N Nature Neuroscience · Dec 05, 2025 The striatal indirect pathway mediates hesitation Hesitation—that is, pausing an action in the face of uncertainty—is ubiquitous in daily life, yet little is known about its underlying neural circuitry. We present a new experimental paradigm that reliably evokes hesitation in mice and find that hesitation is mediated by indirect, but not direct, pathway neurons in the dorsomedial striatum. These data establish a new role for the indirect pathway in suppressing action under uncertainty. Neural circuits Sensorimotor processing biology mouse experiments
N Nature Neuroscience · Dec 04, 2025 In vivo CRISPR screen reveals regulation of macrophage states in neuroinflammation Here we established an in vivo CRISPR screening pipeline using genetically editable progenitor cells to dissect macrophage regulation in mouse models of multiple sclerosis (MS). Screening over 100 cytokine receptors and signaling molecules identified interferon-γ, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor and transforming growth factor-β as essential regulators of macrophage polarization in vivo. Single-cell transcriptomics confirmed that transferred progenitor cells generate all blood-derived CNS myeloid cell populations, enabling Perturb-seq analysis of cytokine actions in neuroinflammation. Combined with biosensor expression, our approach allows monitoring cytokine effects on myeloid cell migration, debris phagocytosis and oxidative activity in vivo. Comparative transcriptomic analyses revealed conserved neuroinflammatory cytokine signatures across myeloid populations, CNS compartments and species, elucidating cytokine cues shaping myeloid function in the cerebrospinal fluid and parenchyma of individuals with MS. This versatile pipeline thus provides a scalable framework for high-resolution analysis of macrophage states and uncovers the cytokine signals that underlie their regulation in MS and MS models. Autoimmunity Monocytes and macrophages Multiple sclerosis Neuroimmunology biology mouse experiments
N Nature Neuroscience · Dec 04, 2025 Rapid motor skill adjustment is associated with population-level modulation of cerebellar error signals A core principle of cerebellar learning theories is that climbing fibers from the inferior olive convey error signals about movement execution to Purkinje cells in the cerebellar cortex. These inputs trigger synaptic changes, which are purported to drive progressive adjustment of future movements. Individually, binary complex spike signals lack information about the sign and magnitude of errors which presents a problem for cerebellar learning paradigms exhibiting fast adaptation. Here, using a newly developed behavioral paradigm in mice, we introduced sensorimotor perturbations into a simple joystick-pulling behavior and found parasagittal bands of Purkinje cells with reciprocal modulation of complex spike activity, along with rapid adaptation of the behavior. Whereas complex spiking showed little modulation in the unperturbed condition, alternating bands were activated or inhibited when the perturbation was introduced and this modulation encoded the sign and magnitude of the resulting sensorimotor mismatch. These findings provide important insight about how the cerebellum uses supervised learning to quickly adapt motor behavior in response to perturbations. Cellular neuroscience Neural circuits biology mouse experiments
N Nature Neuroscience · Dec 02, 2025 The regulatory code of injury-responsive enhancers enables precision cell-state targeting in the CNS Enhancer elements direct cell-type-specific gene expression programs. After injury, cells change their transcriptional state to adapt to stress and initiate repair. Here we investigate how injury-induced transcriptional programs are encoded within enhancers in the mammalian CNS. Leveraging single-nucleus transcriptomics and chromatin accessibility profiling, we identify thousands of injury-induced, cell-type-specific enhancers in the mouse spinal cord after a contusion injury. These are abundant in glial cells and retain cell-type specificity, even when regulating shared wound response genes. By modeling glial injury