with prior work, expected visual stimuli elicited reduced BOLD activity. Critically, sharpening of expected visual stimuli occurred exclusively when visual inputs were attended and the concurrently presented auditory inputs expected. In addition, the magnitude of the sharpening of visual representations correlated positively with participants' explicit knowledge of the visuo-predictive associations. These findings highlight the key roles of attention and explicit knowledge in promoting predictive sharpening and underscore the need to study predictive processing in more ecologically valid, multisensory contexts.

Alzheimers Disease (AD) is marked by early hippocampal and neocortical accumulation of amyloid-beta 42 oligomers (A{beta}42o), driving neuronal hyperactivity and synaptic dysfunction years before symptom onset. While two-pore domain leak potassium channels like TREK1 provide neuroprotection against hyperexcitability, their role in AD remains unknown. Here, we discover an activity-dependent upregulation of TREK1 in AD transgenic mice (3xTg and APP/PS1) and cultured hippocampal/cortical neurons, triggered by A{beta}42o -induced hyperactivity. Mechanistically, we show that increased intracellular calcium activates adenylate cyclase 1/8 (AC1/8), initiating a cAMP-PKA signalling cascade that enhances the expression of chromatin regulator CTCF. This increased CTCF in turn enhances the expression of TREK1 both in vitro and in AD transgenic mice. Using calcium imaging, patch clamp electrophysiology, immunohistochemistry assays, we demonstrate that the upregulation of TREK1 serves as a critical brake on neuronal hyperexcitability and is essential for restoring synaptic balance and mitigating AD pathology. Our study identifies a multi-step signalling cascade triggered by A{beta}42o leading to upregulation of TREK1 that functions as an essential compensatory mechanism for neuronal survival in early AD.

Sleep is universal among animals with synapses, yet the synaptic functions determining the need for sleep remain elusive. By directly measuring synaptic transmission at anatomically defined synapses in Drosophila, we found that synaptic strength remained stable or declined after sleep deprivation in a circuit-specific manner. In contrast, presynaptic release probability (Pr) consistently decreased with sleep loss across circuits and species, stemming from reduced Ca2+ influx or weakened vesicle-channel coupling at presynaptic terminals, and recovered after sleep. Bidirectional manipulations of Pr altered sleep pressure, establishing a causal relationship between presynaptic function and sleep need. Non-synaptic sleep-regulatory signaling pathways consistently modulate Pr but not synaptic strength. Thus, our findings identify Pr, rather than synaptic strength, as the conserved synaptic substrate underlying sleep need.

Impairments in social perception, a hallmark of autism spectrum disorder (ASD), are also evident at subclinical levels in the general population. However, it remains unclear how such variation in autistic traits modulate neural processing of different types of social information. Here, we investigated whether autistic traits in neurotypical individuals are associated with neural responses to a broad array of social perceptual features during viewing naturalistic stimuli using functional magnetic resonance imaging (fMRI). We also tested the generalizability of these effects across two experiments. Ninety-seven participants completed the Autism Spectrum Quotient (AQ) and watched a set of 96 movie clips and a full movie during an fMRI scan. Intensity of 126 social features in the movie stimuli was continuously annotated by independent observers, and 44 most reliably rated features were used to model neural responses. We examined how consistently the responses to each social feature were dependent on the participant's AQ scores. Replicable AQ-dependent neural responses to social features were found in both datasets. The temporal cortex and especially the superior temporal gyrus (STG), served as a central "hub" where autistic traits consistently modulated responses to social features across datasets. Different AQ subscales also revealed distinct association patterns in other brain regions. These findings indicate that autism-related traits broadly influence neural processing of naturalistic social signals, providing insight into how characteristics of autistic symptoms relate to socioemotional processing.

Impairments in social perception, a hallmark of autism spectrum disorder (ASD), are also evident at subclinical levels in the general population. However, it remains unclear how such variation in autistic traits modulate neural processing of different types of social information. Here, we investigated whether autistic traits in neurotypical individuals are associated with neural responses to a broad array of social perceptual features during viewing naturalistic stimuli using functional magnetic resonance imaging (fMRI). We also tested the generalizability of these effects across two experiments. Ninety-seven participants completed the Autism Spectrum Quotient (AQ) and watched a set of 96 movie clips and a full movie during an fMRI scan. Intensity of 126 social features in the movie stimuli was continuously annotated by independent observers, and 44 most reliably rated features were used to model neural responses. We examined how consistently the responses to each social feature were dependent on the participant's AQ scores. Replicable AQ-dependent neural responses to social features were found in both datasets. The temporal cortex and especially the superior temporal gyrus (STG), served as a central "hub" where autistic traits consistently modulated responses to social features across datasets. Different AQ subscales also revealed distinct association patterns in other brain regions. These findings indicate that autism-related traits broadly influence neural processing of naturalistic social signals, providing insight into how characteristics of autistic symptoms relate to socioemotional processing.

Changes in neurotransmitter usage in homologous neurons may drive evolutionary adaptations in neural circuits across animal phylogeny. The predatory nematode Pristionchus pacificus can be used as a model system to examine nervous system evolution by comparing neurotransmitter expression with that of C. elegans and other nematodes. Here we characterize P. pacificus neurotransmitter expression and function in specific neurons, focusing on its complete set of monoaminergic neurons. We discover patterns of conservation as well as novelties. We examine the roles of monoamines in specific behaviors using neurotransmitter synthesis and vesicular transporter mutants, finding possible differences in the control of host-finding and dispersal behavior.

APOE4 is the largest genetic risk factor for late-onset Alzheimer's disease, but the cellular mechanisms by which APOE variants influence risk of disease remain incompletely understood. We have previously found that APOE4 expression led to the intracellular accumulation of lipid droplets in oligodendrocytes, causing decreased myelination. However, the mechanisms by which APOE4 alters lipid metabolism are not fully understood. Here, we leveraged a genome-wide CRISPR screen and ATAC-sequencing in human induced pluripotent stem cell (iPSC)-derived oligodendrocytes to dissect APOE4's lipid-associated mechanisms of action. Using these approaches, we identified decreased Wnt signaling, and overactive GSK3b activity, as regulators of lipid droplet accumulation in oligodendrocytes. Genetic and pharmacological inhibition of GSK3b reduced lipid droplets in APOE4 oligodendrocytes, and increased myelination in three-dimensional iPSC-derived brain organoids. Finally, we show that pharmacological inhibition of GSK3b reduces lipid droplets and improves myelination in APOE4;PS19 Tau transgenic mice. Together, our results provide a framework for understanding the mediation of APOE4-related changes to oligodendrocyte lipid metabolism and myelination.

Objective: Pathogenic variants in SCN1A, which encodes the voltage gated sodium channel NaV1.1, are associated with multiple epilepsy syndromes exhibiting a range of clinical severity. Loss or gain of function SCN1A variants are reported in different syndromes including Dravet syndrome, which is associated with loss-of-function whereas neonatal/infantile-onset developmental and epileptic encephalopathy (DEE) is associated with gain-of-function. Strategies to predict SCN1A variant pathogenicity and dysfunction have been proposed but are limited by available training data. We investigated the functional properties of four epilepsy-associated SCN1A variants affecting the same codon and sought to correlate channel dysfunction with phenotype. Methods: Whole-cell manual patch-clamp recording was performed on heterologously-expressed NaV1.1 variants. Structural modeling of NaV1.1 variant proteins was conducted using AlphaFold 3. Results: We describe an individual with early infantile onset DEE associated with SCN1A-I1347T, and identified three additional cases from the literature or ClinVar with distinct variation of the same codon (I1347N, I1347V, I1347F). Functional studies demonstrated mixed gain and loss of function properties for I1347T, I1347V, and I1347F, but complete loss-of-function for I1347N. Structural models suggest important interactions between isoleucine-1347 and the sixth transmembrane helices of domains 3 and 4 that are disrupted most significantly with asparagine replacement at this position (I1347N). Interpretation: Pathogenic variants in SCN1A involving the same codon can produce divergent functional effects. Our findings suggest that predicting specific functional effects of SCN1A variants should not rely heavily on position in the protein.

Long-term potentiation (LTP) involves alterations in synaptic structure that are believed to underlie the persistent increase in synaptic efficacy. Here we compared structural LTP (sLTP) in EGFP-labelled spines with functional LTP, using field potential recording, at CA3-CA1 synapses in mouse hippocampal slices for ~ 2 h following theta-burst stimulation (TBS). Activity-dependent labelling with FM4-64 allowed us to compare activated (FM+) and non-activated synapses and thereby compare homo- and hetero-synaptic sLTP. In addition, we related spine volume changes according to the probability of release, P(r), of activated synapses. At homosynaptic sites there was the expected NMDA receptor (NMDAR)-dependent potentiation of spine volume that persisted throughout the recording period. We found that this sLTP also required the synaptic activation of CP-AMPARs. There was also sLTP at heterosynaptic sites that, surprisingly, developed more quickly than the associated homosynaptic sLTP. This heterosynaptic sLTP was also dependent on the synaptic activation of both NMDARs and CP-AMPARs. Additionally, we observed a trans- and hetero-synaptic interaction, whereby the heterosynaptic spines grew according to the P(r) of the neighbouring active (homosynaptic) synapse. These observations have therefore advanced our understanding of sLTP in several ways; the first demonstration of the absolute requirement for the synaptic activation of CP-AMPARs for sLTP; the magnitude of heterosynaptic sLTP relative to homosynaptic sLTP and the hitherto unexpected combination of trans- and hetero-synaptic interactions.

The top-down influence of working memory (WM) can manifest as attentional capture and a "tinted lens" that alters perceptual appearance. Yet it remains unclear whether these effects arise from a common mechanism or reflect functionally and mechanistically distinct processes. Across two experiments, we embedded a perceptual estimation task during WM maintenance. Hierarchical Bayesian mixture modeling revealed robust bidirectional attraction between memory and perception. More importantly, time-resolved analyses of mouse trajectories showed that attentional capture emerged as a fast, transient deviation linked to movement initiation, whereas perceptual bias reflected a slower, sustained shift shaping the final perceptual judgment. Notably, the prospective influence of WM on perception engaged both effects, whereas the retrospective influence of perception on WM involved only the sustained shift. These findings indicate that WM deploys distinct top-down signals that operate over different timescales to dynamically shape our perceptual experience.

Brain-age prediction from neuroimaging data provides a proxy of biological aging, yet most models rely on structural magnetic resonance imaging (MRI), a modality that captures macroanatomy but offers limited biological specificity. We tested whether integrating molecular-enriched functional connectivity (FC), from resting-state functional MRI (rs-fMRI) data, improves brain-age prediction and biological explainability. We analyzed MRI data of 2,120 healthy adults (1,243/877 F/M; 18-90 years) from three public datasets. Molecular-enriched connectivity maps were derived with Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) using receptor-density templates for the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporter systems. Support vector regression models were applied to predict chronological age from molecular-enriched FC, structural morphometry, or both combined. The effect of multi-site variability was mitigated via ComBat harmonization with and without Empirical Bayes pooling. We additionally conducted a common-parcellation analysis to assess the impact of differing parcellations between modalities. Single-transporter molecular-enriched FC explained up to 51% of age variance. The most predictive transporter varied by dataset, with DAT dominating in the harmonized and common-parcellation settings. Combining the three molecular-enriched maps consistently improved prediction over any single map and increased explained variance up to 64%. In the merged multi-site cohort using a common parcellation, augmenting structural information with transporter-enriched FC reduced mean absolute error (MAE) from 6.02 to 5.81 years, supporting complementarity of the two modalities. In contrast, when different parcellations were applied, incorporating molecular-enriched FC into brain age prediction resulted in a 2% higher MAE compared to structural morphometry alone, suggesting that parcellation mismatch may obscure the functional contributions. In conclusion, molecular-enriched FC is a feasible and biologically informative extension to brain-age modeling, enhancing prediction and interpretability with respect to neurotransmitter systems.

The neural substrates supporting the beneficial effect of sleep on motor memory consolidation are well described. However, less is known about the brain oscillatory dynamics underlying these processes. We characterized the oscillatory dynamics associated with motor sequence learning and their modulation by post-learning sleep using magnetoencephalography (MEG) in young healthy adults. After learning a motor sequence task while their brain activity was recorded with MEG, participants were distributed in two groups according to whether they slept or were totally sleep deprived during the first post-training night. Consolidation was assessed with a retest in the MEG three days after training. Behaviorally, performance improved over the consolidation interval irrespective of whether sleep was afforded during the first night. MEG results showed that initial motor sequence learning was characterized by a progressive decrease in beta Event Related Desynchronization (ERD, 18-25Hz) over bilateral motor areas. Interestingly, while these practice-related modulations of beta ERD were not influenced by the sleep status, post-learned-movement beta Event Related Synchronization (ERS) over bilateral parietal areas increased over the consolidation interval in the sleep, compared to the sleep deprived, group. These results extend current models of motor memory consolidation by identifying ERS as an oscillatory marker of sleep-dependent consolidation.

How the brain orchestrates the flow of information between its multiple functional units flexibly, quickly, and accurately, remains a fundamental question in neuroscience. Multiple theories identify neural oscillations as a likely basis for this process. However, a lack of empirical validation of proposed theories, particularly at the whole-brain scale, has hampered consensus on oscillatory principles governing neural communication, limiting our understanding of a process central to perception and cognition and its integration into experiments and clinical applications. Here, we empirically validate previously proposed neural-oscillatory communication mechanisms in the human brain - specifically those involving power and interareal phase coherence - at the whole-brain scale. We do this by estimating the dependence of inferred communication on oscillatory measures that have been theorised to facilitate communication, in source-localised resting-state magnetoencephalography (MEG) recordings. We find that power and phase coherence in the alpha, beta, and high-gamma bands track communication better than others. Crucially, the relation between communication and oscillatory measures varied across regions, indicating spatial heterogeneity in routing mechanisms. Notably, power and coherence-based principles tracked communication patterns of unimodal regions better than those of transmodal regions. In sum, these findings suggest that the human brain implements regionally specific communication mechanisms with complex neural-oscillatory dependence.

Traumatic nerve injury is challenging as motor neurons with damaged axons repair slowly, which can lead to muscle degeneration, while in Spinal Muscular Atrophy (SMA), muscle innervation is reduced. While pro-regenerative or neuroprotective compounds have been identified, their specific ability to enhance or restore neuromuscular junction (NMJ) function in patients remains unclear due to a lack of in vitro human models that track axon growth, NMJ innervation and muscle function. We developed a human iPSC-derived motor neuron-myogenic coculture platform that enables real-time monitoring of axon growth NMJ innervation and axon regeneration and muscle activity following axonal injury, and for SMA-derived motor neurons. We identified spontaneous synchronized GCaMP6f muscle activity as a useful functional marker of NMJ formation. Using this platform, we show that blebbistatin, a pro-regenerative non-muscle myosin II (NMII) inhibitor differentially regulates growth cone dynamics in injured versus uninjured motor neurons, resulting in enhanced NMJ reinnervation. This highlights the therapeutic potential of developing pro-regenerative compounds to promote NMJ innervation. We also confirm that NMJ function is reduced in SMA type 0 (prenatal onset) and type I (pediatric onset) patient-derived motor neurons in the coculture. This human stem cell-based framework can be used, therefore, to evaluate pro-regenerative compounds for axon injury and neuroprotective one for neurodevelopmental and neurodegenerative disorders.

The Cocktail Party Problem (CPP) - extracting meaningful signals amid competing voices - remains poorly understood at the neural level, particularly in real-world contexts where it emerges naturally. We investigated the role of the anterior cingulate cortex (ACC) to resolve the CPP, a structure implicated in social monitoring but rarely examined in relation to audition, in freely-moving marmoset monkeys engaged in vocal exchanges with conspecifics in a noisy ecological environment. Analyses revealed that this neural substrate is seemingly integral to resolving the CPP. Not only did neurons encode the calls of either the conversational partner or background callers (i.e. figure/ground separation), but this selectivity persisted even with overlapping background sounds, a hallmark of the CPP. ACC was also sensitive to conversational dynamics by encoding turn-taking structure. These findings reveal that the ACC regulates dynamic vocal interactions in complex social soundscapes in which parsing meaningful calls from competing sounds is essential for effective communication.

Animals have evolved behavioral variation to adapt to distinct environmental features. The expansion of neuron number is a potential neural mechanism underlying this behavioral adaptation. Corticospinal neurons (CSNs) are a classic example: an expansion in the corticospinal system in the primate lineage has been hypothesized to underlie their exceptional dexterity. However, the role of CSN number in behavior has been difficult to assess due to the large evolutionary distance between primates and less dexterous taxa with fewer CSNs. Here, we use deer mice (Peromyscus maniculatus) to overcome this challenge. We compared two closely related subspecies of deer mice: forest mice, which evolved dexterous climbing to support a semi-arboreal lifestyle, and prairie mice, which are less dexterous. We find that forest mice have about two-fold larger corticospinal tracts (CSTs) driven by an increase in CSN number in secondary motor and sensory cortical areas (M2 and S2). Furthermore, in a reach-to-grasp test of dexterity, forest mice display higher success and greater grasping flexibility, using multiple grasp types. In contrast, prairie mice use a stereotyped scooping motion, consistent with the idea that an increase in CSN number supports more dexterous movement. High-throughput neural recordings during this task revealed a difference in the timing of neural activity between forest and prairie mice in M2, but not in primary motor cortex (M1): in forest mice, the peak of activity was shifted towards the time of grasp. Forest mice also outperform their prairie counterparts on an ecologically relevant climbing task, where they spend more time upright crossing a thin rod, move faster, and right themselves more quickly when they fall, suggesting a general difference in motor dexterity not restricted to hand use. To assess whether the increase in CSN number contributes to observed behavioral adaptations, we generated forest-prairie F2 hybrid animals with shuffled genomes, neural features, and behavior. We find that the F2 hybrids with larger CSTs perform better on the rod crossing task, suggesting that expansion of the CS system likely supports the adaptive increase in climbing dexterity in forest mice. Together, our work establishes the forest-prairie deer mouse system as a novel model to investigate the role of neuron number expansion, and CSNs in particular, in dexterous movement.

According to deficit models, early life adversity disrupts normal development, leading to long-term emotional, behavioural, and cognitive difficulties. However, some evidence suggests that certain psychological skills may be preserved or even enhanced by early adversity. We hypothesised that implicit learning and memory would be equally effective in individuals exposed to childhood adversity and those from more favourable backgrounds, and compared the effects of childhood versus adult adversity. To this aim, retrospective childhood harshness and unpredictability measurements and current perceived socio-economic status were collected in a sample of 325 participants at a Hungarian university taking part in an online experiment. They also completed a task allowing the assessment of multiple components of implicit statistical learning, including initial acquisition of regularities, consolidation of established regularities, resistance of established regularities against interference, and acquisition of novel regularities. Results showed that although statistical learning reached the same eventual level, its pace was quicker in individuals with relatively greater early life adversity exposure. Conversely, lower current socio-economic status was linked to reduced learning performance. These findings partially support the hidden talents framework, suggesting that early adversity may promote certain adaptive cognitive skills.

Several ion currents of zebrafish primary motoneurons undergo changes in expression level during early development. Similarly, the firing properties of primary motoneurons and their involvement during locomotor activity change during early development as locomotor control of developing zebrafish matures. To test whether the experimentally observed changes in ion currents during development could underlie changes in firing properties and in participation during locomotor activity, we created models of primary motoneurons at developmental stages. Changes in the expression levels of a persistent outward potassium current, persistent inward potassium current, and several high-voltage activated calcium currents were modelled based on experimental observations. Simulations of our computational models replicated shifts in primary motoneuron firing properties and involvement during light-evoked swimming observed at 3 and 5 days post-fertilization. Our results suggest that developmental changes in specific ion currents of primary motoneurons could be sufficient to foster changes in firing properties of primary motoneurons that shape their activity level during maturation of motor control in developing zebrafish.

Study objectives: Light, acting primarily via melanopsin-mediated signaling, plays a central role in synchronising circadian rhythms. Individuals vary markedly in the sensitivity of their circadian system to light. Whether these differences contribute to the interindividual variability in chronotype, a behavioural manifestation of internal circadian timing, is unclear. The aim of this study was to determine the relationship between melanopsin-dependent light sensitivity and chronotype across the general population. Methods: Participants (adults and children aged [≥] 8 years) were recruited in a science museum. Chronotype was determined using the {micro}MCTQ and the post-illumination pupillary response (PIPR) to short and long-wavelength light stimuli was used as a measure of melanopsin-dependent light sensitivity. The relationship between PIPR and chronotype and their interaction with age and sex were assessed using multiple linear regression. Results: Pupil recordings and questionnaires were available from 457 participants, including 284 adults and 173 children. In adults, the relationship between melanopsin-dependent light sensitivity and chronotype depends on sex and age: in young adult men, greater light sensitivity is linked to a significantly later chronotype, whereas it is significantly associated with an earlier chronotype in older adult women. In children, no evidence was found for a relationship between light sensitivity and chronotype. Conclusions: These findings suggest that individual variation in light sensitivity interacts with sex and age-specific differences in the circadian system and light exposure behaviour to influence circadian timing. Light exposure recommendations should be personalised to take into account these sex and age-specific effects. Statement of significanceWhile individuals differ widely in how their circadian system responds to light, to what extent these individual responses influence internal circadian timing remains unclear. By studying a large and diverse sample of children and adults, our findings reveal that the relationship between light sensitivity and chronotype, a behavioural manifestation of circadian timing, is shaped by both age and sex, offering a more comprehensive understanding of this relationship than previously recognised. Specifically, greater light sensitivity is linked to later chronotype in young men but to earlier chronotype in older women. These results reveal that the impact of light on circadian timing changes across the lifespan and will contribute to the development of personalised light exposure guidelines to promote health and well-being.

Specific Learning Disorders (SLD), including dyslexia, dyscalculia, and dysgraphia, are associated with deficits in executive functions such as auditory working memory (AWM). This study investigated AWM performance and metacognitive monitoring in adolescents diagnosed with SLD using an auditory delayed-match-to-sample task. Thirty-six participants (18 with SLD and 18 neurotypical controls) were assessed on accuracy, reaction time, and confidence ratings. Adolescents with SLD exhibited reduced sensitivity to auditory intensity differences, slower reaction times, and more conservative decision-making strategies. Drift diffusion modeling revealed lower evidence accumulation rates and wider decision boundaries in the SLD group. Moreover, confidence ratings were less influenced by stimulus differences, particularly among participants with dyslexia. These findings highlight impairments in auditory processing, decision-making, and metacognitive self-monitoring in adolescents with SLD. The results underscore the importance of interventions that address not only linguistic skills but also auditory decision-making and metacognitive strategies to support learning outcomes.

OBJECTIVES: To study the differential associations of regional volumes of grey matter (GM) and white matter hyperintensities (WMH) with behavioural and informant-reported measures of cognitive empathy (CE), especially in brain regions understood to have functional connectivity involvement with CE abilities. METHODS: Community-dwelling participants from the Sydney Memory and Ageing Study (Sydney MAS) underwent whole brain MRI. Regional cortical GM volumes were derived using FreeSurfer v7.1 for, and WMH volumes were derived using UBO Detector. On follow-up four years later, CE was indexed via the Reading the Mind in the Eyes Test (RMET; a behavioural task) and Interpersonal Reactivity Index - Perspective Taking subscale (IRI-PT; an informant-reported measure). RESULTS: In 129 participants (mean age 87.01 years), Structural equation modelling (SEM) showed associations between insula GM volumes and RMET scores (p=0.001), and between supramarginal gyrus (SMG) GM volumes and IRI-PT scores (p=0.016). Associations remained significant after inclusion of covariates accounting for age, global cognition, affective symptoms, and social networks. DISCUSSION: CE abilities assessed with RMET (a behavioural task) were positively associated with insula GM volumes. CE abilities on the IRI-PT (an informant-reported measure) were positively associated with SMG GM volumes. No associations between WMH volumes and CE measures were found. These findings may inform clinical workflows that use structural MRI investigations looking at social cognitive disturbances in older adults and provide further evidence of the divergent nature of behavioural and self-report measures of CE.

Motion vision underpins a wide range of adaptive behaviours essential for individual and species survival. Some visual behaviours are sexually dimorphic, including for example male hoverfly high-speed pursuit of conspecifics, matched by improved optics, and faster photoreceptors. Other visual behaviours are monomorphic, with for example similar foraging flight speeds in male and female hoverflies. However, whether the descending neurons responsible for sensorimotor transformation of optic flow are sexually dimorphic is unknown. To redress this, we combined morphological analysis with electrophysiology of optic flow sensitive descending neurons and compared neural responses to the wing beat amplitude in tethered hoverflies. We found that while optomotor flight behaviour is largely sexually monomorphic, the underlying neural responses are sexually dimorphic, especially at higher optic flow velocities. Additionally, neural and behavioural responses to roll stimuli had a slower onset compared to lift, revealing stimulus specific encoding. Together, our findings uncover a nuanced, sex- and stimulus- dependant sensorimotor transformation, shaped by both neural architecture and behavioural demands.

Mild traumatic brain injury (mTBI) is common among adolescents because of their participation in contact sports and mTBI is more likely to lead to depression-related behaviors in girls than boys. Various neuropeptides, often within the limbic system, have been implicated in the regulation of depression-related behaviors. To identify potential neuropeptide involvement in behavioral effects of mTBI, this study used adolescent-age male and female rats to compare the effects of single and repetitive mTBI on depression-like behavior and limbic neuropeptide expression. Female but not male rats displayed increased immobility in the forced swim test compared to sham-injured rats at 5-weeks (chronic), but not 2-weeks (acute) following closed-head injury, and this effect was estrous cycle-dependent following single but not repetitive injury. In the nucleus accumbens (NAc), a major limbic nucleus, mRNA expression of corticotropin-releasing factor (CRF) and dynorphin (DYN) was decreased after single injury only in female rats, particularly during the estrus phase, while expression of enkephalin (ENK) was decreased after repetitive injury. In the paraventricular nucleus of the thalamus (PVT), another limbic nucleus, mRNA expression of pituitary adenylate cyclase-activating polypeptide (PACAP) was increased in repetitively injured female but not male rats at 2- and 5-weeks but was unchanged in single injured female rats compared to sham-injured rats. These data suggest that depression-like behavior emerges in the chronic phase following adolescent mTBI only in females, being estrous cycle-dependent following single-injury. Moreover, reduced ENK in the NAc and elevated PACAP in the PVT may contribute to depression-like behavior in females following repetitive mTBI.

Hyperthyroidism (HT) has been associated with cognitive impairments, but the structural connectomic and molecular mechanisms underlying these deficits remain poorly understood. In this study, we investigated large-scale brain network reorganization using structural connectivity derived from diffusion MRI in patients with 30 hyperthyroidism and 28 matched control participants. Subject level connectomes were analyzed to characterize network topology, with a specific focus on hub architecture, nodal alterations, and hemispheric reorganization. To probe molecular underpinnings, we integrated normative neurotransmitter receptor and transporter density maps with network metrics, assessing their correspondence to observed connectomic disruptions. Individuals with hyperthyroidism exhibited increased structural connectivity, particularly in mid- and long-range connections, alongside disrupted network topology. These changes were characterized by reduced modularity, increased characteristic path length and hub reorganization, most prominently in subcortical and right-hemisphere regions. Importantly, network alterations were functionally relevant, as metrics showed significant associations with clinical and cognitive variables, including FT4 levels, BMI, and perceptuomotor performance in the hyperthyroid group. Spatial neuromolecular correspondence analyses further revealed that DAT, 5-HT2A, and NET were closely aligned with topological changes. Moreover, neurotransmitter-weighted within-module degree z-scores moderately predicted TSH levels in HT. Our findings demonstrate that hyperthyroidism is associated with an increase in redundant, spatially extended white matter connections and a marked right-lateralized asymmetry in network organization. Furthermore, serotonergic (5-HT1a) and dopaminergic (DAT) systems consistently contributed to the modulation of intra-modular hubness, suggesting their role in maladaptive structural reorganization that may underlie perceptuomotor dysfunction in hyperthyroidism.

Intracortical microstructure profiling represents a powerful, scalable approach for investigating the laminar organisation of the human cortex on both in vivo and post-mortem datasets. Building upon a long tradition of histological analysis, this method leverages surface-based intracortical sampling to generate profiles of tissue properties across cortical depths. The present work outlines a standardised workflow for intracortical microstructural profiling, newly packaged as an open-source toolbox "CortPro" (https://github.com/caseypaquola/cortpro). Here, we explore the utility of central moments as descriptors of profile shape. Using these measures, we quantify (i) the extent to which in vivo MRI can capture laminar differentiation, (ii) the test-retest reliability of profiles, and (iii) their replicability across sites and studies. Our results demonstrate that intracortical profiles are remarkably robust and effectively mitigate bias-field related limitations of non-quantitative MRI. As applications of microstructure-sensitive imaging expand across development, aging, and disease, microstructure profiling provides a principled means of linking microstructural neuroanatomy with systems-level brain organisation.

Motor preferences, such as handedness, reflect fundamental asymmetries in brain function and behavior across vertebrate species, including humans and rodents1. Although individual hand or paw preferences are typically stable, they can be reshaped through experience or training, underscoring the plasticity of lateralized motor circuits2. However, the neural mechanisms that enable this behavioral switching remain unclear. Here we show that experience-driven shifts in paw preference in mice arise from asymmetric cholinergic modulation between the two hemispheres. Using a behavioral paradigm designed to induce paw switching, we found that a subset of animals developed a stable change in preference following training. Selective activation or inhibition of cholinergic neurons on one side of the brain was sufficient to bias this switching behavior. During lateralized movements, an endogenous imbalance in cholinergic activity emerges between the hemispheres, suggesting that interhemispheric cholinergic asymmetry enables motor flexibility. These findings identify a previously unrecognized mechanism by which cholinergic signaling dynamically regulates lateralized motor control, providing insight into how hemispheric imbalances may shape persistent individual motor preferences.

Focal cortical dysplasia(FCD) is a leading cause of drug-resistant epilepsy, traditionally attributed to impaired inhibition. However, recent ultrastructural evidence suggests excitatory synaptic alterations may also contribute. To investigate this, we performed computational modeling of human pyramidal neurons in NEURON, incorporating electron microscopy derived dendritic spine morphologies. Baseline and FCD-like models were constructed with differences in spine density and morphology while maintaining comparable net synaptic input. Simulations revealed that reduced spine density increased input resistance and amplified excitatory postsynaptic potentials, enhancing dendritic to somatic transmission. Spine neck geometry, but not head size, critically shaped voltage compartmentalization. The altered model required markedly fewer synchronous inputs to reach spiking threshold and exhibited higher firing rates under Poisson distributed synaptic activity, particularly under sparse input conditions. These results demonstrate that excitatory microstructural changes - reduced spine density and weakened neck compartmentalization - can elevate neuronal excitability, in addition to the inhibitory deficit which is the biggest known effect. These findings highlight excitatory spine remodeling as another key driver of epileptogenesis. We speculate that extending this analysis will be essential to fully understand circuit-level hyperexcitability and to identify new therapeutic targets.

Although functional networks can be consistently identified across cognitive states, they also undergo dynamic reconfigurations across different contexts. For example, naturalistic movie watching paradigms amplify activity in sensory systems compared to resting conditions. However, it remains unclear how these different states affect large-scale brain organization. The current study leveraged high-resolution in vivo 7T fMRI data from the Human Connectome Project (HCP) and the Precision NeuroImaging (PNI) datasets to examine large scale functional connectivity changes between resting and movie-watching conditions. To understand these changes within topographic and geometric principles of brain organization, connectivity shifts were stratified relative to macroscale cortical hierarchy and geodesic distance. Our results revealed that primary sensory areas showed increased local connectivity and reduced long-range interactions during movie watching relative to resting conditions, whereas the default mode network (DMN) exhibited an opposing pattern characterized by reduced within-network long-range connectivity and enhanced connectivity with distant regions outside the DMN. Together, these findings demonstrate that different cognitive states involve geometry- and hierarchy-informed reorganization of large-scale functional networks.

Neuronal assemblies defined by coordination at high temporal resolution are thought to act as functional modules for information processing throughout the brain. Here, we develop a new method for identifying these assemblies from analytical tests of pairwise synchrony, benefiting from three rigorous criteria for assembly detection and sensitivity to rare but significant coordinated firing patterns. Following validation through simulations and in vivo recordings, we perform synchrony-based analysis on datasets from both primary (A1) and non-primary (PEG) ferret auditory cortex during passive listening to complex natural sounds. We show that synchrony-driven assemblies (SDAs) in both areas exhibit regular temporal dynamics, including the production of stereotypical spike sequences. In-keeping with their enhanced inter-neuronal reliability, SDAs are observed to outperform random assemblies in two versions of rate-based decoding. We extend these results to temporal decoding, and consistently observe optimal integration windows of 10-20ms. Thus, we suggest that SDAs are sufficient for the accurate representation of diverse sets of complex auditory stimuli, and that this increase in information depends entirely on coordination at very fine temporal scales.

Theories of the neural mechanism underpinning rapid recognition debate whether it relies solely on a feedforward sweep through the ventral stream or instead requires recurrent processing, possibly engaging additional brain regions. Here we directly tested the "adaptive recurrence hypothesis", that attempts to unify these disparate views by proposing that additional recurrent cortical resources beyond the visual stream are recruited when feedforward processing alone is insufficient to solve object recognition. To investigate this hypothesis, we contrasted functional MRI (fMRI) and electroencephalography (EEG) responses to compare neural responses to images that are equally well recognized by humans, but that differ in whether they could be solved by a feedforward deep neural network; a computational proxy for ventral stream feedforward processing. We found that when feedforward processing in the ventral visual stream is insufficient, additional parieto-frontal networks are rapidly and transiently recruited, representationally reconfiguring the ventral visual stream. Our results reveal that object recognition flexibly adapts through fast, cortex-wide recurrence, providing a unifying framework for competing theories of visual recognition.

Calcium imaging (CI) is a standard method for recording neural population activity, as it enables simultaneous recording of hundreds-to-thousands of individual somatic signals. Accordingly, CI recordings are prime candidates for population-level latent variable analyses, for example using models such as Gaussian Process Factor Analysis (GPFA), hidden Markov models (HMMs), and latent dynamical systems. However, these models have been primarily developed and fine-tuned for electrophysiological measurements of spiking activity. To adapt these models for use with the calcium signals recorded with CI, per-neuron fluorescence time-traces are typically either de-convolved to approximate spiking events or analyzed directly under Gaussian observation assumptions. The former approach, while enabling the direct application of latent variable methods developed for spiking data, suffers from the imprecise nature of spike estimation from CI. Moreover, isolated spikes can be undetectable in the fluorescence signal, creating additional uncertainty. A more direct model linking observed fluorescence to latent variables would account for these sources of uncertainty. Here, we develop accurate and tractable models for characterizing the latent structure of neural population activity from CI data. We propose to augment HMM, GPFA, and dynamical systems models with a CI observation model that consists of latent Poisson spiking and autoregressive calcium dynamics. Importantly, this model is both more flexible and directly compatible with standard methods for fitting latent models of neural dynamics. We demonstrate that using this more accurate CI observation model improves latent variable inference and model fitting on both CI observations generated using state-of-the-art biophysical simulations as well as imaging data recorded in an experimental setting.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with limited treatment options. Mutations in SOD1 are a leading genetic cause of familial ALS, driving motor neuron degeneration through toxic gain-of-function mechanisms. While gene silencing strategies targeting SOD1 hold therapeutic promise, their clinical translation has been hindered by inefficient delivery to the spinal cord and safety concerns associated with conventional viral vectors. Here, we report a minimally invasive gene therapy strategy that combines the retrograde transport capability of rAAV2-retro with the safety of an artificial microRNA (miRNA) to achieve pan-spinal SOD1 suppression. A single intramuscular injection of rAAV2-retro-miRNA into neonatal SOD1G93A mice resulted in widespread transduction of spinal motor neurons, significant reduction of mutant SOD1 protein, and multifaceted therapeutic benefits. Treated mice exhibited delayed disease onset, extended survival, preserved motor function, reduced neuroinflammation, and protection of neuromuscular junctions and spinal motor neurons. Importantly, the artificial miRNA platform demonstrated a superior safety profile compared to shRNA-based constructs, which caused severe toxicity and lethality in wild-type mice. Our study establishes neonatal intramuscular delivery of rAAV2-retro-miRNA as a safe, efficient, and clinically translatable strategy for preemptive intervention in SOD1-mediated ALS, with broad implications for the treatment of other motor neuron diseases.

Chronic pain remains a major unmet medical challenge, and lipid signaling pathways have emerged as key modulators of nociception. Using Caenorhabditis elegans as a genetically tractable model, we investigated how fatty acid composition influences thermal avoidance behavior. Mutant strains lacking functional desaturase enzymes (elo-1, fat-1, fat-2, fat-3, fat-4, fat-6/fat-7), and consequently depleted in polyunsaturated fatty acids (PUFAs) such as arachidonic acid, displayed significantly reduced sensitivity to noxious heat compared to wild-type animals. These findings indicate that intact PUFA biosynthesis is essential for normal thermal nociception in C. elegans. Given that arachidonic acid is a precursor of endocannabinoids (AEA and 2-AG) known to modulate TRPV1-dependent pain signaling, our results suggest that a conserved lipid-based mechanism regulates heat avoidance in nematodes. This study establishes a functional link between fatty acid metabolism and nociceptive behavior, providing a powerful platform to explore metabolic modulation of pain pathways.

Theoretical models emphasize that categorical factors, dimensional factors, or their combination may define the semantic space organization of emotion representations. While recent behavioral work has applied innovative multivariate methods for testing these theories, neuroscientific assessments remain limited due to a focus on a small number of emotions, single theoretical perspectives, univariate methods, or small sample sizes. We overcame these limitations in a comprehensive functional magnetic resonance imaging (fMRI) study in which participants (N = 136) viewed 150 movie clips and 150 text scenarios that reliably induced 15 different emotional states spanning positive, negative, and neutral valence. For the movie inductions, representational similarity analysis yielded a correspondence between the categorical behavioral responses and the brain activity patterns, and partial least squares discriminant analysis achieved strong decoding performance for all 15 emotions from whole-brain fMRI data, with importance maps encompassing cortical, limbic, and subcortical regions. Classification error analyses and a Bayesian model comparison supported the categorical nature of the emotion representations relative to a 2-dimensional arousal-valence model. Hierarchical clustering of the representational dissimilarity matrices revealed that the 15 emotions were organized into similarly meaningful clusters at both the subjective and neural levels. Results from the scenario inductions, while demonstrating similar behavioral effects and behavioral hierarchical structures, were more difficult to decode from the fMRI data. Overall, these findings provide novel insights into how emotions are organized and represented in the human brain and evidence a relationship between our subjective experience of and brain responses to emotional inductions.

The motor cortex supports various cognitive and motor functions. To prevent interference between these processes, the associated neural dynamics may be organized into orthogonal subspaces. In this subspace model, activity in a movement-null subspace encodes internal processes, while activity in a movement-potent subspace relates to movements. The biological implementation of this model, how activity in different subspaces map onto neural circuits, remains unclear. Particularly, it is unknown whether different cell types, with specific connectivity patterns, preferentially contribute to specific subspaces. Here, we test whether the cell type that directly links motor cortex to motor centers in the medulla and spinal cord, lower layer 5b extratelencephalic neurons (L-ETN), preferentially encodes activity contained in the movement-potent subspace. We performed cell-type-specific recordings in the motor cortex while mice performed a delayed-response licking task, and decomposed population activity into movement-null and movement-potent subspaces. We find that L-ETN activity spans both movement-null and movement-potent subspaces in a manner that could not be distinguished from the broader motor cortex population. Notably, downstream medullary circuits retain a subset of the movement-null dynamics contained in motor cortex, with select movement-null signals specifically filtered out. These results indicate that a distinct cortical output alone does not mediate the cancelation of movement-null dynamics; movement-null computations are instead distributed across the descending motor hierarchy.

Objects in motion follow predictable trajectories that the brain can easily anticipate. We investigated the underlying neural mechanisms, focusing on a form of representational momentum (RM), whereby the final state of a rotating object is misperceived along its future trajectory. Participants viewed two simultaneous streams of oriented gratings, one rotating predictably and the other random, and were instructed to attend to one of the two. Using EEG steady-state visual evoked potentials (SSVEPs) and decoding analysis, we found that attending to rotational sequences led to reduced neural response amplitude and systematic anticipatory shifts in the neural representation of orientation, relative to random sequences. These anticipatory biases emerged at early post-stimulus latencies and mirrored behavioral signatures of RM. Our findings suggest that the brain leverages internalized dynamics to form stable anticipatory representations with reduced neural activity strength.

Cerebellar granule cells (GCs) are critical for motor and cognitive functions. Lineage tracing studies have identified a hierarchical developmental progression of GC neurogenesis, transitioning from Sox2+ stem-like cells to Atoh1+ rapidly proliferating granule cell precursors (GCPs), and ultimately to NeuN+ mature GCs. However, the molecular mechanisms governing these transitions remain poorly understood. In this study, we identified a transient, slow-cycling progenitor population defined by co-expression of Sox2 and Atoh1. We show that GC maturation depends critically on the repressive function of the Sin3A/Hdac1 complex, which sequentially silences Sox2 and then Atoh1 to ensure orderly progression through developmental stages. Loss of these repressions prolongs progenitor states, compromises survival, and markedly reduces GC output. We also identify NeuroD1 as a co-repressor that collaborates with Sin3A/Hdac1 to inhibit Atoh1 transcription. Our findings highlight the central role of the Sin3A complex in orchestrating distinct stages of cerebellar GC lineage development and may provide insights into Sin3A-related cerebellar disorders and medulloblastoma in human.

Infantile amnesia, the inability to recall episodic memories formed during early childhood, is a hallmark of postnatal brain development. Yet the underlying mechanisms remain poorly understood. This work aimed to gain a better mechanistic understanding of infantile amnesia. Microglia, specialized macrophages of the central nervous system, are known to play an important role in synaptic refinement during postnatal development and have recently been implicated in memory related functions. Here, we identified microglia as key regulators of memory accessibility in infancy. We profiled dynamic changes in microglial morphology across the postnatal window that parallelled the onset of infantile forgetting. We found that pharmacological inhibition of microglial activity during a specific postnatal window prevents infantile amnesia for a contextual fear memory, implicating microglia as active modulators of infant memory persistence. Using activity-dependent tagging of infant encoded engram cells, we demonstrated that microglial inhibition alters engram size and engram reactivation in the amygdala and results in changes in microglia-engram cell interactions. Furthermore, we characterized a relationship between microglial dysfunction and the lack of infantile amnesia in MIA offspring. Together, these findings reveal a novel role for microglia in regulating infant memory retrieval and suggest that microglial dysfunction may contribute to altered memory trajectories in neurodevelopmental disorders.

How do we translate information from a spatial map to action in our immediate surroundings? Despite the widespread use of various tools for orientation, from paper maps to GPS, this fundamental question remains unanswered in our understanding of human spatial navigation. To investigate this, we implemented a perspective-taking task in immersive virtual reality combined with mobile EEG, aiming to disentangle the neurocognitive processes involved. Thirty-eight young adults were presented with a virtual 2D map in which we manipulated both the perspective shift and the physical angle of rotation required to align with a target, as well as the congruency between these two variables. Behaviourally, angular error during pointing increased slightly and linearly with perspective shift. However, the relationship between rotation angle and accuracy revealed a non-linear pattern, with better performance around the antero-posterior bodily-axis. Regarding congruency, angular error increased for incongruent trials, but only when the perspective-taking angle exceeded 90 degrees. At the neural level, activity in the retrosplenial complex (RSC) revealed a sequential organization with alpha-band modulation during perspective shift, followed by beta-band activity reflecting preparation for the required physical rotation. In addition, incongruency between perspective-taking and physical rotation increased beta activity in the left temporo-parietal junction (lTPJ). Overall, these findings demonstrate the value of immersive virtual environments to investigate the neural correlates of real-world navigation and the complexity of perspective-taking mechanisms.

Human motivation is fundamentally shaped by one's expectations of the reward they could earn for good performance or the punishment they would avoid for poor performance. However, the extent to which distinct brain regions are selectively associated with specific incentives and/or their corresponding influence on control strategy remains unclear. Using model-based fMRI and a novel multi-incentive control task, we observed distinct neural patterns by incentive valence, with ventral striatum and caudal subregion of dorsal anterior cingulate cortex showing greater sensitivity to rewards whereas inferior frontal gyrus and rostral subregion of dorsal anterior cingulate cortex showing greater sensitivity to penalties. Reward-sensitive regions were associated with increased efficiency (e.g., faster responding with moderate decreases in accuracy) whereas penalty-sensitive regions were associated with increased caution (e.g., slower responding with increased accuracy). We disentangled the global and selective influences of motivation on control processes and subjective experience, providing novel insight into the neurocomputational mechanisms of how effort is determined by expected reward and punishment.

Human motivation is fundamentally shaped by one's expectations of the reward they could earn for good performance or the punishment they would avoid for poor performance. However, the extent to which distinct brain regions are selectively associated with specific incentives and/or their corresponding influence on control strategy remains unclear. Using model-based fMRI and a novel multi-incentive control task, we observed distinct neural patterns by incentive valence, with ventral striatum and caudal subregion of dorsal anterior cingulate cortex showing greater sensitivity to rewards whereas inferior frontal gyrus and rostral subregion of dorsal anterior cingulate cortex showing greater sensitivity to penalties. Reward-sensitive regions were associated with increased efficiency (e.g., faster responding with moderate decreases in accuracy) whereas penalty-sensitive regions were associated with increased caution (e.g., slower responding with increased accuracy). We disentangled the global and selective influences of motivation on control processes and subjective experience, providing novel insight into the neurocomputational mechanisms of how effort is determined by expected reward and punishment.

Oligodendrocytes produce myelin, a lipid-rich membrane that wraps neuronal axons in the central nervous system to provide metabolic and trophic support and allow for saltatory conduction. Developmental myelination requires precisely timed and localized neuron-oligodendrocyte communication. In the mature brain, neuronal activity promotes oligodendrocyte precursor cell (OPC) proliferation and differentiation, but how OPCs respond to neuronal activity in early brain development, prior to the onset of myelination, is less well characterized. Here, we investigate how sensory-evoked and chemogenetically altered neuronal activity affect oligodendrocyte maturation in the olfactory system, somatosensory cortex, and corpus callosum in mice. We find that early neuronal activity inhibits oligodendrocyte differentiation and that reduced neuronal activity relieves this inhibition, thereby increasing OPC differentiation. Additionally, single-cell RNA sequencing revealed transcriptional changes in oligodendrocytes when neuronal activity was reduced, including upregulation of glutamate receptor gene expression. Finally, we identify AMPAR signaling as a critical regulator of oligodendrocyte differentiation ex vivo.

To navigate the world, humans must integrate what they see with how they move. As the body moves, for example, the eyes rotate to explore the environment; these eye rotations, in turn, alter the visual signals used to judge body motion. Yet the practical impact of gaze dynamics on self-motion perception remains poorly understood. We tested how gaze position and gaze velocity shape self-motion perception--specifically heading direction--from visual signals in two behavioral experiments. In Experiment 1, we directly manipulated gaze position and velocity; in Experiment 2, a range of task demands evoked distinct gaze patterns. Across both experiments, heading estimates showed systematic, gaze-dependent errors: these estimates shifted toward the direction of eye motion and grew with horizontal gaze eccentricity and speed. A Bayesian ideal observer reproduced these error patterns across participants and tasks when it included three known features of visuomotor processing: (i) encoding retinal motion with eccentricity-dependent noise, (ii) underestimating eye-rotation speed, and (iii) a prior for moving straight ahead. These results reveal a lawful coupling between oculomotor behavior and heading perception. They further suggest that natural gaze strategies, such as keeping gaze near the optic-flow singularity and limiting pursuit speed, help mitigate gaze-dependent biases during navigation.

Gestational age plays a crucial role in neurodevelopment, and individuals born very preterm (VPT) are at elevated risk for cognitive, behavioural and psychiatric problems across the lifespan. Better understanding of the impact of very preterm birth on cortical maturation trajectories could inform mechanistic insights into the origins of these sequelae. Here we compared cortical morphology between VPT individuals and full-term controls in three datasets spanning birth, childhood and adulthood. We identified a consistent cortical signature of VPT birth, characterized by reduced surface area and cortical folding in the frontal, temporal, parietal and insular regions, which persisted across development. Furthermore, in two large infant cohorts, we found that this cortical signature was significantly associated with neonatal clinical factors and with poorer motor outcomes at follow-up, suggesting its potential as a neuroimaging marker for long-term neurodevelopmental risk. Given that early motor development plays a key role in shaping infants interactions with the environment and supporting later cognitive and behavioural development, our findings provide insights into the neurobiological pathways linking VPT birth to subsequent neurodevelopmental difficulties.

Are actions organized like sentences? Recent evidence showed reciprocal transfer between tool use and syntactic comprehension, reflecting shared basal ganglia (BG) resources for action and language. The proposed mechanism is that embedding a tool into the motor plan increases the hierarchical structure of actions paralleling the organization of sentences. If so, overlap with linguistic computations should emerge specifically during the initiation and/or reach-to-grasp phase, when tool embedding dynamically updates the relation with the target, rather than when the object is stably held in the tool grip. Forty French native speakers underwent fMRI while performing a sentence comprehension (object vs. subject relatives), and a motor task (with pliers vs. hand). Only the reach-to-grasp phase with the tool elicited neural patterns resembling those of object-relatives, within overlapping BG regions. This phase-specific convergence identifies the BG as a hub for domain-general hierarchical computations, unifying syntactic embedding for language and tool use.

Neural theories of how the prefrontal cortex (PFC) supports working memory rely on evidence from decades of pioneering macaque research. In some respects, efforts to translate these animal models of working memory in human PFC using neuroimaging have largely failed. One possible explanation, before concluding key non-homologies between the species, is that previous neuroimaging studies used resolutions too coarse to be sensitive to intermixed distributions of neurons tuned to memorized features. To resolve this concern, we scanned human PFC at 900 micron resolution using 7T fMRI. We found that population activity in retinotopically-organized superior precentral sulcus, rather than the predicted midlateral PFC, persists during memory, encodes fine-grained information about memorized items, predicts behavioral errors in memory, and forms a stable subspace with a topological organization yoked to visual space. These results have important implications for both functional homologies between the species and theories of how the PFC supports working memory.

Living systems maintain physiological variables such as temperature, blood pressure, and glucose within narrow ranges; a process known as homeostasis. Homeostasis involves not only reactive feedback but also anticipatory adjustments shaped by experience. Prior homeostatic reinforcement learning (HRL) models have provided a computational account of anticipatory regulation under homeostatic challenges. However, existing formulations lack mechanisms for gradual, trial-by-trial adjustment and for extinction learning. To address this issue, we developed a continuous HRL framework that enables trial-wise tuning of anticipatory regulation. The model incorporates biologically informed components: asymmetric reinforcement, weighting negative outcomes more than positive outcomes; and a dual-unit, context-gated inhibitory mechanism. We applied the framework to thermoregulatory conditioning with ethanol-induced hypothermia and successfully reproduced cue-triggered compensation, gradual tolerance, and rapid reacquisition after extinction. We then extended the framework to multiple physiological variables influenced by shared neural or hormonal control signals, and found that when regulatory priorities across variables were uneven, a deviation in one variable propagated through shared control to others, yielding a cascading, system-wide failure to return to ideal state (non-recovery); a pattern reminiscent of autonomic dysregulation (e.g., dysautonomia, ME/CFS). Overall, our framework provides a computational basis to advances a systems-level understanding of multi-organ homeostatic dysregulation in vivo.

Stress is known to play a critical role in relapse to drug use as well as in food craving. Craving itself is a key determinant of relapse, and cue-induced drug craving has been shown to increase, or incubate, over time for certain drugs such as cocaine and nicotine, though this effect is less consistent for others such as opiates. However, the contribution of stress-related biochemical systems to the incubation of seeking has not yet been systematically examined in animal models, nor has the specificity of these mechanisms been tested across different drug classes or reinforcers. To address this gap, we trained rats to self-administer cocaine (0.75 mg/kg, i.v.), heroin (0.075 mg/kg, i.v.), or saline, and subsequently assessed changes in plasma corticosterone, ornithine and other stress-related amines, alongside central gene and protein expression (CRH, CRH2 receptor, and alpha- and beta-adrenergic receptor subunits) after 1 or 30 days of withdrawal. A parallel experiment was conducted using sucrose as a reinforcer. Our findings indicate that although most effects were substance-specific, convergent adaptations were also observed, particularly within noradrenergic systems, suggesting that these mechanisms may represent a common substrate of incubation and a potential target for pharmacological interventions in relapse.

Within-situation disengagement - the mental withdrawal during conversations in acoustically challenging environments - is a common experience of older people with hearing difficulties. Yet, most research on the neural mechanisms of attentional disengagement from speech listening has focused on the distraction by one competing speaker, whereas within-situation disengagement is often characterized by distraction towards external visual stimuli or internal thoughts and occurs in situations with ambient, multi-talker background masking. Across three electroencephalography (EEG) experiments, the current study examined how disengagement due to external and internal distractions affect the neural tracking of speech masked by different levels of multi-talker babble (speech in quiet, +6 dB, and -3 dB SNR). We observed early (<200 ms), enhanced neural responses to the speech envelope for speech masked by background babble compared to speech in quiet (Experiments 1-3), suggesting stochastic facilitation. Importantly, neural tracking of the speech envelope was reduced when individuals were distracted by a visual-stimulus stream (Experiment 2) and by internal thought and imagination (Experiment 3). There were some indices suggesting the greatest disengagement-related decline in neural speech tracking occurs for the most difficult speech-masking condition, but this was not consistent across all measures. The current data show that disengagement due to external and internal distractions yield decreases in neural speech tracking, potentially suggesting a common neural pathway through which gain is downregulated in auditory cortex. These results indicate that disengagement from listening can be identified through non-invasive neural measures.

Background and Hypothesis Cognitive and negative symptoms in schizophrenia remain poorly treated. Iron dysregulation has been implicated as a potential mechanism underlying cognitive dysfunction and schizophrenia. While elevated postmortem iron in Brodmann areas 10-11 has been linked to schizophrenia, this has not been assessed in vivo. We therefore used iron-sensitive MRI to test whether cortical iron is elevated in individuals with schizophrenia compared to healthy controls. Study Design We acquired quantitative susceptibility mapping (QSM) MRI to measure magnetic susceptibility ({chi}), a marker of iron, in 158 participants aged 18-45 (73 with schizophrenia and 76 matched healthy controls). As {chi} is reduced by myelin, we conducted diffusion tensor imaging (DTI) to assess mean diffusivity, an iron-insensitive marker also reduced by myelin. Study Results Primary analyses showed no significant case-control differences in {chi} in the whole cortex (p=0.675) or Brodmann areas 10-11 (p=0.537). Exploratory analyses examined {chi} for 362 cortical regions and a voxelwise analysis, correcting for multiple comparisons. Two left temporo-parieto-occipital (TPO) junction regions showed significantly elevated {chi} in schizophrenia: the posterior TPO junction (d=0.752, p<0.001) and the superior temporal visual area (d=0.638, p=0.033), which remained significant after adjusting for mean diffusivity and clinical covariates (p=0.001 and p=0.023, respectively). Voxelwise analysis confirmed elevated {chi} in schizophrenia in the left TPO junction (peak t=5.62). Conclusions This study provides the first in vivo evidence of elevated cortical iron in schizophrenia, suggesting regional iron accumulation may contribute to cortical pathology.

Spinal cord injury (SCI) causes devastating functional deficits, in part due to neuroinflammation, oxidative stress, and excitotoxicity that drive death of lesion-adjacent viable neurons. One signaling protein that promotes neuronal apoptosis and activates stress-responsive genes is dual leucine zipper kinase (DLK), which is a neuron-enriched kinase that responds to extracellular stress by activating the c-Jun N-terminal kinase (JNK) pathway. We hypothesized that SCI would robustly activate DLK signaling and that acute pharmacological inhibition of DLK would suppress JNK pathway activation, thereby enhancing neuroprotection and locomotor recovery in our mouse model of moderate contusion SCI. Using western blotting, we observed that SCI induced strong and sustained activation of the JNK pathway in the injured spinal cord starting at 4 hours post-injury through 7 days. Complementary analysis of single-nucleus RNA-seq revealed that DLK expression is highly enriched in neurons across all injury phases. Following SCI, neurons exhibited robust, time-dependent upregulation of multiple DLK-responsive transcripts, consistent with sustained pathway activation during the acute and subacute periods. Systemic treatment with the selective DLK inhibitor IACS'825 effectively suppressed intraspinal JUN activation in a dose-dependent manner. However, unexpectedly, DLK inhibition delayed functional recovery in male mice and expanded lesion volume by 71%, with no significant effect in females. These findings highlight the complex roles of DLK signaling after SCI, revealing a need to understand the sex-specific molecular mechanisms that modulate injury outcomes. Future studies should further optimize timing, location, and cellular targeting of DLK therapeutic strategies to improve neuroprotection and neurologic recovery after SCI.

Apnea of prematurity (AOP) affects 50% of preterm infants causing intermittent hypoxia (IH), which can lead to long-term neurodevelopmental deficits. Cerebellar abnormalities have been observed in AOP but the relationship between vascular alterations and neural development remains unclear. This study investigates how IH affects cerebellar angiogenesis using a murine model of AOP. We developed an innovative 3D imaging workflow combining IMARIS and VesselVio software to quantitatively analyze cerebellar vascularization at different postnatal stages (P4, P8, P12, P21, and P70). We correlate these results with a transcriptomic analysis of 23 angiogenesis-related genes in the same stages to uncover the associated molecular pathways. We found that IH induced significant vascular changes, particularly at P4, with a global increase in vascular-network dimensions. By P8, the vascular network normalized, but genes were downregulated in all pathways studied. After P12, at the end of the IH protocol, transcriptional regulations vary but persist long-term. Moreover, differential analysis showed distinct effects on superficial versus deep vascular networks, allowing for a more precise understanding of remodeling patterns throughout development. Overall, transcriptomic changes were associated with morphological alterations in a time-dependent manner, suggesting a multiphasic IH response through development with lasting effects. Key regulations included VEGF, angiopoietin, and matrix metalloprotease signaling. These findings demonstrate that IH disrupts cerebellar angiogenesis in parallel with neurogenesis, potentially contributing to the neurodevelopmental deficits observed in AOP. Thus, the interconnected nature of angio- and neurogenesis during cerebellar development makes it crucial to take vascular aspects into account in therapeutic approaches to neurodevelopmental disorders.

Astrocytic glia regulate brain assembly, synapse formation/activity, neuronal energetics, and brain metabolism. Gene programs driving astrocyte specification are only partly understood. Here, we use lineage-restricted single-cell RNA sequencing to uncover a two-phase developmental program for C. elegans CEPsh astrocyte differentiation. In phase one, newly generated astrocytes acquire common transcription profiles despite arising from lineally and transcriptionally distinct progenitors. Convergent differentiation is mediated by the distal-less transcription factor CEH-43. CEH-43 is expressed in astrocytes and their progenitors, binds conserved astrocyte-expressed genes, and cell-autonomously controls astrocyte-specific gene expression. Forced misexpression of CEH-43 in the embryo promotes ectopic expression of astrocyte-specific reporters. The second gene expression phase, directing astrocyte maturation, is also under CEH-43 control. Homologs of CEPsh astrocyte-enriched genes are preferentially enriched in mammalian astrocytes, and the CEH-43 homologs DLX1/2 are expressed in mouse astrocytes. Our findings suggest parallels between CEPsh and mammalian astrocyte development, implicating conserved regulators in astrocyte cell-fate acquisition.

Suckling by newborns is an instinctive behavior defining the mammalian class. Yet, due to experimental difficulty in assessing neural function in the very young, little is known about the neural control of this fundamental behavior. Here we develop molecular-genetic approaches to interrogate neuronal connectivity and function in newborn mice and used these tools to identify a population of pro-dynorphin (PDYN) and somatostatin (SST) expressing neurons in the central amygdala that are activated during suckling. CeA PDYN+SST+ neurons connect with brainstem areas mediating oral sensorimotor and reward function in adults, and their ablation in newborns decreases suckling vigor and impairs growth. These results uncover the crucial role of a specific neuronal population of the central amygdala in maintaining the infants propensity to suckle and thrive throughout infancy.

Motor memory is essential for our daily activities. It involves complex neural processes during learning and sleep. However, unlike explicit memory where its neural activation and role in memory consolidation are well-studied, the properties of cell ensembles for motor memory are less understood. In this study, we re-examined rats' behavior and neural activity in the primary motor cortex (M1) and hippocampus while the animals were trained daily on a single-pellet reaching task. Recordings included both the training and 3 hr rest epochs before and after training. Behaviorally, the animals were classified into two learning types: rapid and gradual learners. Unsupervised cell ensemble detection on M1 neurons revealed that about 60% of the ensembles were modulated during reaching behavior. Those reach-related ensembles were further categorized into four types, and their replay was detected during both slow-wave sleep (SWS) and REM sleep. In SWS, replay preferentially occurred during spindles, especially slow-oscillation coupled spindles (SO-spindles). In addition, about 30% of the reach-related cell ensembles were modulated during the hippocampal sharp-wave ripples (SWRs). The direction of modulation and the temporal coupling between SWRs and SO-spindles depended on the training phase and the animals' learning types. Our results demonstrate the replay of rats' skilled-reaching memory during SWS and REM sleep and the possible involvement of the hippocampus through the modulation of M1 activations during SWRs. This study will advance our understanding of how neural activity patterns evolve during skilled-reaching learning and sleep, and help develop medical applications that leverage sleep's memory functions.

The preservation of cognitive function during aging remains a key challenge in neuroscience. In this study, we applied an integrative approach, combining behavioral assays with neurophysiological recordings, to investigate hippocampal circuit integrity. We used Octodon degus, a rodent with exceptional longevity (up to 10 years in laboratory conditions), as a natural model of aging and neurodegenerative disease such as Alzheimer. To assess age-related cognitive changes, we employed three behavioral tasks: Novel Object Recognition (NOR), Open Field (OF), and the Burrowing Test (BT). The BT reflects Activities of Daily Living (ADLs) and is based on species-typical spontaneous burrowing behavior, which has been linked to neurodegenerative markers in degus. We also performed multielectrode electrophysiological recordings to assess GABAergic function in the hippocampus. Aged degus with high BT performance (classified as good burrowers, or GB) showed robust hippocampal activity, especially in the CA3 region, a key hub for signal integration and memory encoding. In contrast, degus with poor BT performance (bad burrowers, or BB) exhibited reduced spontaneous hippocampal activity, suggesting potential compensation via GABA-independent synaptic mechanisms. Altogether, our findings suggest that preserved GABAergic function supports cognitive resilience in aging degus. These results offer new insights into the neural mechanisms underlying healthy cognitive aging and may inform future strategies for preventing or mitigating neurodegeneration.

Alzheimer's disease (AD) research has been hindered by the lack of models that faithfully recapitulate the full profile of disease progression in a human genetic background. We developed a 3D assembloid model ("Masteroid") using iPSC-derived neurons, astrocytes, and microglia from APOE4/4 and isogenic control lines. Neurons were seeded with tau oligomers, then combined with astrocytes and microglia to form mature 3D Masteroids, followed by amyloid-{beta} oligomer exposure. After four weeks, AD-Masteroids exhibited hallmark pathologies, including extracellular amyloid-{beta} deposits, intracellular tau aggregation, neurodegeneration, astrogliosis, and microglial activation, with APOE4 exacerbating all phenotypes. Single-cell RNA sequencing further identified novel roles of IGFBP pathways in amyloid-{beta} and tau-mediated pathology. This innovative platform provides a robust system to dissect cellular and molecular mechanisms of AD progression and offers a powerful tool for therapeutic discovery.

Intracortical brain-computer interfaces (BCI) leverage knowledge about neural representations to translate movement-related neural activity into actions. BCI implants have targeted broad cortical regions known to have relevant motor representations, but emerging technologies will allow flexible targeting to specific neural populations. The structure of motor representations at this scale, however, has not been well characterized across frontal motor cortices. Here, we investigate how motor representations and population dynamics (temporal coordination) vary across a large expanse of frontal motor cortices. We used high-density, laminar, microelectrode arrays to simultaneously record many neurons and then sampled neural populations across frontal motor cortex in two monkeys while they performed a reaching task. Our experiments allowed us to map neuronal activity across three spatial dimensions and relate them to movement. Target decoding analysis revealed that task information was heterogeneously distributed across the cortical surface and in depth. Similarly, we found that the temporal dynamics of different neural populations were heterogeneous, but that the amount of task information predicted which neural populations had similar dynamics. The neural populations with the most similar dynamics were composed of neurons with high task information regardless of spatial location. Our results highlight the spatiotemporal complexity of motor representations across frontal motor cortex at the level of neurons and neural populations, where well-learned movements consistently recruit a spatially distributed subset of neurons. Further insights into the spatiotemporal structure of neural activity patterns across frontal motor cortex will be critical to guide future implants for improved BCI performance.

The essence of empathy is generalization of emotion across persons. Here, we leverage recent theoretical advances in the neuroscience of generalization to help us understand empathy. We measured brain activity in human neurosurgical patients performing two tasks, one focused on identifying their own emotional response and one identifying emotional responses in others. We quantified the representational geometry of local field potential (LFP) high-gamma activity in four regions: the medial temporal lobe, anterior cingulate cortex, orbitofrontal cortex, and insula. We found encoding of both self- and other-emotions in all four regions, but codes for emotion and person are disentangled (that is, factorized) in the insula, but not the other regions. This factorized representation allows for cross-person generalization of emotion in a way that tangled (non-factorized) representations do not. Together, these results support the hypothesis that the insula uniquely contributes to social mirroring processes by which we understand emotions across individuals.

Retinal ganglion cells have traditionally been grouped into cells that are sensitive to luminance but not spatial structure and cells with responses that are enhanced by spatial structure. Neither category captures responses of mouse Off Transient alpha cells, which are largest for spatially homogeneous inputs and are suppressed by spatial structure. We identified two circuit mechanisms that together can explain this unusual spatial selectivity. First, inhibition to these cells is tuned to finer spatial structure than excitation, causing the balance of excitation and inhibition to depend on spatial scale. Second, the excitatory synapses onto these cells undergo strong synaptic depression and the modulation of that depression by presynaptic inhibition amplifies responses to the transition from spatially structured to homogeneous inputs. A spatiotemporal computational model incorporating these circuit features quantitatively recapitulates the observed dynamics. These findings reveal how localized inhibition and short-term plasticity jointly create the distinctive spatial selectivity of Off Transient cells.

The transcriptome of a brain cell encodes both its stable identity and its dynamic responses to environmental stimuli. While significant progress has been made in categorizing cell types within the brain, deciphering to what extent transcriptional identity and transcriptional state are related remains a major technical and conceptual challenge. Here, we present a single-nucleus RNA-sequencing atlas of the mouse hippocampus spanning physiological and pathological stimuli and multiple circadian phases, enabling unified analysis of activity-, circadian-, and cell-type-dependent transcriptional programs. Taxonomically assigned cell types are largely stable despite the induction of different activity states, with a notable exception in the dentate gyrus. Activity and circadian rhythm each drive robust, largely nonoverlapping transcriptional responses, with convergent regulation on genes involved in specific pathways, including endocannabinoid signaling, excitability, and chromatin remodeling. These results underscore the necessity of integrating cell-type taxonomy with transcriptional state to capture how diverse cell types respond to experience.

Microglia rapidly respond to injury, stress, and perturbations to neurons in the brain and retina and perform phagocytosis to clear dying cells and debris. Oxidative stress is a frequent feature of neurodegeneration, and while glia are crucial for managing such stress, microglia may also be dysfunctional in diseased tissue. Here we examine the role of microglia in management of oxidative stress upon death of rod photoreceptors in the larval zebrafish retina. Using rho:nfsb-eGFP transgenic zebrafish and treatment with the pro-drug metronidazole (MTZ), we coupled the generation of reactive oxygen species (ROS) in dying rods to their ablation. Microglia efficiently engulfed and cleared the ROS-laden rods, effectively undertaking the oxidative load. Despite abundant ROS upon MTZ-mediated cell death, oxidative stress overall was minimal in retinal tissue when microglia were present, indicating that they rapidly and efficiently performed redox functions. In irf8-/- mutants, which are deficient in microglia, retinas with MTZ-induced rod ablation showed widespread ROS that localized, at least in part, to Muller glia. Further, there was evidence of increased oxidative stress, and increased numbers of off-target inner retinal neurons that stained positive for the cell death marker TUNEL. Supplementation with the antioxidant Glutathione (GSH) reduced the number of off-target TUNEL+ cells detected in microglia-deficient retinas following rod ablation. Our results indicate that microglial redox functions are important in restoring homeostasis following acute retinal damage.

Researchers have long noted the differences in synapse count between different EM reconstructions of similar circuitry. In this paper we attempt to determine the portion of these differences that may be due to different sample preparation and imaging techniques, in particular serial-section transmission imaging (SS-TEM) compared to focused ion beam with scanning electron microscopy (FIB-SEM). To do this, we compare synapse detection in the major Drosophila EM reconstructions - FANC, MANC, FAFB (with original and new synapses), male CNS, BANC, and HemiBrain, plus several smaller reconstructions. We look at raw synapse counts to avoid any dependence on proofreading, and compensate insofar as possible for the confounds of sample sizes differences and different software detection efficiency. The result are estimates, per compartment and for the sample as a whole, of the number of synapses that would be visible to a skilled human observer. These are then compared across all samples, using regions which are reconstructed in common for each sample pair. We find that in almost all known cases where a volume has been reconstructed by both techniques, isotropic FIB-SEM reconstructions show more human-visible synapses than microtome sliced reconstructions, typically by more than 40%. This strongly suggests, but does not conclusively prove, that synapses are easier to see in isotropic FIB-SEM data.

Visual behavior requires coordinated activity across hierarchically organized brain circuits. Understanding this complexity demands datasets that are both large-scale (sampling many areas) and dense (recording many neurons in each area). Here we present a database of spiking activity across the mouse visual system--including thalamus, cortex, and midbrain--while mice perform an image change detection task. Using Neuropixels probes, we record from >75,000 high-quality units in 54 mice, mapping area-, cortical layer-, and cell type-specific coding of sensory and motor information. Modulation by task-engagement increased across the thalamocortical hierarchy but was strongest in the midbrain. Novel images modulated cortical (but not thalamic) responses through delayed recurrent activity. Population decoding and optogenetics identified a critical decision window for change detection and revealed that mice use an adaptation-based rather than image-comparison strategy. This comprehensive resource provides a valuable substrate for understanding sensorimotor computations in neural networks.

Magnetic resonance imaging (MRI) is a critical tool for translational neuroscience, offering cross-species insights into brain structure and function; however, its application in preclinical research is constrained by routine anesthesia use or sedation, which alters neural activity and limits comparisons to awake human imaging. Awake rodent functional MRI (fMRI) provides a powerful platform for investigating brain function under physiologically relevant conditions, but implementation is limited by technical challenges, particularly head motion and stress during scanning. Most restraint systems employ initial anesthesia, compromising translatability of findings, and highlighting the need for improved designs. We developed a novel restraint system optimized for awake rat fMRI. The system consists of modular 3D-printed components and can be assembled in under five minutes. It is accompanied by a protocol that includes head-post implantation followed by an 11-day habituation period post-surgical recovery. The system eliminates the need for isoflurane anesthesia, ear bars, and bite bars, reducing stress and improving animal comfort. It supports integration with behavioral paradigms such as pupil tracking and licking responses. High-resolution T2-weighted anatomical images and functional scans obtained using the system showed excellent spatial clarity and minimal motion artifacts. Quality control metrics, including head motion parameters and temporal signal-to-noise ratio, confirmed the system's stability and suitability for awake imaging. Functional connectivity analysis revealed robust positive correlations between functionally relevant regions. This system offers a scalable, reproducible, and animal-friendly solution for awake rat fMRI. While the current design limits direct cranial access for multimodal recordings, it enables high-quality, behaviorally enriched imaging without anesthesia.

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AbstractLarge-scale metagenomic and data-mining efforts have revealed an expansive diversity of bacteriophages (phages) within the human gut1–3. However, functional understanding of phage–host interactions within this complex environment is limited, largely due to a lack of cultured isolates available for experimental validation. Here we characterize 134 inducible prophages originating from 252 human gut bacterial isolates using 10 different induction conditions to expand the experimentally validated temperate phage–host pairs originating from the human gut. Importantly, only 18% of computationally predicted prophages could be induced in pure cultures. Moreover, we construct a 78-member synthetic microbiome that, when co-cultured in the presence of human colonic cells (Caco2), led to the induction of 35% phage species. Using cultured isolates, we demonstrate that human host-associated cellular products may act as induction agents, providing a possible link between gastrointestinal cell lysis and temperate phage populations4,5. We provide key insights into prophage diversity and genetics, including a genetic pathway for domestication, finding that polylysogeny was common and resulted in coordinated prophage induction, and that differential induction can be influenced by divergent prophage integration sites. More broadly, our study highlights the importance of culture-based techniques, alongside experimental validation, genomics and computational prediction, to understand the biology and function of temperate phages in the human gut microbiome. These culture-based approaches will enable applications across synthetic biology, biotechnology and microbiome fields.

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AbstractQuantum computers promise to tackle quantum simulation problems that are classically intractable1. Although a lot of quantum algorithms2–4have been developed for simulating quantum dynamics, a general-purpose method for simulating low-temperature quantum phenomena remains unknown. In classical settings, the analogous task of sampling from thermal distributions has been largely addressed by Markov Chain Monte Carlo (MCMC) methods5,6. Here we propose an efficient quantum algorithm for thermal simulation that—akin to MCMC methods—exhibits detailed balance, respects locality and serves as a toy model for thermalization in open quantum systems. The enduring impact of MCMC methods suggests that our new construction may play an equally important part in quantum computing and applications in the physical sciences and beyond.

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AbstractWater is essential for almost every aspect of life on our planet and, unsurprisingly, its properties have been studied in great detail1. However, disproportionately little remains known about the electrical properties of interfacial and strongly confined water2,3, in which the structure deviates from that of bulk water, becoming distinctly layered4,5. The structural change is expected to affect the conductivity of water and particularly its polarizability, which in turn modifies intermolecular forces that play a crucial role in many physical and chemical processes6–9. Here we use scanning dielectric microscopy (SDM)10to probe the in-plane electrical properties of water confined between atomically flat surfaces separated by distances down to 1 nm. For confinement exceeding several nanometres, water exhibits an in-plane dielectric constant close to that of bulk water and its proton conductivity is notably enhanced, gradually increasing with decreasing water thickness. This trend abruptly changes when the confined water becomes only a few molecules thick. Its in-plane dielectric constant reaches large, ferroelectric-like values of about 1,000, whereas the conductivity peaks at several S m−1, close to values characteristic of superionic liquids. We attribute the enhancement to strongly disordered hydrogen bonding induced by the few-layer confinement, which facilitates both easier in-plane polarization of molecular dipoles and faster proton exchange. This insight into the electrical properties of nanoconfined water is important for understanding many phenomena that occur at aqueous interfaces and in nanoscale pores.

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AbstractRecalled memories become transiently labile and require stabilization1–3. The mechanism for stabilizing memories of survival-critical experiences, which are often emotionally salient and repeated, remains unclear4. Here we identify an astrocytic ensemble that is transcriptionally primed by emotional experience and functionally triggered by repeated experience to stabilize labile memory. Using a novel brain-wideFostagging and imaging method, we found that astrocyticFosensembles were preferentially recruited in regions with neuronal engrams5and were more widespread during fear recall than during conditioning. We established the induction mechanism of the astrocytic ensemble, which involves two steps: (1) an initial fear experience that induces day-long, slow astrocytic state changes with noradrenaline receptor upregulation; and (2) enhanced noradrenaline responses during recall, a repeated experience, enabling astrocytes to integrate coincident signals from local engrams and long-range noradrenergic projections, which induce secondary astrocytic state changes, including the upregulation ofFosand the neuromodulatory molecule IGFBP2. Pharmacological and genetic perturbation of the astrocytic ensemble signalling modulate engrams, and memory stability and precision. The astrocytic ensemble thus acts as a multiday trace in a subset of astrocytes after experience-dependent neural activity, which are eligible to capture future repeated experiences for stabilizing memories.

AbstractHighly pathogenic avian influenza A(H5) viruses globally impact wild and domestic birds, and have caused severe infections in mammals, including humans, underscoring their pandemic potential1–5. The antigenic evolution of the A(H5) haemagglutinin (HA) poses challenges for pandemic preparedness and vaccine design6. Here the global antigenic evolution of the A(H5) HA was captured in a high-resolution antigenic map. The map was used to design immunogenic and antigenically central vaccine HA antigens, eliciting antibody responses that broadly cover the A(H5) antigenic space. In ferrets, a central antigen protected as well as homologous vaccines against heterologous infection with two antigenically distinct viruses. This work showcases the rational design of subtype-wide influenza A(H5) pre-pandemic vaccines and demonstrates the value of antigenic maps for the evaluation of vaccine-induced immune responses through antibody profiles.

AbstractAll mammalian organs depend on resident macrophage populations to coordinate repair and facilitate tissue-specific functions1–3. Functionally distinct macrophage populations reside in discrete tissue niches and are replenished through a combination of local proliferation and monocyte recruitment4,5. Declines in macrophage abundance and function have been linked to age-associated pathologies, including atherosclerosis, cancer and neurodegeneration6–8. However, the mechanisms that coordinate macrophage organization and replenishment within ageing tissues remain largely unclear. Here we show that capillary-associated macrophages (CAMs) are selectively lost over time, contributing to impaired vascular repair and reduced tissue perfusion in older mice. To investigate resident macrophage behaviour in vivo, we used intravital two-photon microscopy in live mice to non-invasively image the skin capillary plexus, a spatially well-defined vascular niche that undergoes rarefication and functional decline with age. We find that CAMs are lost at a rate exceeding capillary loss, resulting in macrophage-deficient vascular niches in both mice and humans. CAM phagocytic activity was locally required to repair obstructed capillary blood flow, leaving macrophage-deficient niches selectively vulnerable under homeostatic and injury conditions. Our study demonstrates that homeostatic renewal of resident macrophages is less precisely regulated than previously suggested9–11. Specifically, neighbouring macrophages do not proliferate or reorganize to compensate for macrophage loss without injury or increased growth factors, such as colony-stimulating factor 1 (CSF1). These limitations in macrophage renewal may represent early and targetable contributors to tissue ageing.

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AbstractStencilling, in which patterns are created by painting over masks, has ubiquitous applications in art, architecture and manufacturing. Modern, top-down microfabrication methods have succeeded in reducing mask sizes to under 10 nm (refs.1,2), enabling ever smaller microdevices as today’s fastest computer chips. Meanwhile, bottom-up masking using chemical bonds or physical interactions has remained largely unexplored, despite its advantages of low cost, solution-processability, scalability and high compatibility with complex, curved and three-dimensional (3D) surfaces3,4. Here we report atomic stencilling to make patchy nanoparticles (NPs), using surface-adsorbed iodide submonolayers to create the mask and ligand-mediated grafted polymers onto unmasked regions as ‘paint’. We use this approach to synthesize more than 20 different types of NP coated with polymer patches in high yield. Polymer scaling theory and molecular dynamics (MD) simulation show that stencilling, along with the interplay of enthalpic and entropic effects of polymers, generates patchy particle morphologies not reported previously. These polymer-patched NPs self-assemble into extended crystals owing to highly uniform patches, including different non-closely packed superlattices. We propose that atomic stencilling opens new avenues in patterning NPs and other substrates at the nanometre length scale, leading to precise control of their chemistry, reactivity and interactions for a wide range of applications, such as targeted delivery, catalysis, microelectronics, integrated metamaterials and tissue engineering5–11.

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AbstractThe site-specific encoding of non-canonical amino acids (ncAAs) provides a powerful tool for expanding the functional repertoire of proteins1–4. Its widespread use for basic research and biotechnological applications is, however, hampered by the low efficiencies of current ncAA incorporation strategies. Here we reveal poor cellular ncAA uptake as a main obstacle to efficient genetic code expansion and overcome this bottleneck by hijacking a bacterial ATP-binding cassette (ABC) transporter5to actively import easily synthesizable isopeptide-linked tripeptides that are processed into ncAAs within the cell. Using this approach, we enable efficient encoding of a variety of previously inaccessible ncAAs, decorating proteins with bioorthogonal6and crosslinker7moieties, post-translational modifications8,9and functionalities for chemoenzymatic conjugation. We then devise a high-throughput directed evolution platform to engineer tailored transporter systems for the import of ncAAs that were historically refractory to efficient uptake. CustomizedEscherichia colistrains expressing these evolved transporters facilitate single and multi-site ncAA incorporation with wild-type efficiencies. Additionally, we adapt the tripeptide scaffolds for the co-transport of two different ncAAs, enabling their efficient dual incorporation. Collectively, our study demonstrates that engineering of uptake systems is a powerful strategy for programmable import of chemically diverse building blocks.

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AbstractQuantifying physical mechanisms driving sea-level change—including global mean sea level (GMSL) and regional-to-local components (that is, sea-level budget)—is essential for reliable future projections and effective coastal management1,2. Although previous research has attempted to resolve China’s sea-level budget from the 1950s3,4, these studies capture short timescales and lack the long-term context necessary to fully assess modern sea-level rise in southeastern China5—one of the world’s most densely populated regions with immense socioeconomic importance6. Here we show that GMSL followed three distinct stages from 11,700 years before present (BP) to the modern day: (1) rapid early Holocene rise driven by the deglacial melt of land ice; (2) 4,000 years of stability from around 4200 BP to the mid-nineteenth century when regional processes dominated sea-level change; and (3) accelerating rise from the mid-nineteenth century. Our results arise from spatiotemporal hierarchical modelling of geological sea-level proxies and tide gauge data to produce site-specific sea-level budget estimates with uncertainty quantification. It is extremely likely (P≥ 0.95) that the GMSL rise rate since 1900 (1.51 ± 0.16 mm year−1, 1σ) has exceeded any century over at least the past four millennia. Moreover, our analysis indicates that at least 94% of rapid modern urban subsidence is attributable to anthropogenic activities, with localized subsidence rates often exceeding GMSL rise. Such concurrent acceleration of global sea-level rise and rapid localized subsidence has not been observed in our Holocene geological record.

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AbstractNonlinear optics1plays a central role in many photonic technologies, both classical2–5and quantum6–8. However, the function of a nonlinear-optical device is typically determined during design and fixed during fabrication9, restricting the use of nonlinear optics to scenarios in which this inflexibility is tolerable. Here we present a photonic device with highly programmable nonlinear functionality: an optical slab waveguide with an arbitrarily reconfigurable two-dimensional distribution ofχ(2)nonlinearity. The nonlinearity is realized using electric-field-inducedχ(2)(refs.10–16), and the programmability is engineered by massively parallel control of the electric-field distribution within the device using a photoconductive layer and optical programming with a spatial light pattern. To showcase the versatility of our device, we demonstrate spectral, spatial and spatio-spectral engineering of second-harmonic generation by tailoring arbitrary quasi-phase-matching grating structures1in two dimensions. The programmability of the device makes it possible to perform inverse design of grating structures in situ, as well as real-time feedback to compensate for fluctuations in operating and environmental conditions. Our work shows that we can break from the conventional one-device–one-function paradigm, potentially expanding the applications of nonlinear optics to situations in which fast device reconfigurability is desirable—such as in programmable optical quantum gates and quantum light sources7,17–19, all-optical signal processing20, optical computation21and adaptive structured light for sensing22–24.

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AbstractAs we age, many tissues become colonized by microscopic clones carrying somatic driver mutations1–7. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of this phenomenon remains limited due to the challenge of detecting mutations in small clones. Here we introduce a new version of nanorate sequencing (NanoSeq)8, a duplex sequencing method with an error rate lower than five errors per billion base pairs, which is compatible with whole-exome and targeted capture. Deep sequencing of polyclonal samples with single-molecule sensitivity simultaneously profiles large numbers of clones, providing accurate mutation rates, signatures and driver frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 blood samples from a twin cohort, we report an extremely rich selection landscape, with 46 genes under positive selection in oral epithelium, more than 62,000 driver mutations and evidence of negative selection in essential genes. High-resolution maps of selection across coding and non-coding sites are obtained for many genes: a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition or selection of somatic mutations. Accurate single-molecule sequencing provides a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

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AbstractMutations that occur in the cell lineages of sperm or eggs can be transmitted to offspring. In humans, positive selection of driver mutations during spermatogenesis can increase the birth prevalence of certain developmental disorders1–3. Until recently, characterizing the extent of this selection in sperm has been limited by the error rates of sequencing technologies. Here we used the duplex sequencing method NanoSeq4to sequence 81 bulk sperm samples from individuals aged 24–75 years. Our findings revealed a linear accumulation of 1.67 (95% confidence interval of 1.41–1.92) mutations per year per haploid genome driven by two mutational signatures associated with human ageing. Deep targeted and exome NanoSeq5of sperm samples identified more than 35,000 germline coding mutations. We detected 40 genes (31 newly identified) under significant positive selection in the male germline that have activating or loss-of-function mechanisms and are involved in diverse cellular pathways. Most of the positively selected genes are associated with developmental or cancer predisposition disorders in children, whereas four of the genes exhibited increased frequencies of protein-truncating variants in healthy populations. We show that positive selection during spermatogenesis drives a 2–3-fold increased risk of known disease-causing mutations, which results in 3–5% of sperm from middle-aged to older individuals with a pathogenic mutation across the exome. These findings shed light on germline selection dynamics and highlight a broader increased disease risk for children born to fathers of advanced age than previously appreciated.

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AbstractMen are at higher risk of several cancer types than women1. For bladder cancer the risk is four times higher for reasons that are not clear2. Smoking is also a principal risk factor for several tumour types, including bladder cancer3. As tumourigenesis is driven by somatic mutations, we wondered whether the landscape of clones in the normal bladder differs by sex and smoking history. Using ultradeep duplex DNA sequencing (approximately 5,000×), we identified thousands of clonal driver mutations in 16 genes across 79 normal bladder samples from 45 people. Men had significantly more truncating driver mutations inRBM10,CDKN1AandARID1Athan women, despite similar levels of non-protein-affecting mutations. This result indicates stronger positive selection on driver truncating mutations in these genes in the male urothelium. We also found activatingTERTpromoter mutations driving clonal expansions in the normal bladder that were associated strongly with age and smoking. These findings indicate that bladder cancer risk factors, such as sex and smoking, shape the clonal landscape of the normal urothelium. The high number of mutations identified by this approach offers a new strategy to study the functional effect of thousands of mutations in vivo—natural saturation mutagenesis—that can be extended to other human tissues.

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AbstractEven with the rapid development of renewable energy sources, improving the efficiency of energy conversion from fossil or synthetic fuels remains a challenge because, for example, combustion engines in long-range aircraft will still be needed in the upcoming decades1. Increasing their operating temperatures (1,050–1,150 °C (refs.2–4)) is one option. This requires replacing single-crystalline Ni-based superalloys in the hottest sections of turbines by refractory-element-based materials, which exhibit much higher solidus temperatures beyond 2,000 °C (refs.5–7). Here we introduce a single-phase Cr-36.1Mo-3Si (at.%) alloy that meets, for the first time, to our knowledge, the most important critical requirements for refractory-element-based materials: (1) relevant resistance against pesting, nitridation and scale spallation at elevated temperatures, minimum up to 1,100 °C, and (2) sufficient compression ductility at room temperature. Although strength and creep resistance in such alloys were already superior to Ni-based superalloys in several cases, oxidation/corrosion resistance, mandatory to withstand the combustion atmosphere, and ductility/toughness, needed for damage tolerance and device setting, still pose barriers for the development or application of refractory-element-based candidate materials. Any previous successful attempts to address the otherwise catastrophic oxidation of Mo and nitridation of Cr during oxidation suffered from a loss in ductility at ambient temperatures.

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AbstractThe ancient South Pole–Aitken impact basin provides a key data point for our understanding of the evolution of the Moon, as it formed during the earliest pre-Nectarian epoch of lunar history1, excavated more deeply than any other known impact basin2,3and is found on the lunar far side, about which less is known than the well-explored near side. Here we show that the tapering of the basin outline and the more gradual topographic and crustal thickness transition towards the south support a southward impact trajectory, opposite of that commonly assumed. A broad thorium-rich and iron-rich ejecta deposit southwest of the basin is consistent with partial excavation of late-stage magma ocean liquids. These observations indicate that thorium-rich magma ocean liquids persisted only beneath the southwestern half of the basin at the time of impact, matching predictions for the transition from a global magma ocean to a local enrichment of potassium, rare-earth elements and phosphorus (KREEP) in the near-side Procellarum KREEP Terrane. These results have important implications for the upcoming human exploration of the lunar south pole by Artemis, as proposed landing sites are now recognized to sit on the downrange rim and thorium-rich impact ejecta of the basin.

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AbstractThe amount of biological sequencing data available in public repositories is growing rapidly, forming a critical resource for biomedicine. However, making these data efficiently and accurately full-text searchable remains challenging. Here we build on efficient data structures and algorithms for representing large sequence sets1–6. We present MetaGraph, a methodological framework that enables us to scalably index large sets of DNA, RNA or protein sequences using annotated de Bruijn graphs. Integrating data from seven public sources7–13, we make 18.8 million unique DNA and RNA sequence sets and 210 billion amino acid residues across all clades of life—including viruses, bacteria, fungi, plants, animals and humans—full-text searchable. We demonstrate the feasibility of a cost-effective full-text search in large sequence repositories (67 petabase pairs (Pbp) of raw sequence) at an on-demand cost of around US$100 for small queries up to 1 megabase pairs (Mbp) and down to US$0.74 per queried Mbp for large queries. We show that the highly compressed representation of all public biological sequences could fit on a few consumer hard drives (total cost of around US$2,500), making it cost-effective to use and readily transportable for further analysis. We explore several practical use cases to mine existing archives for interesting associations, demonstrating the use of our indexes for integrative analyses, and illustrating that such capabilities are poised to catalyse advancements in biomedical research.

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AbstractOxygen redox chemistry is central to life1and many human-made technologies, such as in energy storage2–4. The large energy gain from oxygen redox reactions is often connected with the occurrence of harmful reactive oxygen species3,5,6. Key species are superoxide and the highly reactive singlet oxygen3–7, which may evolve from superoxide. However, the factors determining the formation of singlet oxygen, rather than the relatively unreactive triplet oxygen, are unknown. Here we report that the release of triplet or singlet oxygen is governed by individual Marcus normal and inverted region behaviour. We found that as the driving force for the reaction increases, the initially dominant evolution of triplet oxygen slows down, and singlet oxygen evolution becomes predominant with higher maximum kinetics. This behaviour also applies to the widely observed superoxide disproportionation, in which one superoxide is oxidized by another, in both non-aqueous and aqueous systems, with Lewis and Brønsted acidity controlling the driving forces. Singlet oxygen yields governed by these conditions are relevant, for example, in batteries or cellular organelles in which superoxide forms. Our findings suggest ways to understand and control spin states and kinetics in oxygen redox chemistry, with implications for fields, including life sciences, pure chemistry and energy storage.

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AbstractMicrobial and viral co-evolution has created immunity mechanisms involving oligonucleotide signalling that share mechanistic features with human antiviral systems1. In these pathways, including cyclic oligonucleotide-based antiphage signalling systems (CBASSs) and type III CRISPR systems in bacteria and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) in humans, oligonucleotide synthesis occurs upon detection of virus or foreign genetic material in the cell, triggering the antiviral response2–4. Here, in an unexpected inversion of this process, we show that the CRISPR-related enzyme mCpol synthesizes cyclic oligonucleotides constitutively as part of an active mechanism that represses a toxic effector. Cell-based experiments demonstrated that the absence or loss of mCpol-produced cyclic oligonucleotides triggers cell death, preventing the spread of viruses that attempt immune evasion by depleting host cyclic nucleotides. Structural and mechanistic investigation revealed mCpol to be a di-adenylate cyclase whose product, c-di-AMP, prevents toxic oligomerization of the effector protein 2TMβ. Analysis of cells by fluorescence microscopy showed that lack of mCpol allows 2TMβ-mediated cell death due to inner membrane collapse. These findings unveil a powerful defence strategy against virus-mediated immune suppression, expanding our understanding of the role of oligonucleotides in immunity.

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AbstractBacteria combat phage infection using antiphage systems and many systems generate nucleotide-derived second messengers upon infection that activate effector proteins to mediate immunity1. Phages respond with counter-defences that deplete these second messengers, leading to an escalating arms race with the host. Here we outline an antiphage system we call Panoptes that indirectly detects phage infection when phage proteins antagonize the nucleotide-derived second-messenger pool. Panoptes is a two-gene operon,optSE, wherein OptS is predicted to synthesize a nucleotide-derived second messenger and OptE is predicted to bind that signal and drive effector-mediated defence. Crystal structures show that OptS is a minimal CRISPR polymerase (mCpol) domain, a version of the polymerase domain found in type III CRISPR systems (Cas10). OptS orthologues from two distinct Panoptes systems generated cyclic dinucleotide products, including 2′,3′-cyclic diadenosine monophosphate (2′,3′-c-di-AMP), which we showed were able to bind the soluble domain of the OptE transmembrane effector. Panoptes potently restricted phage replication, but phages that had loss-of-function mutations in anti-cyclic oligonucleotide-based antiphage signalling system (CBASS) protein 2 (Acb2) escaped defence. These findings were unexpected because Acb2 is a nucleotide ‘sponge’ that antagonizes second-messenger signalling. Our data support the idea that cyclic nucleotide sequestration by Acb2 releases OptE toxicity, thereby initiating inner membrane disruption, leading to phage defence. These data demonstrate a sophisticated immune strategy that bacteria use to guard their second-messenger pool and turn immune evasion against the virus.

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AbstractThe doughnut-shaped framework of social and planetary boundaries (the ‘Doughnut’) provides a concise visual assessment of progress towards the goal of meeting the needs of all people within the means of the living planet1–3. Here we present a renewed Doughnut framework with a revised set of 35 indicators that monitor trends in social deprivation and ecological overshoot over the 2000–2022 period. Although global gross domestic product (GDP) has more than doubled, our median results show a modest achievement in reducing human deprivation that would have to accelerate fivefold to meet the needs of all people by 2030. Meanwhile, the increase in ecological overshoot would have to stop immediately and accelerate nearly two times faster towards planetary boundaries to safeguard Earth-system stability by 2050. Disaggregating these global findings shows that the richest 20% of nations, with 15% of the global population, contribute more than 40% of annual ecological overshoot, whereas the poorest 40% of countries, with 42% of the global population, experience more than 60% of the social shortfall. These trends and inequalities reaffirm the case for overcoming the dependence of nations on perpetual GDP growth4,5and reorienting towards regenerative and distributive economic activity—within and between nations—that assigns priority to human needs and planetary integrity.

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AbstractAlthough autism has historically been conceptualized as a condition that emerges in early childhood1,2, many autistic people are diagnosed later in life3–5. It is unknown whether earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Using longitudinal data from four independent birth cohorts, we demonstrate that two different socioemotional and behavioural trajectories are associated with age at diagnosis. In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, similar to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance. We further demonstrate that the polygenic architecture of autism can be broken down into two modestly genetically correlated (rg= 0.38, s.e. = 0.07) autism polygenic factors. One of these factors is associated with earlier autism diagnosis and lower social and communication abilities in early childhood, but is only moderately genetically correlated with attention deficit–hyperactivity disorder (ADHD) and mental-health conditions. Conversely, the second factor is associated with later autism diagnosis and increased socioemotional and behavioural difficulties in adolescence, and has moderate to high positive genetic correlations with ADHD and mental-health conditions. These findings indicate that earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Our findings have important implications for how we conceptualize autism and provide a model to explain some of the diversity found in autism.

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AbstractIn Gram-negative bacteria, the outer membrane is the first line of defence against antimicrobial agents and immunological attacks1. A key part of outer membrane biogenesis is the insertion of outer membrane proteins by the β-barrel-assembly machinery (BAM)2–4. Here we report the cryo-electron microscopy structure of a BAM complex isolated fromFlavobacterium johnsoniae, a member of the Bacteroidota, a phylum that includes key human commensals and major anaerobic pathogens. This BAM complex is extensively modified from the canonicalEscherichia colisystem and includes an extracellular canopy that overhangs the substrate folding site and a subunit that inserts into the BAM pore. The novel BamG and BamH subunits that are involved in forming the extracellular canopy are required for BAM function and are conserved across the Bacteroidota, suggesting that they form an essential extension to the canonical BAM core in this phylum. For BamH, isolation of a suppressor mutation enables the separation of its essential and non-essential functions. The need for a highly remodelled and enhanced BAM complex reflects the unusually complex membrane proteins found in the outer membrane of the Bacteroidota.

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Changes in global mean sea level (GMSL) during the late Cenozoic remain uncertain. We use a reconstruction of changes in δ18O of seawater to reconstruct GMSL since 4.5 million years ago (Ma) that accounts for temperature-driven changes in the δ18O of global ice sheets. Between 4.5 and 3 Ma, sea level highstands remained up to 20 m above present whereas the first lowstands below present suggest onset of Northern Hemisphere glaciation at 4 Ma. Intensification of global glaciation occurred from 3 Ma to 2.5 Ma, culminating in lowstands similar to the Last Glacial Maximum lowstand at 21,000 years ago and that reoccurred throughout much of the Pleistocene. We attribute the middle Pleistocene transition in ice sheet variability (1.2 Ma to 0.62 Ma) to modulation of 41-thousand-year (kyr) obliquity forcing by an increase in ~100-kyr CO2variability.

Spongelike materials called metal-organic frameworks can separate and store gases

A unified mechanism directs synaptic vesicle release

A psychologist explores common knowledge and coordination

Single-cell RNA sequencing (scRNA-seq) has facilitated the characterization of cell state heterogeneity and recapitulation of differentiation trajectories. However, the exclusive use of messenger RNA (mRNA) measurements comes at the risk of missing important biological information. We leveraged recent technological advances in single-cell proteomics by mass spectrometry (scp-MS) to generate an scp-MS dataset of an in vivo differentiation hierarchy encompassing >2500 human CD34+ hematopoietic stem and progenitor cells. Through integration with scRNA-seq, we identified proteins important for stem cell function, which were not indicated by their mRNA transcripts. Further, we showed that modeling translation dynamics can infer cell progression during differentiation and explain substantially more protein variation from mRNA than linear correlation. Our work offers a framework for single-cell multiomics studies across biological systems.

Molecular nanobelts are fascinating analogs of carbon nanotubes. Their rigid geometries and strongly coupled π-electrons have the potential to generate a wave function resembling that of a quantum ring. Here, we report the synthesis of triple stranded nanobelts consisting of 8 to 12 edge-fused porphyrin units with diameters of 21 to 32 angstroms. We synthesized these nanobelts by nickel-mediated coupling ofmeso-bromoporphyrins to form singly linked nanorings, followed by oxidation with gold(III) chloride. Experimental1H nuclear magnetic resonance spectra, supported by computational simulations, revealed that belts containing odd numbers of porphyrins, with circuits of 90 or 110 π-electrons, display global aromatic ring currents, whereas even-numbered belts, with 80, 100, or 120 π-electrons, are globally antiaromatic.

An interphase shields polymer electrolytes from electrochemical oxidation in an alkaline environment

Head-direction neurons maintain stable directional signals during large-scale navigation in the wild

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Museum specimens reveal loss of genetic diversity in marine fishes of the Philippines

Editors’ selections from the current scientific literature

Quantum fluid of trions is demonstrated in two-dimensional material systems

The reshuffling of genomic variation from multiple origins is an important contributor to phenotypic diversification, yet insights into the evolutionary trajectories of this combinatorial process and their interplay with genetic architecture remain scarce. We show that convergent plumage color evolution in wheatears involves a monogenic architecture with modular variation introgressed at the agouti signaling protein (ASIP) locus. Introgression of a new transposable element insertion and linked protein-coding variation underpin a transspecific throat color polymorphism, which stable isotopes suggest is associated with alternative foraging niches. Cointrogression of linked regulatory ASIP variation resulted in mantle color convergence in one species, whereas convergent color evolution at the genus level required new variation. Our results demonstrate evolutionary trajectories from introgressed variation realized within the constraints of a monogenic architecture.

Anion-exchange membrane water electrolyzers (AEMWEs) promise scalable, low-cost hydrogen production but are limited by the electrochemical instability of their anode ionomers. We report interphase engineering using inorganic-containing molecular additives that coassemble with ionomer, enabling pure water–fed AEMWEs to operate with a degradation rate <0.5 millivolt per hour at 2.0 amperes per square centimeter and 70°C—a >20-fold durability improvement. Analysis of different additives and ionomers shows that the stabilization mechanism involves cross-links between metal oxo/hydroxo oligomers and ionomers. Under operation, the inorganic additive enriches, forming an interphase near the water-oxidation catalyst that passivates the anode ionomer against continuous degradation while maintaining mechanical integrity and hydroxide conductivity. This additive-based interphase-engineering strategy provides a path to durable AEMWEs that operate without supporting electrolytes and is adaptable across diverse catalysts and ionomers for electrochemical technologies.

Synaptic vesicle (SV) exocytosis underpins neuronal communication, yet its nanoscale dynamics remain poorly understood owing to limitations in visualizing rapid events in situ. Here, we used optogenetics-coupled, time-resolved cryo–electron tomography to capture SV exocytosis in rat hippocampal synapses. Within 4 milliseconds of synaptic activation, SVs transiently “kiss” the plasma membrane, forming a ~4-nanometer lipidic fusion pore flanked by putative soluble NSF-attachment protein receptor (SNARE) complexes and then rapidly “shrink” to approximately half of their original surface area. By 70 milliseconds, most shrunken SVs recycle via a “run-away” pathway, whereas others collapse into the presynaptic membrane. Ultrafast endocytosis retrieves the expanded presynaptic membrane after 100 milliseconds. These findings reveal a “kiss-shrink-run” mechanism of SV exocytosis and hyperfast recycling, reconciling conflicting models and elucidating the efficiency and fidelity of synaptic transmission.

Matter-antimatter asymmetry underlines the incompleteness of the current understanding of particle physics. Neutrinoless double-beta decay (0vββ) may help explain this asymmetry, while unveiling the Majorana nature of the neutrino. The CUORE experiment searches for 0vββ of130Te using a tonne-scale cryogenic calorimeter operated at milli-kelvin temperatures. We report no evidence of 0vββ and place a lower limit on the half-life ofT1/2> 3.5 × 1025years (90% C.I.) with over 2 tonne·year TeO2exposure. The tools and techniques developed for this result and the 5 year stable operation of nearly 1000 detectors demonstrate crucial infrastructure for a future-generation experiment capable of searching for 0vββ across multiple isotopes.

Alkene hydrogenation is a cornerstone of chemical synthesis, yet enzymatic strategies remain limited to electron deficient substrates via hydride transfer. Using heme enzymes, we unlock a hydrogenation pathway for the asymmetric reduction of unactivated olefins. A silane promoted heme-cysteine redox cycle in the active site catalyzes sequential hydrogen atom transfer to challenging scaffolds including 1,1-disubstituted as well as tri- and tetrasubstituted alkenes. The evolved enzymes are promiscuous, oxygen-tolerant, utilize earth-abundant iron, and can operate on gram scale under ambient conditions. Orthogonal hydrogen atom sources enable site-divergent asymmetric isotope labeling. Mechanistic and computational studies support a stepwise radical process. Our work introduces a biochemical approach for stereoselective olefin reduction and provides a platform for next-generation biocatalytic hydrogenation.

The transplantation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offers a potential treatment for heart failure, but arrhythmogenic automaticity arising from transplanted cells can arise. In this study, we investigated the effects of RADA16, a clinically approved self-assembling peptide that forms nanofibers after injection, on the vascularization, myofibril structure, and electrophysiological adaptation of hiPSC-CMs transplanted into rat hearts. RADA16 accelerated the transition of hiPSC-CMs toward adult-like gene expression profiles, enhanced sarcomere organization, and improved vascularization in the transplanted site. Flexible mesh nanoelectronics revealed fibrillation of transplanted hiPSC-CMs within the beating recipient heart, and RADA16 dramatically reduced the automaticity of hiPSC-CMs. Our findings demonstrate the potential of self-assembling nanofibers to advance cardiac cell therapy and how flexible mesh nanoelectronics technology could improve safety.

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A trion is a bound state of two electrons and one hole or two holes and one electron. To date, trions have been observed only as optically excited states in doped semiconductors. We report the emergence of an equilibrium trion liquid in Coulomb-coupled molybdenum diselenide (MoSe2) and tungsten diselenide (WSe2) monolayers. By electrically tuning the hole density in WSe2to be two times the electron density in MoSe2, we generated equilibrium interlayer trions with binding energy in the milli–electron volt energy scale at temperatures two orders of magnitude below the Fermi temperature. We observed a density-tuned phase transition to an electron-hole plasma, spin-singlet correlations for the constituent holes, and Zeeman field–induced dissociation of the trions. Our results pave the way for exploration of the correlated phases of composite particles in solids.

Charting the spatiotemporal dynamics of cell fate determination in development and disease is a long-standing objective in biology. Here, we present the design, development, and extensive validation of PEtracer, a prime editing (PE)–based, evolving lineage tracing technology compatible with both single-cell sequencing and multimodal imaging methodologies, created to jointly profile cell state and lineage in dissociated cells or while preserving cellular context in tissues with high spatial resolution. Using PEtracer coupled with MERFISH spatial transcriptomic profiling in a syngeneic mouse model of tumor metastasis, we reconstructed the growth of individually seeded tumors in vivo and uncovered distinct modules of cell-intrinsic and -extrinsic factors that coordinate tumor growth. More generally, PEtracer enables systematic characterization of cell state and lineage relationships in intact tissues over biologically relevant temporal and spatial scales.

Dinidorid stinkbugs were reported to possess a conspicuous tympanal organ on female hindlegs. In this study, we show that this organ is specialized to retain microbial symbionts rather than to perceive sound. The organ’s surface is not membranous but consists of porous cuticle in which each pore connects to glandular secretory cells. In reproductive females, the hindleg organ is covered with fungal hyphae that grow from the pores. Upon oviposition, the females transfer the fungi from the organ to the eggs, where the hyphae physically protect the eggs against wasp parasitism. The fungi comprise a diversity of mostly low-pathogenicity Cordycipitaceae.

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Research managers and investors need better approaches to weigh risks and potential benefits of scalable, transformational technologies

Catalytically transforming abundant hydrocarbon feedstocks into structurally complex, high-value molecules is a pivotal yet challenging goal in organic synthesis. The key difficulty lies in the simultaneous activation of chemically inert feedstocks and precise stereochemical control. Here, we report a catalytic stereodivergent allylation of unprotected cyclic hemiacetal aldols with butene, enabling the programmable synthesis of polypropionates—privileged structural motifs prevalent in biologically active compounds, including pharmaceuticals. This visible light–driven, selective transformation exhibits broad functional group compatibility, furnishing 1,3-polyols with multiple contiguous stereocenters in high yield and stereochemical fidelity. Moreover, this method provides a concise and practical route to key natural product intermediates with minimal protection–deprotection sequences. This strategy has the potential to streamline polypropionate synthesis while reducing the time, cost, and environmental impact.

Mass layoffs, and subsequent reversals, have added to research spending woes

The combination of repulsive and attractive Coulomb interactions in a quantum electron-hole (e-h) fluid can produce correlated phases of multiparticle charge complexes, such as excitons, trions, and biexcitons. We report an experimental realization of an electrically controlled interlayer trion fluid in van der Waals heterostructures. In strongly coupled e-h bilayers, electrons and holes spontaneously form three-particle trion bound states. The interlayer trions can assume 1e-2h and 2e-1h configurations. We show that the two holes in 1e-2h trions form a spin-singlet with a spin gap of approximately one milli–electron volt. By electrostatic gating, the equilibrium state can be continuously tuned into an exciton fluid, a trion fluid, an exciton-trion mixture, or a trion-charge mixture. Our work demonstrates a platform to study correlated phases of tunable Bose-Fermi mixtures.

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PLOS, Frontiers, and others announce policies intended to stem the tide of suspect papers

In animal groups, spatial structure shapes social interaction patterns, thereby influencing the transmission of infectious diseases. Active modifications to the spatial environment could therefore be a potent tool to mitigate epidemic risk. We tested whetherLasius nigerants modify their nest architecture in response to pathogens by introducing control- or pathogen-treated individuals into nest-digging groups and monitoring three-dimensional nest morphogenesis. Pathogen exposure led to architectural changes, including faster nest growth, increased interentrance distance, transmission-inhibitory changes in nest network topology, and reduced chamber centrality. Simulations confirmed that these changes reduced transmission and highlighted a synergy between architectural and behavioral responses to disease. These results provide evidence for architectural immunity in a social animal and offer insights into how spatial organization can be leveraged to decrease epidemic susceptibility.

Animals and humans rely on their navigation skills to survive. However, spatial neurons in the brain’s “navigation circuit” had not previously been studied under real-world conditions. We conducted an electrophysiological study of spatial neurons in the wild: We recorded head-direction cells from the presubiculum of bats flying unconstrained and navigating outdoors on a remote oceanic island. These neurons represented the bats’ orientation stably across the island’s entire geographical scale and irrespective of the dynamics of the Moon and the Milky Way. The directional tuning stabilized over several nights from the first exploration of the island. These results imply that head-direction cells can serve as a learned, reliable neural compass for real-world navigation—highlighting the power of taking neuroscience out into the wild.

On an Arctic archipelago, frozen soil may preserve a hidden history of viruses

Highlights from theSciencefamily of journals

The European Union (EU) has the world’s largest funding program exclusively for research and innovation (R&I)—Horizon Europe—which is now preparing its 10th edition for 2028–2034. The good news is that the EU aims to raise Horizon Europe’s budget by 83% and continue the trend of supporting all types of institutions and partnerships, including universities, research institutes, small- and medium-sized enterprises, nonprofit organizations, and a widening circle of international collaborations.

Cyclin-dependent kinases (CDKs) are prototypical regulators of the cell cycle. The CDK-activating kinase (CAK) acts as a master regulator of CDK activity by catalyzing the activating phosphorylation of CDKs on a conserved threonine residue within the regulatory T-loop. However, structural data illuminating the mechanism by which the CAK recognizes and activates CDKs have remained elusive. Here, we determine high-resolution structures of the CAK in complex with CDK2 and CDK2-cyclin A2 by cryogenic electron microscopy. Our structures reveal a T-loop–independent kinase-kinase interface with contributions from both kinase lobes. Computational analysis and structures of CAK in complex with CDK1-cyclin B1 and CDK11 indicate that these structures represent the general architecture of CAK-CDK complexes. These results advance our mechanistic understanding of cell cycle regulation and kinase signaling cascades.

“Bold” hypothesis suggests tolerance for lead allowedHomo sapiensto outlive Neanderthals

A philosopher’s seminal book traced how science shaped the mentality of the modern world

The rise of multidrug-resistant pathogens poses a major threat to global health, with methicillin-resistantStaphylococcus aureus(MRSA) among the most challenging. One promising approach to overcoming resistance is using small molecules that resensitize MRSA to existing drugs. Here, we report the enantioselective total synthesis of one such promising candidate, (−)-spiroaspertrione A, a complex meroterpenoid of the andiconin family. This natural product has long eluded synthesis because of its densely functionalized polycyclic backbone. Our route features a stereoselective Diels-Alder cycloaddition, followed by a key divinylcyclopropane rearrangement forming the spirobicyclo[3.2.2]nonane core, which proved to be reversible and was further investigated by density functional theory calculations. Strategic late-stage functionalization of the compact cage architecture enabled access to the natural product and provided evidence for a plausible biosynthetic relationship with (−)-aspermerodione.

Optical nanoscopy of intact biological specimens has been transformed by recent advancements in hydrogel-based tissue clearing and expansion, enabling the imaging of cellular and subcellular structures with molecular contrast. However, existing high-resolution fluorescence microscopes are physically limited by objective-to-specimen distance, which prevents the study of whole-mount specimens without physical sectioning. To address this challenge, we developed a photochemical strategy for spatially precise sectioning of specimens. By combining serial photochemical sectioning with lattice light-sheet imaging and petabyte-scale computation, we imaged and reconstructed axons and myelin sheaths across entire mouse olfactory bulbs at nanoscale resolution. An olfactory bulb–wide analysis of myelinated and unmyelinated axons revealed distinctive patterns of axon degeneration and de-/dysmyelination in the neurodegenerative brain, highlighting the potential for peta- to exabyte-scale super-resolution studies using this approach.

Ongoing review of international drug policy should correct long-standing, misguided, and harmful conflation

Understanding how genetic variation translates into complex phenotypes remains a fundamental challenge. In this work, we address this by mapping genome-to-proteome relationships in 800 progeny of a cross between two yeast strains adapted to distinct environments. Despite the modest genetic distance between the parents, we observed notable proteomic diversity and mapped more than 6400 genotype-protein associations, with more than 1600 linked to individual genetic variants. Proteomic adaptation emerged from a conserved network of cis- and trans-regulatory variants, often originating from proteins not traditionally linked to gene regulation. This atlas allowed us to forecast organismal fitness effects across diverse conditions. By connecting genomic and proteomic landscapes at unprecedented resolution, our study provides a framework for predicting the phenotypic outcomes of natural genetic variation.

Genetic disruption of the RAS binding domain (RBD) of Phosphoinositide 3-kinase alpha(PI3Kα) impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα’s role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3Kα interaction may represent a strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3Kα lipid kinase activity. We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block RAS activation of PI3Kα activity. In mice, inhibitors slow the growth of RAS mutant tumors and Human Epidermal Growth Factor Receptor 2 (HER2) overexpressing tumors, particularly when combined with other inhibitors of the RAS/Mitogen-activated protein kinase pathway, without causing hyperglycemia.Oncogenic mutations in the small guanosine triphosphatase RAS occur in 20% of human cancers, with RAS proteins activating both the mitogen-activated protein kinase (MAPK) and Phosphoinositide 3-kinase (PI3K) pathways (1–3). As each of these pathways has oncogenic potential, simultaneous activation, as occurs in mutant RAS driven cancers, generates aggressive disease. In RAS-driven cell and animal models, inhibition of both the MAPK and PI3K pathways is more efficacious than targeting the individual pathways (4); however, dose-limiting toxicities in humans prevent clinical success of this strategy. Although physiological activation of the MAPK pathway is RAS-dependent, the interaction between RAS and the catalytic subunit of PI3Kα, p110α, serves as an amplifier but not a primary activator of this pathway, and is less important in normal cellular regulation than it is in cancer (5).

Bacteria undergo rapid genetic changes that are selected by alterations in the human gut environment

Last month at the 80th session of the United Nations, the call to be “better together” was especially appropriate for discussions on the Early Warnings for All global initiative. About half the world’s countries now have multihazard weather alert systems, and disaster-related mortality is considerably lower in countries with such warning capacities. But much more is needed to achieve the 2027 goal of ensuring that everyone on Earth is protected from extreme and hazardous weather events. This will require the continued free sharing of data and the improvement of observation systems and weather service facilities.

Transcriptional initiation and termination decisions drive messenger RNA (mRNA) isoform diversity but the relationship between them remains poorly understood. By systematically profiling joint usage of transcription start and end sites, we observed that mRNA using upstream starts preferentially use upstream end sites and that the usage of downstream sites is similarly coupled. Our results suggest a positional initiation termination axis (PITA), in which usage of alternative terminal sites are coupled based on their genomic order. PITA is enriched in longer genes with distinct chromatin features. We find that mRNA 5′ start choice directly influences 3′ ends depending on RNA polymerase II trafficking speed. Our results indicate that spatial organization and transcriptional dynamics couple transcription initiation and mRNA 3′ end decisions to define mRNA isoform expression.

The intrinsic pathways that control membrane organization in immune cells and their impact on cellular functions are poorly defined. We found that the nonvesicular cholesterol transporter Aster-A linked plasma membrane (PM) cholesterol availability in CD4 T cells to systemic metabolism. Aster-A was recruited to the PM during T cell receptor (TCR) activation, where it facilitated the removal of accessible cholesterol. Loss of Aster-A increased cholesterol accumulation in the PM, which enhanced TCR nanoclustering and signaling. Aster-A associated with stromal interaction molecule 1 (STIM1) and negatively regulated calcium (Ca2+) flux. Aster-A deficiency promoted CD4 T cells to acquire a T helper 17 (TH17) phenotype and stimulated interleukin-22 production, which reduced intestinal fat absorption and conferred resistance to diet-induced obesity. These findings delineate how immune cell membrane homeostasis links to systemic physiology.

A DNA repair function in a cytosolic sensor demonstrates a potential role in naked mole-rat longevity

Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated byUbiquitin-specific peptidase 30(Usp30) during the maternal-zygotic transition. In vitro,Usp30inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.

Long interspersed nuclear element–1 (LINE-1 or L1), the only autonomously active retrotransposon in humans today, constitutes a large proportion of the genome and continues to evolve the genome and impact fundamental biological processes. L1 retrotransposition critically depends on its endonuclease and reverse transcriptase subunit open reading frame 2 protein (ORF2p), which targets genomic loci and nicks DNA using an evolutionarily distinct yet not fully understood mechanism. Our structural and biochemical analyses revealed that ORF2p is a structure-dependent endonuclease. It binds a double-stranded DNA region upstream of the nicking site and recognizes a downstream forked or flap structure for efficient DNA nicking. This discovery suggests that L1 mobilization piggybacks on chromosomal processes with noncanonical DNA structure intermediates.

The mouse is a tractable model for human ovarian biology, however its utility is limited by incomplete understanding of how transcription and signaling differ interspecifically and with age. We compared ovaries between species using three-dimensional imaging, single-cell transcriptomics, and functional studies. In mice, we mapped declining follicle numbers and oocyte competence during aging; in human ovaries, we identified cortical follicle pockets and decreases in density. Oocytes had species-specific gene expression patterns during growth that converged toward maturity. Age-related transcriptional changes were greater in oocytes than granulosa cells across species, although mature oocytes change more in humans. We identified ovarian sympathetic nerves and glia; axon density increased in aged ovaries and, when ablated in mice, perturbed folliculogenesis. This comparative atlas defines shared and species-specific hallmarks of ovarian biology.

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On 8 April 2024, a total solar eclipse disrupted light-dark cycles for North American birds during the lead-up to spring reproduction. Compiling more than 10,000 community observations and artificial intelligence analyses of nearly 100,000 vocalizations, we found that bird behavior was substantially affected by these few minutes of unexpected afternoon darkness. More than half of wild bird species changed their biological rhythms, with many producing a dawn chorus in the aftermath of the eclipse. This natural experiment underscores the power of light in structuring animal behavior: Even when “night” lasts for just 4 minutes, robust behavioral changes ensue.

Cytosolic nucleic acid–sensing pathways are potential targets for cancer immunotherapy. Although stimulator of interferon genes (STING) agonists have shown substantial antitumor effects in animal models, their clinical efficacy in human tumors remains unclear. Deletion of methylthioadenosine phosphorylase (MTAP) is a common genomic alteration in human tumors but is rare in preclinical syngeneic mouse models. We found that homozygousMTAPdeletion in human tumors creates a tumor microenvironment that obstructs cytosolic nucleic acid–sensing pathways by down-regulating interferon regulatory factor 3 (IRF3), leading to resistance to STING agonists. Targeting polyamine biosynthesis reverses IRF3 down-regulation, restoring sensitivity to STING agonists in MTAP-deficient tumors. Our findings suggest that MTAP genetic status may inform patient responses to STING agonist therapy and offer an alternative strategy for boosting antitumor immune responses using STING agonists inMTAP-deleted tumors.

The human blood proteome provides a holistic readout of health states through the assessment of thousands of circulating proteins. Here, we present a pan-disease resource to enable the study of diverse disease phenotypes within a harmonized proteomics dataset. By profiling protein concentrations across 59 diseases and healthy cohorts, we identified proteins associated with age, sex, and BMI, as well as disease-specific signatures. This study highlights shared and distinct protein patterns across conditions, demonstrating the power of a unified proteomics approach to uncover biological insights. The dataset, covering 8,262 individuals and up to 5,416 proteins, serves as an online resource for exploring disease-specific protein profiles and advancing precision medicine research.

Circularly polarized light provides a direct control of ferroaxiality

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Astronomical surveys have identified numerous exoplanets with bulk compositions that are unlike the planets of the Solar System, including rocky super-Earths and gas-enveloped sub-Neptunes. Observing the atmospheres of these objects provides information on the geological processes that influence their climates and surfaces. In this Review, we summarize the current understanding of these planets, including insights into the interaction between the atmosphere and interior based on observations made with the JWST. We describe the expected climatic and interior planetary regimes for planets with different density and stellar flux and how those regimes might be observationally distinguished. We also identify the observational, experimental, and theoretical innovations that will be required to characterize Earth-like exoplanets.

Microbes, immune cells, and enterocytes interact to regulate the intake of lipids in the mouse gut

Somatically acquired mitochondrial DNA (mtDNA) mutations accumulate with age, but the mechanisms and consequences of this accumulation are poorly understood. Here we show that transient injuries induce a burst of persistent mtDNA mutations that impair resilience to future injuries. mtDNA mutations suppressed energy-intensive nucleotide metabolism. Repletion of adenosine, but not other nucleotides, restored adenosine triphosphate generation, which required a nuclear-encoded purine biosynthetic enzyme, adenylate kinase 4 (AK4). Analysis of 369,912 UK Biobank participants revealed a graded association between mutation burden and chronic kidney disease severity as well as an independent increase in the risk of future acute kidney injury events (P< 10−7). Heteroplasmic mtDNA mutations may therefore reflect the cumulative effect of acute injuries to metabolically active cells, impairing major functions in a fashion amenable to nuclear-controlled purine biosynthesis.

Salicylic acid (SA) is a key phytohormone that orchestrates immune responses against pathogens, includingPseudomonas syringaebacteria. The timing and extent of SA accumulation are tightly controlled by plants but can be suppressed by pathogens to overcome immunity. Understanding SA dynamics at high spatiotemporal resolution remains challenging owing to limitations in existing detection methods that are indirect, destructive, or lacking in cellular precision and temporal resolution. We developed SalicS1, a genetically encoded fluorescence resonance energy transfer (FRET) biosensor specific to SA. SalicS1 enables real-time, reversible monitoring of SA levels in vivo with minimal perturbation of endogenous signaling. We reveal the propagation of an SA surge spreading from bacterial infection sites with spatiotemporal fidelity. SalicS1 unlocks precise understanding of SA dynamics underpinning crop resilience to pathogens.

Despite billions of passerines seasonally migrating during the night at high altitudes, only three bat species have been found to consistently tap into this rich prey resource. However, it remains unknown where and how these bats locate, catch, and ingest relatively large passerine prey. Here, we used high-resolution biologging tags to reveal that greater noctule bats (Nyctalus lasiopterus) ascend to high altitudes, engage in long echo-guided chases, and consume migrating passerines in flight. By using a private sensory channel through ultrasonic echolocation, prolonged chasing, and mid-air prey consumption, these predators can hunt nocturnally migrating passerines at high altitudes and therefore exploit a rich food resource that remains largely inaccessible to most predators.

Legislation proposals seek to bring certainty, clarification, harmonization, and simplification

REDD+ (Reducing Emissions from Deforestation and Degradation Plus) projects generate carbon credits to offset emissions, but recent studies have questioned their effectiveness. We evaluated 52 voluntary REDD+ projects across 12 tropical countries using synthetic control methods. Only a minority of project units showed statistically significant reductions in deforestation, and just 19% met their reported emissions targets. Nonetheless, many underperforming projects still delivered partial climate benefits, with an estimated 13.2% of tradable credits supported by counterfactual analysis. Effectiveness varied by region, with stronger performance in Brazil and Africa. Although systematic over-crediting remains a concern, our results suggest greater climate benefits than previous assessments. Improving baseline methodologies and strengthening verification frameworks will be essential for enhancing the credibility and impact of forest carbon offsets.

Antimicrobial drugs changed everything, but misuse and resistance have been constant companions

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Ultrafast switching of ferroic phases is an active research area with technological potential. Yet, some key challenges remain, ranging from limited speeds in ferromagnets to intrinsic volatility of switched domains owing to depolarizing fields in ferroelectrics. Unlike these ferroic systems, ferroaxial materials host bistable states that preserve spatial-inversion and time-reversal symmetry and are therefore immune to depolarizing fields but also difficult to manipulate with conventional methods. We demonstrate photo-induced switching of ferroaxial order by engineering an effective axial field composed of circularly driven terahertz phonon modes. A switched ferroaxial domain remains stable for many hours and can be reversed back with a second terahertz pulse of opposite helicity. The effects demonstrated in this work may lead to the development of a robust platform for ultrafast information storage.

High-power fiber lasers are powerful tools used in science, industry, and defense. A major roadblock for further power scaling of single-frequency fiber laser amplifiers is stimulated Brillouin scattering. Efforts have been made to mitigate this nonlinear process, but these were mostly limited to single-mode or few-mode fiber amplifiers, which have good beam quality. Here, we explored a highly multimode fiber amplifier in which stimulated Brillouin scattering was greatly suppressed due to a reduction of light intensity in a large fiber core and a broadening of the Brillouin scattering spectrum by multimode excitation. By applying a spatial wavefront shaping technique to the input light of a nonlinear amplifier, the output beam was focused to a diffraction-limited spot. Our multimode fiber amplifier can operate at high power with high efficiency and narrow linewidth, which ensures high coherence. Optical wavefront shaping enables coherent control of multimode laser amplification, with potential applications in coherent beam combining, large-scale interferometry and directed energy delivery.

Researchers are testing multiple treatments for the rare genetic conditions

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Editors’ selections from the current scientific literature

Diversity-generating retroelements (DGRs) accelerate evolution by rapidly diversifying variable proteins. The human gastrointestinal microbiota harbors the greatest density of DGRs known in nature, suggesting that they play adaptive roles in this environment. We identified >1100 distinct DGRs among human-associatedBacteroidesspecies and discovered a subset that diversify adhesive components of type V pili and related proteins. We show thatBacteroidesDGRs are horizontally transferred across species, display activity levels ranging from high to low, and preferentially alter the functional characteristics of ligand-binding residues on adhesive organelles. Specific variable protein sequences are enriched whenBacteroidesstrains compete with other commensal bacteria in gnotobiotic mice. Analysis of >2700 DGRs from diverse phyla in mother-infant pairs shows thatBacteroidesDGRs are disproportionately transferred to vaginally delivered infants where they actively diversify. Our observations provide a foundation for understanding the potential roles of targeted genome plasticity in shaping host-associated microbial communities.

Some theorists think unusual event could be a black hole devouring a star from within

Three scientists honored for revealing how regulatory T cells prevent autoimmune disease

As government websites go dark, some nonprofits are trying to provide classroom materials

The discovery of chlorophyll f-containing photosystems, with their long-wavelength photochemistry, represented a distinct, low-energy paradigm for oxygenic photosynthesis. Structural studies on chlorophyll f-containing photosystem I could identify some chlorophylls f sites, but none among the photochemically active pigments and concluded that chlorophyll f plays no photochemical role. Here, we report two cryo-EM structures of far-red PSI fromChroococcidiopsis thermalisPCC 7203, allowing the assignment of eight chlorophylls f molecules, including the redox active A-1B. Simulations of absorption difference spectra induced by charge separation indicate that the experimental spectra can be reproduced only by considering the presence of a chlorophyll f at the A-1Bsite. The chlorophyll f locations, wavelength assignments, and conserved far-red-specific residues provide functional insights for efficient use of long wavelength photons.

Data produced by “silicon samples” vary with researchers’ exact choice of models, prompts, and settings, study finds

Breakthrough paved the way to many of today’s budding quantum computers

Efficient DNA repair might make possible the longevity of naked mole-rats. However, whether they have distinctive mechanisms to optimize functions of DNA repair suppressors is unclear. We find that naked mole-rat cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) lacks the suppressive function of human or mouse homologs in homologous recombination repair through the alteration of four amino acids during evolution. The changes enable cGAS to retain chromatin longer upon DNA damage by weakening TRIM41-mediated ubiquitination and interaction with the segregase P97. Prolonged chromatin binding of cGAS enhanced the interaction between repair factors FANCI and RAD50 to facilitate RAD50 recruitment to damage sites, thereby potentiating homologous recombination repair. Moreover, the four amino acids mediate the function of cGAS in antagonizing cellular and tissue aging and extending life span. Manipulating cGAS might therefore constitute a mechanism for life-span extension.

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Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal–regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.

Highlights from theSciencefamily of journals

Solid-state batteries are attractive energy storage systems as a result of their inherent safety, but their development hinges on advanced solid-state electrolytes (SSEs). Most SSEs remain largely confined to single-anion systems (e.g., sulfides, oxides, halides, and polymers). Through mixed-anion design strategy, we develop crystalline Li3Ta3O4Cl10(LTOC) and its derivatives with excellent ionic conductivities (up to 13.7 millisiemens per centimeter at 25°C) and electrochemical stability. The LTOC structure features mixed-anion spiral chains, consisting of corner-shared oxygen and terminal chlorine atoms, which induces continuous “tetrahedron-tetrahedron” Li-ion migration pathways with low energy barriers. Additionally, LTOC demonstrates holistic cathode compatibility, enabling solid-state batteries operation at 4.9 volts versus Li/Li+and low temperature, down to −50°C. These findings describe a promising class of superionic conductors for high-performance solid-state batteries.

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A social scientist questions the importance of a key mineral in “green” technology

A Japanese botanist is revealing the secrets of plants that have given up photosynthesis

The inventor of the World Wide Web reflects on his life-altering creation

Adenosine triphosphate (ATP)–dependent chromatin remodeling enzymes mobilize nucleosomes, but how such mobilization affects chromatin condensation is unclear. We investigate effects of two major remodelers, ACF and RSC, using chromatin condensates and single-molecule footprinting. We find that both remodelers inhibit the formation of condensed chromatin. However, the remodelers have distinct effects on preformed chromatin condensates. ACF spaces nucleosomes without decondensing the chromatin, explaining how ACF maintains nucleosome organization in transcriptionally repressed genomic regions. By contrast, RSC catalyzes ATP-dependent decondensation of chromatin. RSC also drives micron-scale movements of entire chromatin condensates. These additional activities of RSC may contribute to its central role in transcription. The biological importance of remodelers may thus reflect both their effects on nucleosome mobilization and the corresponding consequences on chromatin dynamics at the mesoscale.

Highlights from theSciencefamily of journals

Climate change and land mismanagement are creating increasingly fire-prone built and natural environments. However, despite worsening fire seasons, evidence is lacking globally for trends in socially and economically disastrous wildfires, partly due to sparse systematic records. Using a 44-year dataset (1980 to 2023) we analyze the distribution, trends, and climatic conditions connected with the most lethal and costly wildfires. Disastrous wildfires occurred globally over this period but were concentrated in the Mediterranean and temperate conifer biomes. Disaster risk was highest where highly energetic daily fire events intersected affluent, populated areas. Economic disasters increased sharply from 2015 onward, with 43% of the 200 most damaging events occurring in the last decade. Disasters coincided with increasingly extreme climatic conditions, highlighting the urgent need to adapt to a more fire-prone world.

As direct and indirect costs of fires continue to grow, so too might motivation to invest more heavily in mitigation

Polyolefins and their chlorinated derivatives such as polyvinyl chloride (PVC) are among the most prevalent plastics in global production and waste streams. Traditional waste-to-energy methods such as incineration and pyrolysis, as well as most chemical upcycling methods for PVC utilization, require thorough, high-temperature dechlorination to prevent the release of toxic chlorinated compounds. We present here a strategy for upgrading discarded PVC into chlorine-free fuel range hydrocarbons and hydrogen chloride in a single-stage process catalyzed by chloroaluminate ionic liquids. This approach offsets endothermic dechlorination and carbon-carbon bond cleavage with exothermic alkylation and hydrogen transfer by isobutane or isopentane in a low-temperature tandem process. The light isoalkanes are available from refinery processes and partly from recycling of the product stream. This process is suitable for handling real-world mixed and contaminated PVC and polyolefin waste streams.

A veteran science writer returns with a whirlwind tour of body modification and repair

Machine learning method counts nearly 12 million dead trees, many likely killed by rising seas

Diboron trioxide (B2O3) represents an unusual case among polymorphic oxides, because its vitrified state features superstructural units—planar boroxol groups—that are never observed in its three-dimensional crystalline polymorphs. Crystalline polymorphs that incorporate boroxol groups have only been predicted theoretically, although their formation is crucial to rationalize the ability of B2O3to vitrify. Here we present the synthesis of a two-dimensional crystalline B2O3polymorph constituted by boroxol groups arranged in an atomically thin honeycomb lattice. By combining surface science experimental techniques with ab initio calculations, we characterize the structural and electronic properties of this B2O3polymorph down to the atomic level. This discovery enlarges the family of two-dimensional materials and enables the atomic tracking of individual structural units in trioxides.

The analysis of DNA sequence outcomes provides molecular insights into double-strand break (DSB) repair mechanisms. Using parallel in-pool profiling of Cas9-induced insertions and deletions (indels) within a genome-wide knockout library, we present a comprehensive catalog that assesses the influence of nearly every human gene on DSB repair outcomes. This REPAIRome resource uncovers uncharacterized mechanisms, pathways, and factors involved in DSB repair, including opposing roles for XLF and PAXX, a molecular explanation for Cas9-induced multinucleotide insertions, HLTF functions in Cas9-induced DSB repair, the involvement of the SAGA complex in microhomology-mediated end joining, and an indel mutational signature linked to VHL loss, renal carcinoma, and hypoxia. These results exemplify the potential of REPAIRome to drive future discoveries in DSB repair, CRISPR-Cas gene editing and the etiology of cancer mutational signatures.

Directed evolution can rapidly generate genetic variants with new and enhanced properties, yet efficient platforms for performing such evolution directly in plant cells have been lacking. We developedGeminivirusReplicon-Assisted inPlanta DirectedEvolution (GRAPE), a system that links gene function to geminivirus rolling circle replication (RCR) to enable high-throughput selection for desired activities. GRAPE supports the screening of up to 105variants on a singleNicotiana benthamianaleaf within four days. Using GRAPE, we evolved the immune receptor NRC3 to resist inhibition by the nematode effector SPRYSEC15 and broadened the recognition spectrum of the rice immune receptor Pikm-1 to recognize all six alleles of the fungal effector AVR-Pik. GRAPE provides a rapid, scalable, and generalizable platform for directed evolution of diverse genes in plant cellular context.

A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.

Dendritic nanotubes extend brain connectivity beyond synapses

Intercellular nanotubular networks mediate material exchange, but their existence in neurons remains to be explored in detail. We identified long, thin dendritic filopodia forming direct dendrite–dendrite nanotubes (DNTs) in mammalian cortex. Super-resolution microscopy in dissociated neurons revealed DNTs’ actin-rich composition and dynamics, enabling long-range calcium ion (Ca2+) propagation. Imaging and machine learning–based analysis validated in situ DNTs as anatomically distinct from synaptic spines. DNTs actively transported small molecules and human amyloid-β (Aβ); DNT density increased before plaque formation in the medial prefrontal cortex of APP/PS1 mice (APP, Aβ precursor protein; PS1, presenilin-1), suggesting that the dendrite-DNT network might play a role in Alzheimer’s disease pathology. Computational models of DNT-mediated Aβ propagation recapitulated early amyloidosis, predicting selective intracellular accumulation. These findings uncover a nanotubular connectivity layer in the brain, extending neuronal communication beyond classical synapses.

A new generation of radiotherapies promises a more targeted attack on cancer

During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stresses. GCN2 activation has been linked to its association with uncharged tRNAs, specific ribosomal proteins, and conditions of translational arrest, but their relative contribution to activation is unclear. Here, we used in vitro translation to reconstitute GCN2 activation by amino acid stress and compared collided ribosome populations induced by diverse translational stressors. Initiation of GCN2 signaling required the di-ribosome sensor GCN1, which recruits GCN2 to ribosomes in a collision-dependent manner, where GCN2 becomes activated by key ribosomal interactions and stably associated with collided ribosomes. Our findings define the molecular requirements and dynamics of GCN2 activation.

The underlying reaction mechanism in lithium-ion batteries remains poorly understood. We provide experimental and theoretical evidence that lithium intercalation occurs by coupled ion-electron transfer, where ion transfer across the electrode-electrolyte interface is facilitated by electron transfer to a neighboring redox site. Electrochemical measurements for a variety of common electrode and electrolyte materials reveal a universal dependence of the (de-)intercalation rate on Li+vacancy fraction, as well as temperature and electrolyte effects consistent with the theory, which could be used to guide the molecular design of lithium-ion battery interfaces.

Adaptive evolution is key for species to persist in a warming climate. However, how adaptive genetic variants arise and shape both past and future evolutionary trajectories remains largely unknown. In this work, we integrate genomics with functional and ecological assays to unravel the evolutionary history and adaptive potential of alleles governing adaptation to climate through flowering time in an Alpine carnation. We reveal that “warm” and “cold” alleles of the flowering inhibitorCENTRORADIALIS(DsCEN/2) originated through recombination of highly divergent haplotypes during the carnation radiation, implicating ancestral variation in seeding climate-adaptive alleles. These alleles survived in glacial refugia before mediating the species’ range expansion in response to postglacial warming. We predict that, by recapitulating past evolution, warm alleles will continue to facilitate adaptation under future climate change.

The atmospheres of low-temperature brown dwarfs and gas giant planets are expected to contain the phosphine molecule, PH3. However, previous observations have shown much lower abundances of this molecule than predicted by atmospheric chemistry models. We report JWST spectroscopic observations of phosphine in the atmosphere of the brown dwarf Wolf 1130C. Multiple absorption lines due to phosphine are detected around 4.3 μm, from which we calculate a phosphine abundance of 0.100 ± 0.009 parts per million. This abundance is consistent with disequilibrium atmospheric chemistry models that reproduce the phosphine abundances in Jupiter and Saturn, and is much higher than abundances previously reported for other brown dwarfs or exoplanets. This difference may be related to the low abundance of elements heavier than helium in Wolf 1130C.

25-year plan will tap brain-mapping prowess in China and two dozen other countries

Small study suggests uniQure drug could be first successful treatment for devastating brain disorder

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Upwelling generates a nutrient-rich “cold tongue” in the eastern equatorial Pacific Ocean (EEP), with impacts on global climate, oceanic biological productivity, and the carbon cycle. The cold tongue was reduced during the Pliocene Epoch, a feature attributed to weaker upwelling and an associated deepening of the surface mixed layer in the EEP. Here, we report nitrogen-isotope evidence that modern-like upwelling occurred in the EEP during the Pliocene and has persisted over the past 5 million years. We explain the reduced Pliocene cold tongue as an expression of the reduced temperature difference between surface and subsurface waters in the tropical Pacific. The attendant reduction in the vertical density gradient may have maintained EEP upwelling despite the expected slackening of the trade winds under Pliocene warmth.

Nationalist narrative holds that Austronesian language and culture originated in China, not Taiwan

Paleogenomic studies suggest thatMammuthus columbiderives from an ancient hybridization betweenMammuthus primigeniusandMammuthus trogontherii. Although its habitat spanned from North to Central America, available genetic data are limited to temperate regions, leaving gaps in knowledge of the species’ demographic history on the continent. In this study, we generated 61 capture-enrichedM. columbimitogenomes from the Basin of Mexico, located in Central Mexico. Our analysis reveals that these mitogenomes belong to a mitochondrial lineage distinct from that of other North American mammoth mitogenomes. These divergent mitogenomes suggest a deep population structure in their ancestors and challenge prior assumptions based on geographically restricted samples. Our findings underscore the importance of wider spatial sampling to reconstruct mammoths’ evolutionary history and demonstrate the feasibility of studying megafauna from tropical latitudes.

Plant roots release exudates to encourage microbiome assembly, which influences the function and stress resilience of plants. How specific exudates drive spatial colonization patterns remains largely unknown. In this study, we demonstrate that endodermal Casparian strips—forming the root’s extracellular diffusion barrier—restrict nutrient leakage into the rhizosphere, coinciding with and controlling spatial colonization patterns of rhizobacteria. We find that vasculature-derived glutamine leakage is a major bacterial chemoattractant and enhancer of proliferation, defining a previously unknown pathway for root exudate formation. Bacteria defective in amino acid chemoperception display reduced attraction toward leakage sites, and roots with Casparian strip defects display bacterial overproliferation, dependent on bacterial capacity for amino acid metabolization. Associated chronic immune stimulation suggests that endodermal nutrient restriction is crucial for regulating microbial colonization and assembly, limiting excessive proliferation that could compromise plant health.

Indonesian scientists celebrate repatriation of fossil collection from the colonial era

Negotiators again failed to finalize the text for a global plastics treaty in Geneva in August 2025. The talks exposed two harsh truths. Consensus on the treaty text, where no state formally objects, cannot be reached. And securing a high-ambition treaty is going to require launching a new process outside the United Nations (UN) framework.

Optically addressable electronic spins in polyatomic molecules are a promising platform for quantum information science, with the potential to enable scalable qubit design and integration through atomistic tunability and nanoscale localization. However, optical state- and site-selection are an open challenge. In this work, we introduce an organo-erbium spin qubit in which narrow (megahertz-scale) optical and spin transitions couple to provide high-resolution access to spin degrees of freedom with telecommunication-frequency light. This spin-photon interface enables demonstration of optical spin polarization and readout that distinguishes between spin states and magnetically inequivalent sites in a molecular crystal. Operation at frequencies compatible with mature photonic and microwave devices provides an opportunity for engineering scalable, integrated molecular spin-optical quantum technologies.

Editors’ selections from the current scientific literature

Advances in artificial intelligence (AI)–assisted protein engineering are enabling breakthroughs in the life sciences but also introduce new biosecurity challenges. Synthesis of nucleic acids is a choke point in AI-assisted protein engineering pipelines. Thus, an important focus for efforts to enhance biosecurity given AI-enabled capabilities is bolstering methods used by nucleic acid synthesis providers to screen orders. We evaluated the ability of open-source AI-powered protein design software to create variants of proteins of concern that could evade detection by the biosecurity screening tools used by nucleic acid synthesis providers, identifying a vulnerability where AI-redesigned sequences could not be detected reliably by current tools. In response, we developed and deployed patches, greatly improving detection rates of synthetic homologs more likely to retain wild type–like function.

Otophysans, known for their enhanced hearing enabled by the complex Weberian apparatus, comprise two-thirds of extant freshwater fish species. Previously, they were thought to have originated in fresh water before the breakup of Pangea, implying a nearly 80-million-year gap between the origin and oldest known fossil. However, the discovery of a Late Cretaceous freshwater otophysan challenges this view. Integrating fossil, morphological, and genomic data, we estimate a younger crown group origin of ~154 million years ago. Notably, ancestral range and habitat reconstructions indicate marine origins for the otophysan crown groups, with at least two transitions to fresh water. Functional simulations of the Weberian ossicles of this fossil suggest that the distinctive hearing capabilities of otophysans evolved in conjunction with fusion of hearing ossicle parts and freshwater adaptations.

Over the past 3 years, the idea that artificial intelligence (AI) development should be accelerated without restraint to drive radical societal change—a phenomenon known as AI accelerationism—has gained traction in Silicon Valley. The most prominent form of this belief is known as “effective accelerationism,” and adherents view unrestricted progress in AI as a solution to humanity’s problems. Rooted in the broader political ideology of accelerationism, this movement positions itself directly in opposition to “AI doomers” or “decelerationists,” who advocate for AI safety and slow, cautious development. Effective accelerationists often dismiss concerns about existential risk, arguing that technological stagnation is a greater danger than uncontrolled advancement.Public interest AIinverts AI accelerationism, promoting more equitable, sustainable, and democratically accountable technological progress. This approach directly addresses the risks and potential harms of unregulated acceleration by aligning AI with public values rather than solely with private interests.

Root barriers and metabolite leakage shape microbial colonization of plants

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Sedimentary records hint at how the equatorial Pacific may evolve in a future warm climate

Farmers and supporters—including RFK Jr. and Dr. Oz—urge government to spare birds, citing research potential

Lithium-ion batteries charge through coupled classical and quantum-mechanical processes

Communication at synapses is facilitated by postsynaptic receptors, which convert a chemical signal into an electrical response. For ligand-gated ion channels, agonist binding triggers rapid transitions through intermediate states leading to a transient open-pore conformation, with these transitions shaping the post-synaptic response. Here, we determine structures of the muscle-type nicotinic acetylcholine receptor in unliganded, mono-liganded, and di-liganded states. Agonist binding to a single site stabilizes a closed structure where an entire principal agonist-binding subunit transitions to an active-like conformation, while the other unoccupied principal subunit remains inactive, albeit poised for activation. Uniting this intermediate structure with single-channel recordings informs a sequential activation mechanism where asynchronous subunit transitions prime the receptor for activation, a finding with implications for an entire superfamily of pentameric ligand-gated ion channels.

We used a retrained machine learning workflow to enhance the performance of the seismic monitoring network at Campi Flegrei caldera (CFc) for improved tracking of the evolution of volcanic unrest. We analyzed the recent (21 January 2022 to 20 March 2025) continuous seismic data, which showed a sharp increase in seismicity at the highly populated CFc. Our analysis expanded the seismicity catalog from around 12,000 to more than 54,000 earthquakes. The more complete picture of seismicity revealed a sharply defined caldera ring fault system (RFS) featuring a very narrow depth range of seismicity, clearly illuminated shallow faults in the northern part of the caldera, and uncovered a source of very shallow hybrid earthquakes likely related to the hydrothermal system. To date, we have not observed any direct signature of upward migration of magma, nor have we observed seismic activity at depths below 3.7 kilometers on or inside the RFS.

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AbstractSingle-cell multimodal omics technologies have empowered the profiling of complex biological systems at a resolution and scale that were previously unattainable. These biotechnologies have propelled the fast-paced innovation and development of data integration methods, leading to a critical need for their systematic categorization, evaluation and benchmarking. Navigating and selecting the most pertinent integration approach poses a considerable challenge, contingent upon the tasks relevant to the study goals and the combination of modalities and batches present in the data at hand. Understanding how well each method performs multiple tasks, including dimension reduction, batch correction, cell type classification and clustering, imputation, feature selection and spatial registration, and at which combinations will help guide this decision. Here we develop a much-needed guideline on choosing the most appropriate method for single-cell multimodal omics data analysis through a systematic categorization and comprehensive benchmarking of current methods. The stage 1 protocol for this Registered Report was accepted in principle on 30 July 2024. The protocol, as accepted by the journal, can be found athttps://springernature.figshare.com/articles/journal_contribution/Multi-task_benchmarking_of_single-cell_multimodal_omics_integration_methods/26789902.

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AbstractStructural RNAs exhibit a vast array of recurrent short three-dimensional (3D) elements found in loop regions involving non-Watson–Crick interactions that help arrange canonical double helices into tertiary structures. Here we present CaCoFold-R3D, a probabilistic grammar that predicts these RNA 3D motifs (also termed modules) jointly with RNA secondary structure over a sequence or alignment. CaCoFold-R3D uses evolutionary information present in an RNA alignment to reliably identify canonical helices (including pseudoknots) by covariation. Here we further introduce the R3D grammars, which also exploit helix covariation that constrains the positioning of the mostly noncovarying RNA 3D motifs. Our method runs predictions over an almost-exhaustive list of over 50 known RNA motifs (‘everything’). Motifs can appear in any nonhelical loop region (including three-way, four-way and higher junctions) (‘everywhere’). All structural motifs as well as the canonical helices are arranged into one single structure predicted by one single joint probabilistic grammar (‘all-at-once’). Our results demonstrate that CaCoFold-R3D is a valid alternative for predicting the all-residue interactions present in a RNA 3D structure. CaCoFold-R3D is fast and easily customizable for novel motif discovery and shows promising value both as a strong input for deep learning approaches to all-atom structure prediction as well as toward guiding RNA design as drug targets for therapeutic small molecules.

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AbstractHigh-resolution tissue imaging is often compromised by sample-induced optical aberrations that degrade resolution and contrast. Although wavefront sensor-based adaptive optics (AO) can measure these aberrations, such hardware solutions are typically complex, expensive to implement and slow when serially mapping spatially varying aberrations across large fields of view. Here we introduceAOViFT(adaptive optical vision Fourier transformer)—a machine learning-based aberration sensing framework built around a three-dimensional multistage vision transformer that operates on Fourier domain embeddings.AOViFTinfers aberrations and restores diffraction-limited performance in puncta-labeled specimens with substantially reduced computational cost, training time and memory footprint compared to conventional architectures or real-space networks. We validatedAOViFTon live gene-edited zebrafish embryos, demonstrating its ability to correct spatially varying aberrations using either a deformable mirror or postacquisition deconvolution. By eliminating the need for the guide star and wavefront sensing hardware and simplifying the experimental workflow,AOViFTlowers technical barriers for high-resolution volumetric microscopy across diverse biological samples.

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AbstractDeep brain stimulation (DBS) effectively treats drug-resistant neurological and psychiatric disorders, yet its mechanisms remain unclear. Here we show that high-frequency DBS of the subthalamic nucleus (STN), a common target for Parkinson’s disease (PD), activates afferent axons while inhibiting STN neurons. These contrasting presynaptic and postsynaptic effects arise from a decrease in local neurotransmitter release with a larger decrease in glutamate than GABA, shifting the excitation/inhibition balance toward inhibition. Chemogenetic inhibition, but not excitation, of STN neurons mimics the therapeutic effects of DBS in 6-OHDA-lesioned PD mice. Acute and chronic bilateral chemogenetic STN inhibition restores motor function in a progressive PD mouse model. These findings suggest that inhibition of STN, caused by differential depression of glutamatergic and GABAergic synapses, is a key mechanism of therapeutic DBS. ‘Chemogenetic DBS’, direct chemogenetic inhibition of postsynaptic neurons, may offer a less invasive and more affordable alternative to electrical DBS for PD and other neurological disorders.

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AbstractMany neurological diseases are characterized by the accumulation of toxic proteins in the brain. This accumulation has been associated with improper clearance from the parenchyma. Recent discoveries highlighted perivascular spaces, which are cerebrospinal fluid (CSF)-filled spaces, as the channels of brain clearance. The forces driving CSF mobility within perivascular spaces are still debated. Here we present a noninvasive, CSF-specific magnetic resonance imaging technique (CSF-Selective T2-prepared REadout with Acceleration and Mobility-encoding) that enables detailed in vivo measurement of CSF mobility in humans, down to the level of perivascular spaces located around penetrating vessels, which is close to protein production sites. We find region-specific drivers of CSF mobility and demonstrate that CSF mobility can be increased by entraining vasomotion. Furthermore, we find region-specific CSF mobility alterations in patients with cerebral amyloid angiopathy, a brain disorder associated with clearance impairment. The availability of this technique opens up avenues to investigate the impact of CSF-mediated clearance in neurodegeneration and sleep.

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Abstract“Core knowledge” refers to a set of cognitive systems that underwrite early representations of the physical and social world, appear universally across cultures, and likely result from our genetic endowment. Although this framework is canonically considered as a hypothesis about early-emergingconception— how we think and reason about the world — here we present an alternative view: that many such representations are inherentlyperceptualin nature. This “core perception” view explains an intriguing (and otherwise mysterious) aspect of core-knowledge processes and representations: that they also operate in adults, where they display key empirical signatures of perceptual processing. We first illustrate this overlap using recent work on “core physics”, the domain of core knowledge concerned with physical objects, representing properties such as persistence through time, cohesion, solidity, and causal interactions. We review evidence that adult vision incorporates exactly these representations of core physics, while also displaying empirical signatures of genuinely perceptual mechanisms, such as rapid and automatic operation on the basis of specific sensory inputs, informational encapsulation, and interaction with other perceptual processes. We further argue that the same pattern holds for other areas of core knowledge, including geometrical, numerical, and social domains. In light of this evidence, we conclude that many infant results appealing to precocious reasoning abilities are better explained by sophisticated perceptual mechanisms shared by infants and adults. Our core-perception view elevates the status of perception in accounting for the origins of conceptual knowledge, and generates a range of ready-to-test hypotheses in developmental psychology, vision science, and more.

AbstractAdaptation to cellular stresses entails an incompletely understood coordination of transcriptional and post-transcriptional gene expression programs. Here, by quantifying hypoxia-dependent transcriptomes, epigenomes and translatomes in T47D breast cancer cells and H9 human embryonic stem cells, we show pervasive changes in transcription start site (TSS) selection associated with nucleosome repositioning and alterations in H3K4me3 distribution. Notably, hypoxia-associated TSS switching was induced or reversed via pharmacological modulation of H3K4me3 in the absence of hypoxia, defining a role for H3K4me3 in TSS selection independent of HIF1-transcriptional programs. By remodelling 5′UTRs, TSS switching selectively alters protein synthesis, including enhanced translation of messenger RNAs encoding pyruvate dehydrogenase kinase 1, which is essential for metabolic adaptation to hypoxia. These results demonstrate a previously unappreciated mechanism of translational regulation during hypoxia driven by epigenetic reprogramming of the 5′UTRome.

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AbstractMitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson’s disease-related genes, includingVPS35andLRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL,LRRK2orVPS35inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria–lysosome pathway at the nexus of immune signalling and cell death.

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AbstractA select few genes act as pivotal drivers in the process of cell state transitions. However, finding key genes involved in different transitions is challenging. Here, to address this problem, we present CellNavi, a deep learning-based framework designed to predict genes that drive cell state transitions. CellNavi builds a driver gene predictor upon a cell state manifold, which captures the intrinsic features of cells by learning from large-scale, high-dimensional transcriptomics data and integrating gene graphs with directional connections. Our analysis shows that CellNavi can accurately predict driver genes for transitions induced by genetic, chemical and cytokine perturbations across diverse cell types, conditions and studies. By leveraging a biologically meaningful cell state manifold, it is proficient in tasks involving critical transitions such as cellular differentiation, disease progression and drug response. CellNavi represents a substantial advancement in driver gene prediction and cell state manipulation, opening new avenues in disease biology and therapeutic discovery.

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AbstractTau misfolding into β-sheet–rich filaments and subsequent recruitment of monomeric tau are central to Alzheimer’s disease (AD) pathogenesis. While cryo-EM has resolved the conformation of the AD tau core, the structural features conferring biological activity remain unclear. Here, we investigated how tau filament core structure and post-translational modifications influence seeding capacity in neurons and mice. Our findings show that although filament structure impacts seeding, the AD tau core alone is insufficient to fully replicate AD tau’s biological activity. The unstructured fuzzy coat, particularly phosphorylation within this region, is essential for full seeding competence. Importantly, recombinant tau filaments bearing twelve phospho-mimetic residues (PAD12 tau) and adopting the AD fold recapitulate the seeding activity of native AD tau. These results demonstrate that tau filament pathogenicity arises from the combined contributions of both the ordered core structure and post-translational modifications within the fuzzy coat, providing critical insights into mechanisms underlying tau-driven neurodegeneration.

AbstractElectrical control of magnetization in nanoscale devices can be significantly improved through the efficient generation of orbital currents and their conversion into spin currents. In nonmagnetic/ferromagnetic bilayers, this conversion produces a torque on the magnetization, enabling magnetization switching and dynamic manipulation. While previous studies focus on metallic ferromagnets, we demonstrate a large orbital torque and enhanced orbital-to-spin conversion by an antiferromagnetic insulating CoO layer. Measurements in CuOx/CoO/Co trilayers show that inserting CoO reverses the torque’s sign and triples its magnitude compared to CuOx/Co. This behaviour stems from the inverted oxygen gradient at the CuOx/CoO interface and CoO’s high orbital multiplicity, which favours the transmission of orbital momenta and efficient orbital-to-spin conversion. At low temperatures, the onset of antiferromagnetic order induces a further many-fold increase of the torque, which we attribute to the efficient excitation and propagation of spin-orbit excitons induced by magnetic coupling. Comparative measurements of CuOx/NiO/Co and CuOx/MnO/Co trilayers show that the torque efficiency scales with the orbital momentum of the Co2+, Ni2+, and Mn2+ions in the antiferromagnet. These results reveal that antiferromagnetic insulators like CoO provide highly effective orbital-to-spin transduction, combining orbital torque and exchange bias functionalities to improve the performance of spintronic devices.

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AbstractMoraxella catarrhalisis an important cause of infectious exacerbations of chronic obstructive pulmonary disease and otitis media. To investigate the population structure ofM. catarrhalis, we developed a core-genome multilocus sequence typing (cgMLST) scheme using 1319 core genes, and a life identification number (LIN) barcode classification system. Whole-genome analyses of nearly 2000 genomes confirmed divergent seroresistant (SR) and serosensitive (SS)M. catarrhalislineages with distinct evolutionary trajectories. SR genomes are more conserved, while SS genomes exhibited greater genetic variability. Virulence gene analyses revealed lineage-specific variations in ubiquitous surface proteins (UspA1 and UspA2) and lipooligosaccharide (LOS) types. Thebroβ-lactamase, andmcbbacteriocin cluster, are more common in SR lineages, which suggested different selective pressures and adaptation. Here, we show that this cgMLST scheme and LIN code system provide a robust method for characterisingM. catarrhalis, distinguish between SR and SS lineages, and offer a unified framework for population structure analyses.

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AbstractA hallmark of obesity is a pathological expansion of white adipose tissue (WAT), accompanied by marked tissue dysfunction and fibrosis. Autophagy promotes adipocyte differentiation and lipid homeostasis, but its role in obese adipocytes and adipose tissue dysfunction remains incompletely understood. Using a mouse model, we demonstrate that autophagy is a key tissue-specific regulator of WAT remodelling in diet-induced obesity. Importantly, loss of adipocyte autophagy substantially exacerbates pericellular fibrosis in visceral WAT. Change in WAT architecture correlates with increased infiltration of macrophages with tissue-reparative, fibrotic features. We uncover that autophagy restrains purine nucleoside metabolism in obese adipocytes. This ultimately leads to a reduced release of the purine catabolites xanthine and hypoxanthine. Purines signal cell-extrinsically for fibrosis by driving macrophage polarisation towards a tissue reparative phenotype. Our findings in mice reveal a role for adipocyte autophagy in regulating tissue purine nucleoside metabolism, thereby limiting obesity-associated fibrosis and maintaining the functional integrity of visceral WAT. Purine signals may serve as a critical balance checkpoint and therapeutic target in fibrotic diseases.

AbstractPd nanoparticles, together with bulk and thin film Pd, constitute the archetype model system for metal-hydrogen interactions. The density of defects in Pd nanoparticles, such as grain boundaries and dislocations, combined with their size, shape, composition and lattice strain, dictate their hydrogen sorption kinetics and thermodynamics. Despite decades of research and its relevance in applications, such as solid-state hydrogen storage, hydrogen sensors, hydrogen embrittlement, and hydrogen separation membranes, a coherent picture of the intricate interplay between defects, strain and Pd nanoparticle hydrogen sorption properties is missing. Here, we employ a combination of single particle nanocompression, single particle plasmonic nanoimaging and high-resolution cross-sectional single particle TEM imaging to investigate hydrogen absorption kinetics and hydride phase formation pressures in a nanofabricated array of Pd nanoparticles on sapphire substrate with systematically varied levels of plastic deformation – and thus defects and strain. We not only show a clear deformation-level dependent trend of both the kinetics and the hydride formation pressure, but also reveal their complex evolution upon hydrogen cycling. We discuss how these results provide a quantitative view of the impact of plastic deformation on nanoscale metal hydrides, and how they reveal the surface and bulk morphology of Pd nanoparticles upon repeated hydrogen cycling.

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AbstractIn the context of rapid human-caused climate change, regular updates of the state of knowledge of current and future climate are needed. New statistical methods using observational constraints underpinned estimates of present-day human-induced warming and projected future warming in the most recent IPCC report. As time goes by, and new updated observational records become available, how should estimates of the current and projected human-caused climate change be updated? Here, we use a perfect model framework and show that incorporating observations from every new year in observationally constrained projections improves their accuracy, without causing major year-to-year spurious variability on outcomes. The forced warming estimated for the current year also exhibits high enough stability to be considered as a robust indicator of the state of the climate system.

AbstractCryo-EM and X-ray crystallography provide crucial experimental data for obtaining atomic-detail models of biomacromolecules. Refining these models relies on library-based stereochemical data, which, in addition to being limited to known chemical entities, do not include meaningful noncovalent interactions. Quantum mechanical (QM) calculations could alleviate these issues but are too expensive for large molecules. Here we present a novel AI-enabled Quantum Refinement (AQuaRef) based on AIMNet2 machine learned interatomic potential (MLIP) mimicking QM at substantially lower computational costs. By refining 41 cryo-EM and 30 X-ray structures, we show that this approach yields atomic models with superior geometric quality compared to standard techniques, while maintaining an equal or better fit to experimental data. Notably, AQuaRef aids in determining proton positions, as illustrated in the challenging case of short hydrogen bonds in the parkinsonism-associated human protein DJ-1 and its bacterial homolog YajL.

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AbstractRecent advancements in spatial transcriptomics technologies have significantly enhanced resolution and throughput, underscoring an urgent need for systematic benchmarking. Here, we generate serial tissue sections from colon adenocarcinoma, hepatocellular carcinoma, and ovarian cancer samples for systematic evaluation. Using these uniformly processed samples, we generate spatial transcriptomics data across four high-throughput platforms with subcellular resolution: Stereo-seq v1.3, Visium HD FFPE, CosMx 6K, and Xenium 5K. To establish ground truth datasets, we profile proteins on tissue sections adjacent to all platforms using CODEX and perform single-cell RNA sequencing on the same samples. Leveraging manual nuclear segmentation and detailed annotations, we systematically assess each platform’s performance across capture sensitivity, specificity, diffusion control, cell segmentation, cell annotation, spatial clustering, and concordance with adjacent CODEX. The uniformly generated and processed multi-omics dataset could advance computational method development and biological discoveries. The dataset is accessible via SPATCH, a user-friendly web server for visualization and download.

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AbstractRheology aims at quantifying the response of materials to mechanical forcing. However, standard rheometers provide only global macroscopic quantities, such as viscoelastic moduli. They fail to capture the heterogeneous flow of soft amorphous materials at the mesoscopic scale, arising from the rearrangements of the microstructural elements, that must be accounted for to build predictive models. To address this experimental challenge, we have combined shear rheometry and time-resolved X-ray micro-tomography on 3D liquid foams used as model soft jammed materials, yielding a unique access to the stresses and contact network topology at the bubble scale. We reveal a universal scaling behavior of the local stress build-up and relaxation associated with topological modifications. Moreover, these plastic events redistribute stress non-locally, as if the foam were an elastic medium subjected to a quadrupolar deformation. Our findings clarify how the macroscopic elastoplastic behavior of amorphous materials emerges from the spatiotemporal stress variations induced by microstructural rearrangements.

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AbstractMulti-template polymerase chain reaction (PCR) is a critical technique enabling the parallel amplification of diverse DNA molecules, thereby facilitating applications in fields from quantitative molecular biology to DNA data storage. However, non-homogeneous amplification due to sequence-specific amplification efficiencies often results in skewed abundance data, compromising accuracy and sensitivity. In this study, we address amplification efficiency in complex amplicon libraries by employing one-dimensional convolutional neural networks (1D-CNNs) to predict sequence-specific amplification efficiencies, based on sequence information alone. Trained on reliably annotated datasets derived from synthetic DNA pools, these models achieve a high predictive performance (AUROC: 0.88, AUPRC: 0.44), thereby enabling the design of inherently homogeneous amplicon libraries. We further introduce CluMo, a deep learning interpretation framework that identifies specific motifs adjacent to adapter priming sites as closely associated with poor amplification. This insight leads to the elucidation of adapter-mediated self-priming as the major mechanism causing low amplification efficiency, challenging long-standing PCR design assumptions. By addressing the basis for non-homogeneous amplification in multi-template PCR, our deep-learning approach reduces the required sequencing depth to recover 99% of amplicon sequences fourfold, and opens new avenues to improve the efficiency of DNA amplification in fields such as genomics, diagnostics, and synthetic biology.

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AbstractPt/CeO2ensemble catalysts are promising for propylene (C3H6) oxidation in vehicle exhaust, yet identifying the intrinsic active sites and understanding how the metal-support interface evolves at varying reaction temperatures remains contentious. Herein, we demonstrate that H2-activated Pt/CeO2ensemble catalysts feature metallic Pt ensembles as intrinsic active sites, lowering the 50% conversion temperature by 120 °C after hydrogen activation. Various operando characterization techniques reveal an approximately 170 °C threshold temperature for the dynamic change of the reaction models. Meanwhile, kinetics and theoretical analysis illustrates that oxygen-facilitated dehydrogenation ofsp3C-H bonds is the rate-determining step. At low temperatures, both C3H6and O2adsorb and activate on metallic Pt, without CeO2involvement. Once the temperature exceeds threshold, C3H6fully covers Pt sites, while O2activates over Pt-O-Ce interfaces and participates in dehydrogenation. This study highlights the dynamic nature of oxygen activation, leading to distinct reaction temperature regimes during C3H6oxidation.

AbstractRecent demonstrations on specialized benchmarks have reignited excitement for quantum computers, yet their advantage for real-world problems remains an open question. Here, we show that probabilistic computers, co-designed with hardware to implement Monte Carlo algorithms, provide a scalable classical pathway for solving hard optimization problems. We focus on two algorithms applied to three-dimensional spin glasses: discrete-time simulated quantum annealing and adaptive parallel tempering. We benchmark these methods against a leading quantum annealer. For simulated quantum annealing, increasing replicas improves residual energy scaling, consistent with extreme value theory. Adaptive parallel tempering, supported by non-local isoenergetic cluster moves, scales more favorably and outperforms simulated quantum annealing. Field Programmable Gate Arrays or specialized chips can implement these algorithms in modern hardware, leveraging massive parallelism to accelerate them while improving energy efficiency. Our results establish a rigorous classical baseline for assessing practical quantum advantage and present probabilistic computers as a scalable platform for real-world optimization challenges.

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AbstractCoupling a Rydberg vapour medium to both microwave and optical fields enables the benefits of all-optical detection, such as minimal disturbance of the measured field and resilience to very strong signals, since no conventional antenna is required. However, peak sensitivity typically relies on adding a microwave local oscillator, which compromises the all-optical nature of the measurement. Here we introduce an alternative,optical-bias detection, that maintains fully optical operation while achieving high sensitivity. To address laser phase noise, which is critical in this approach, we perform a simultaneous measurement of the noise using a nonlinear process and correct it in real time via data processing. This yields a 35 dB improvement in signal-to-noise ratio compared with the basic method. We demonstrate a sensitivity of$$176\,{{{\rm{nV}}}}/{{{\rm{cm}}}}/\sqrt{{{{\rm{Hz}}}}}$$176nV/cm/Hz, reliable operation up to 3.5 mV/cm at 13.9 GHz, and quadrature-amplitude modulated data transmission, underlining the ability to detect microwave field quadratures while preserving the unique advantages of all-optical detection.

AbstractThe long-term effects of Earth’s magnetosphere on solar wind (SW) irradiation asymmetry between the lunar nearside and farside, and their implications for space weathering processes, remain poorly characterized. Here, we measure exposure ages and SW-induced amorphous rim thicknesses of individual grains from the Chang’E-5 (CE-5) and Chang’E-6 (CE-6) lunar soils to derive rim growth rates. Comparative analysis of SW irradiation records from CE-5, CE-6, and Apollo (11, 16, 17) samples reveals that CE-6 grains from the southern mid-latitude farside exhibit higher rim growth rates than those from the low-latitude nearside Apollo sites. This trend aligns with simulated lunar surface SW fluxes and is consistent with the hypothesis that reduced SW exposure on the nearside, due to Earth’s magnetospheric shielding, may contribute to a persistent hemispheric asymmetry in SW irradiation. However, CE-5 samples from the northern mid-latitude nearside yield unexpectedly high rim growth rates, suggesting the potential involvement of additional local factors. The exact reasons for this anomaly remain unclear and warrant further investigation.

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AbstractWhile doxycycline postexposure prophylaxis (doxyPEP) can prevent bacterial sexually transmitted infections (STIs), concern surrounds the volume of antibiotic use needed to realize this benefit. We estimated incidence rates of gonorrhea, chlamydia, and syphilis diagnoses and related antibiotic prescribing among US males and transgender individuals using Merative MarketScan® Research Databases during 2017-2019. Follow-up encompassed 38,543 person-years among recipients of HIV pre-exposure prophylaxis (PrEP), 29,228 person-years among people living with HIV (PLWH), and 19,918 person-years among people with prior-year STI diagnoses. Incidence rates of STI diagnoses among PLWH and PrEP recipients with ≥1 prior-year STI diagnosis totaled 33.3-35.5 per 100 person-years. Direct effects of doxyPEP could prevent 7.4-9.6 gonorrhea diagnoses, 7.3-8.1 chlamydia diagnoses, and 3.1-5.9 syphilis diagnoses per 100 person-years of use. However, expected increases in tetracycline consumption resulting from doxyPEP implementation totaled 271.9-312.9 additional 7-day doxycycline treatment courses per 100 person-years of use. These increases corresponded to 37.0-38.7, 36.5-37.0, and 46.1-100.2 additional 7-day doxycycline treatment courses for each prevented gonorrhea, chlamydia, and syphilis diagnosis, respectively. Increases in doxycycline use exceeded anticipated reductions in STI-related prescribing of cephalosporins, macrolides, and penicillins by 16–69-fold margins. Anticipated changes in antibiotic use as well as STI incidence should inform priority-setting for doxyPEP.

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AbstractEarth experienced state-specific climate-carbon cycle feedbacks during the Late Cenozoic Ice Age (LCIA). Whether similar feedbacks existed in the penultimate icehouse, the Late Paleozoic Ice Age (LPIA), remains uncertain. Here, we present phase relationships between eccentricity-paced climate cycles and carbonate carbon isotope across ~337–300 Ma. Up to 307 Ma, low-latitude continental carbon reservoirs expanded during eccentricity-forced coolings, resembling the Oligocene and Miocene climate-carbon cycle dynamics. After 307 Ma, this relationship reversed, analogous to the Plio-Pleistocene dynamics. We attribute this reversal to the increasing importance of high-latitude biome dynamics, comparable to what occurred at 6 Ma in the LCIA. Paralleling LPIA (335–301 Ma) and LCIA (past 34 Myr) records using this event reveals quasi-synchronization in the interaction of astronomical forcing, carbon cycling and glacial events from onset to apex of two icehouses. We propose that, despite different boundary conditions, extraterrestrial forcing shaped the evolutionary trajectory of Phanerozoic vegetated icehouses.

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AbstractHerpes simplex virus (HSV) infection poses global public health concerns with lifelong impacts. Acyclovir, the standard therapy, has limited efficacy in preventing subclinical shedding, and drug resistance occurs in immunocompromised patients, highlighting the need for novel therapeutics. Here we show that acyclovir is significantly less effective in skin-derived keratinocytes than donor-matched fibroblasts. Using 3D bioprinted human skin equivalents (HSEs) in a 96-well plate format, we have screened 738 compounds with broad targets and mechanisms of action, identifying potent antivirals, including 23 known or experimental HSV treatments. Unlike acyclovir, antivirals against HSV helicase/primase or host replication pathways display similar potency across cell types and donor sources in both 2D and 3D models. The reduced potency in keratinocytes may explain acyclovir’s limited clinical efficacy. Our 3D bioprinted HSE assay platform enables the integration of patient-derived cells early in drug development and offers a physiologically relevant approach for HSV drug discovery.

AbstractIn materio computing offers the potential for widespread embodied intelligence by leveraging the intrinsic dynamics of complex systems for efficient sensing, processing, and interaction. While individual devices offer basic data processing capabilities, networks of interconnected devices can perform more complex and varied tasks. However, designing such networks for dynamic tasks is challenging in the absence of physical models and accurate characterization of device noise. We introduce the Noise-Aware Dynamic Optimization (NADO) framework for training networks of dynamical devices, using Neural Stochastic Differential Equations (Neural-SDEs) as differentiable digital twins to capture both the dynamics and stochasticity of devices with intrinsic memory. Our approach combines backpropagation through time with cascade learning, enabling effective exploitation of the temporal properties of physical devices. We validate this method on networks of spintronic devices across both temporal classification and regression tasks. By decoupling device model training from network connectivity optimization, our framework reduces data requirements and enables robust, gradient-based programming of dynamical devices without requiring analytical descriptions of their behaviour.

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AbstractOver the last decade, there have been significant advances in our understanding of anaerobic hydrocarbon oxidation in archaea. However, the ability to oxidise hydrocarbons aerobically has been described in bacteria but not yet in archaea. Here, we provide evidence supporting potential aerobic hydrocarbon oxidation ability in archaea belonging to a novel order within the class Syntropharchaeia, which we propose to name Candidatus ‘Aerarchaeales’. This order is represented by six metagenome-assembled genomes (MAGs) spanning three genera that are found in terrestrial and marine ecosystems. In particular, MAGs belonging to a newly defined genus, Ca. ‘Aerovita’, encode a copper monooxygenase complex with homology to bacterial hydrocarbon monooxygenases. The presence of genes encoding other oxygen-dependent enzymes, such as haem-copper oxygen reductase, indicates that Ca. ‘Aerovita’ may be capable of aerobic respiration. Our findings suggest that horizontal gene transfer between archaeal and bacterial domains facilitated the evolution of aerobic hydrocarbon-oxidizing archaea.

AbstractCancers arising from dysregulation of generally operative signaling pathways are often tissue specific, but the mechanisms underlying this paradox are poorly understood. Based on striking cell-type specificity, we postulated that these mechanisms must operate early in cancer development and set out to study them in a model of von Hippel Lindau (VHL) disease. Biallelic mutation of the VHL ubiquitin ligase leads to constitutive activation of hypoxia inducible factors HIF1A and HIF2A and is generally a truncal event in clear cell renal carcinoma. We used an oncogenic tagging strategy in whichVHL-mutant cells are marked by tdTomato, enabling their observation, retrieval, and analysis early afterVHL-inactivation. Here, we reveal markedly different consequences of HIF1A and HIF2A activation, but that both contribute to renal cell-type specific consequences ofVHL-inactivation in the kidney. Early involvement of HIF2A in promoting proliferation within the proximal tubular epithelium supports therapeutic targeting of HIF2A early in VHL disease.

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AbstractThe gold standard in the treatment of ischaemic stroke is set by evidence from randomized controlled trials, typically using simple estimands of presumptively homogeneous populations. Yet the manifest complexity of the brain’s functional, connective, and vascular architectures introduces heterogeneities that violate the underlying statistical premisses, potentially leading to substantial errors at both individual and population levels. The counterfactual nature of interventional inference renders quantifying the impact of this defect difficult. Here we conduct a comprehensive series of semi-synthetic, biologically plausible, virtual interventional trials across 100M+ distinct simulations. We generate empirically grounded virtual trial data from large-scale meta-analytic connective, functional, genetic expression, and receptor distribution data, with high-resolution maps of 4K+ acute ischaemic lesions. Within each trial, we estimate treatment effects using models varying in complexity, in the presence of increasingly confounded outcomes and noisy treatment responses. Individualized prescriptions inferred from simple models, fitted to unconfounded data, are less accurate than those from complex models, even when fitted to confounded data. Our results indicate that complex modelling with richly represented lesion data may substantively enhance individualized prescriptive inference in ischaemic stroke.

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AbstractWhile cap-dependent translation remains the primary focus in mRNA-based therapeutics, cap-independent translation holds promise for targeting diseases ranging from cancer to neurodegeneration. However, cap-independently translated mRNAs are unstable, produce less protein than capped mRNAs, and current methods for their improvement are imperfect. Here, we propose the use of in vitro transcription priming with azido-modified dinucleotide primer and post-transcriptional modification utilising click chemistry to improve the properties of cap-independently translated mRNAs. Our results demonstrate a significant enhancement in mRNA stability and protein output without eliciting immunogenicity. Moreover, we show how the mRNA 5′-end modification strategy can be used to investigate transfection and cap-independent translation processes in cells overcoming burdens associated with previous methods. Together, our findings support cap-independent translation as a viable alternative to the established cap-dependent process and provide tools for further exploration and enhancement of this modality.

AbstractLong-range resonant quantum tunneling of electrons happens across potential barriers when the wavefunction interferes constructively outside the barrier. Here we demonstrate an analogy in optical systems based on epsilon-near-zero materials, achieving phase-modulated, long-range optical interactions between transparent semiconducting oxide layers beyond the evanescent photonic coupling. Distinct from weak thin-film interference, intense electromagnetic fields confined within the epsilon-near-zero thin films show anti-correlated intensity oscillations as a function of interlayer separation up to hundreds of microns. The oscillatory, anti-correlated electromagnetic field intensities were probed by second harmonic generation from wedged indium tin oxide multilayers. Such a system that hosts subwavelength mode footprint and simultaneously long-range radiative coupling offers prospects for long-distance optical communication, large-scale photonic circuits, and hybrid quantum photonic systems.

AbstractTo tackle elevated blood glucose, multidrug-resistant (MDR) bacterial infections, and persistent inflammation in diabetic wounds, we present a therapeutic strategy that employs a photoswitch-controlled catalytic cascade reaction, utilizing a photocatalytic material engineered through the synergistic regulation of nitrogen vacancies and single-atom embedding. Under visible light illumination, the N vacancy exist in g-C3N4(CN) significantly enhances photocatalytic glucose oxidation to regulate the hyperglycemia condition at diabetic wound sites, and the atomically dispersed Cu promotes the generation of •OH and •O2–to efficiently eliminate MDR bacteria ( > 99.9%). Under dark conditions, excess ROS are scavenged by Cu/CN, reducing inflammation of wounds and promoting polarization of M2 macrophages. Serum biochemical and vital organs histopathological analyses after 14 days of treatment confirm the biosafety profile of Cu/CN. This photoswitchable cascade reaction effectively treats MDR bacterial-infected diabetic wounds in male mice, highlighting its potential for antibiotic-free therapy with promising clinical translation applications.

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AbstractThe insulin receptor entrains tissue growth and metabolism to nutritional conditions. Complete loss of function in humans leads to extreme insulin resistance and infantile mortality, while loss of 80-90% function permits longevity of decades. Even low-level activation of severely compromised receptors, for example by anti-receptor monoclonal antibodies, thus offers the potential for decisive clinical benefit. A barrier to genetic diagnosis and translational research is the increasing identification of variants of uncertain significance in theINSRgene, encoding the insulin receptor. By coupling saturation mutagenesis to flow-based assays, we stratified approximately 14,000 INSR extracellular missense variants by cell surface expression, insulin binding, and insulin- or monoclonal antibody-stimulated signalling. Resulting function scores correlate strongly with clinical syndromes, offer insights into dynamics of insulin binding, and reveal novel potential gain-of-function variants. This INSR sequence-function map has biochemical, diagnostic and translational utility, aiding rapid identification of variants amenable to activation by non-canonical INSR agonists.

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AbstractMillennial-scale deoxygenation of Antarctic Bottom Water (AABW) in the Atlantic Southern Ocean during past interglacials was linked to West Antarctic Ice Sheet (WAIS) melt-driven suppression of dense water formation along the Antarctic margin. However, the circum-Antarctic extent of these ‘AABW stagnation events’ and drivers of WAIS retreat remain unclear. Here, we identify recurring bottom water O2minima in the central Pacific Southern Ocean during Marine Isotope Stage (MIS) 11 (424–374 ka ago) that are synchronous with their Atlantic Southern Ocean counterparts. As they (partially) align with Circumpolar Deep Water (CDW) warming above present-day levels and/or a reorganization of deep-ocean circulation, we postulate recurring and synchronized Pacific-Atlantic AABW perturbation events during MIS11 through WAIS retreat and enhanced exposure to ocean heat (i.e., CDW) from below. This indicates a significant contribution of WAIS meltwater to sea-level high-stands during MIS11 and, by analogy, to sea-level rise due to ocean warming in the future.

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AbstractAging is the most important risk factor for multiple pathologies including cardiovascular, neoplastic, metabolic and neurodegenerative diseases. Potential geroprotective strategies involve lifestyle-related, nutritional and pharmacological interventions. Recently, chalcones, a subgroup of secondary plant metabolites, have gained attention. 4,4’-dimethoxychalcone was the first chalcone to be shown to mediate geroprotection and lifespan extension across different species. Several other chalcones also exert anti-aging effects at the cellular and organismal levels. Defined mechanistic routes that are causally involved in these protective effects have been delineated. Here, we summarize current evidence supporting the potential of 4,4’-dimethoxychalcone and other chalcones as geroprotective agents.

AbstractConventional studies suggest that faults in the shallow subsurface resist earthquake nucleation, because their frictional strength increases as slip accelerates (i.e., velocity-strengthening friction). Contrary to this widely held notion, such nominally stable faults frequently host earthquakes induced by human activities. Here, we resolve this contradiction using numerical models that simulate both geological and earthquake timescales using rate-and-state friction. Faults could develop significant interface strength, expressed as increase in static frictions by around 0.25, due to “healing” over thousands to millions of years. This strength gain can be released to nucleate earthquakes, also on velocity-strengthening faults. These earthquakes exhibit efficient frictional weakening similar to those natural earthquakes on velocity-weakening faults but follow revised nucleation stages and length scales. Seismic hazard for subsequent earthquakes is reduced and vastly different. Velocity-strengthening faults can no longer host earthquakes, because subsequent slip on human lifetimes is stable. Velocity-weakening fault segments may still nucleate earthquakes, but with sharply reduced stress drops. Neighboring ruptured velocity-strengthening segments impede rupture propagation and hence reduce anticipated future earthquake magnitudes. Both the increased hazard for the first induced earthquake and less hazardous subsequent events need to be properly assessed and communicated to maintain public confidence for using the subsurface for the energy transition.

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AbstractMulti-material 3D printing concerns the use of two or more 3D printable materials within a single printed part. The result is a composite that benefits from the combined properties of the individual 3D printed materials. Typically, a distinct differentiation between material properties can only be achieved using multiple feedstocks and advanced engineering solutions. In this work, we create multi-material 3D printed photopolymer parts from a single monomer mixture through simple adjustments in printing temperature and light intensity. We achieve this by employing a liquid crystalline (LC) monomer that forms a highly stable LC phase in conjunction with a trifunctional thiol crosslinker. A drastic change in mechanical and optical properties was achieved depending on the presence of an LC phase during polymerization. The proof of principle from bulk experiments could be translated fully into 3D printing, achieving pixel-to-pixel resolution of the material properties solely guided by changing the printing parameters temperature and light intensity. The versatility of produced multi-material composite parts is demonstrated in shape memory applications and methods for chemical data storage and encryption.

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AbstractMechanosensitive ion channels such as Piezo1 have fundamental roles in sensing the mechanical properties of the extracellular matrix. However, whether and how Piezo1 senses time-dependent matrix mechanical properties, that is, viscoelasticity, remains unknown. To address this question, we combine an immortalised mesenchymal stem cell line, in which Piezo1 expression can be silenced, with soft and stiff viscoelastic hydrogels that have independently tuneable elastic and viscous moduli. We demonstrate that Piezo1 is a regulator of the mechanotransduction of viscoelasticity in soft matrices, both experimentally and through simulations incorporating Piezo1 into a modified viscoelastic molecular clutch model. Using RNA sequencing, we also identify the transcriptomic responses of mesenchymal stem cells to matrix viscoelasticity and Piezo1 activity, identifying gene signatures that reflect their mechanobiology in soft and stiff viscoelastic hydrogels.

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AbstractApoptotic cells communicate to phagocytic cells through releasing soluble factors and apoptotic cell-derived extracellular vesicles. However, whether there are additional factors that remain attached at the site of cell death to signal to phagocytic cells is currently unknown. Here we show that apoptotic cell retraction generates a membrane-encased, F-actin-rich ‘footprint’ tightly anchored to the substrate that marks the site of cell death, coined ‘the FOotprint Of Death’ or FOOD. Formation of FOOD is observed frequently across many different cell types, apoptotic stimuli and surface composition. Mechanistically, FOOD formation is regulated by the protein kinase ROCK1. 3D time-lapse microscopy studies revealed that FOOD vesicularises into distinct large extracellular vesicles. These extracellular vesicles expose the ‘eat-me’ signal phosphatidylserine and can function to ‘flag’ the site of cell death to neighbouring phagocytes for efferocytosis. Under a viral infection setting, FOOD can harbour viral proteins and virions, and propagate infection to healthy cells. Together, this study has revealed another route of apoptotic cell-phagocyte communication.

AbstractDemand for mass spectrometry imaging (MSI) technologies offering subcellular resolution for tissues and cell imaging is rapidly increasing. To accomplish this, efficient analyte ionisation is essential, given the small amounts of sample material in each pixel. Herein, we describe an atmospheric pressure transmission-geometry matrix-assisted laser desorption source equipped with plasma ionisation. By utilising a pre-staining method for sample preparation, lipid signal intensities were enhanced by an order of magnitude compared to conventional matrix-only methods, while serendipitously enabling imaging of numerous nucleotides. The system enables detection of up to 200 lipids and nucleotides in tissues at 1 µm-pixel size while informative MSI data is still obtained down to 250 nm pixel size. The use of sub-micron pixels is shown to discern subcellular features through combinations with fluorescence microscopy. This method provides a powerful tool for cellular and sub-cellular imaging of small molecules from tissues and cells for spatial biology applications.

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AbstractMonitoring skin health through parameters like skin hydration (SH) and transepidermal water loss (TEWL) is vital for diagnosing skin conditions and identifying disease factors. Conventional devices and survey-based methods often fail to deliver accurate diagnoses due to circadian rhythms of skin health data, limited measurement frequency, and patient subjectivity. Previous research has shown that prolonged device usage also causes sweat accumulation, compromising reliable monitoring. Here, we present a breathable skin health analyzer (BSA), a wearable device designed for prolonged use, capable of accurate, long-term measurement of SH and TEWL. The BSA addresses considerable obstacles in skin health monitoring by employing a breathable chamber and a bistable actuator that ensures both ventilation and consistent sensor contact with the skin. Validated through a 28-day clinical trial, the BSA and data processing algorithms demonstrated their effectiveness in providing reliable data by analyzing the correlation between particulate matter exposure and the skin barrier health. These results not only highlight the potential to improve the diagnosis and treatment of diseases but also show the possibility of contributing to individual environmental health impact assessments and translational studies.

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AbstractThe Great Oxidation Event (GOE) represents a major increase in atmospheric O2concentration between ca. 2430 and 2060 million years ago, culminating in the permanent shift to an oxygenated atmosphere. It’s causes remain debated. Here we use the carbonate-associated phosphate (CAP) proxy to reconstruct oceanic phosphorus concentrations during the GOE from globally distributed sedimentary rocks. We find that the CAP and the inorganic carbon isotope composition of marine sediments co-varied during the GOE, suggesting synchronous fluctuations in marine phosphorus, biological productivity, and atmospheric O₂. Biogeochemical modelling shows that transient increases in P bioavailability can raise oxygenic primary production and organic carbon burial, yielding isotopically heavy seawater inorganic carbon and reproducing the observed patterns. Consequently, geochemical and modelling data together suggest that P availability was a likely contributor to the rapid oxygenation of Earth during the GOE.

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AbstractSpatial biology pursues the analysis of cells in their native microenvironment, often with regard to morphology and gene- or protein expression. The spatial analysis of lipid and metabolic profiles by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) can add another layer of molecular information. A seamless integration of MSI data with other (multimodal) methods at a single-cell level is often hampered by insufficient co-registration and resolution. Here, we introduce a MALDI-MSI based method that integrates in-source bright-field and fluorescence microscopy, allowing for a coupled (sub-)cellular investigation of the same sample in both modalities. Presented examples from cell culture and tissue analysis include the visualization of intracellular lipid distributions in macrophages during phagocytosis, and the heterogeneity of lipid profiles of tumor infiltrating neutrophils correlated to their individual microenvironments. The achieved combination of lipid profiling with morphological features and protein expression on the single-cell level constitutes a powerful method for cell biology.

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AbstractMicroRNAs may act as diagnostic and prognostic biomarkers of chronic kidney disease and are functionally important in disease pathogenesis. To identify novel microRNA biomarkers, we performed small RNA-sequencing on plasma from individuals with type 2 diabetes, with and without chronic kidney disease. MiR-190a-5p abundance was significantly lower in the circulation of type 2 diabetic patients with reduced function compared to those with normal kidney function. In an independent cohort of patients with chronic kidney disease of diverse aetiology, miR-190a-5p abundance predicted disease progression in individuals with no or moderate albuminuria ( < 300 mg/mmol). miR-190a-5p expression in kidney biopsy tissue correlated with the level of miR-190a-5p in the circulation and with estimated glomerular filtration rate, tubular mass and negatively with histological fibrosis. Administration of a miR-190a-5p mimic in a murine ischaemia-reperfusion injury model in male mice reduced tubular injury and fibrosis and increased expression of genes associated with tubular health. Our analyses suggest that miR-190a-5p is a biomarker of tubular cell health, low circulating levels may predict chronic kidney disease progression independent of existing risk factors and strategies to preserve miR-190a-5p may be an effective treatment for restoring tubular cell health following kidney injury.

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AbstractDeveloping monovalent anion-selective membranes (MAPMs) faces challenges, including the trade-off between flux and selectivity, membrane stability, and cost-effective fabrication. Overcoming these requires advanced material design and scalable techniques. Here, we introduce in situ interfacial polymerization (ISIP) to prepare MAPMs. Base membranes are synthesized via superacid polymerization and modified with anion channels and -NH2groups. During ISIP, trimesoyl chloride reacts with surface -NH2groups, forming a partially crosslinked structure with -COOH groups to regulate ion transport via electrostatic interactions. This results in low membrane resistance (4.7 Ω cm2) and selective transport of weakly hydrated ions (Cl−, Br−, NO3−), while strongly hydrated ions (SO42−, F−) face higher barriers. MAPMs demonstrate high performance, achieving a limiting current density (>90 mA cm−2), Cl−flux (1.98 mol m−2h−1at 5 mA cm−2), and selectivity (244 for Cl−/SO42−), confirming effective hydration dynamics control and balanced performance. Simulations reveal how charge distribution affects ion migration pathways.

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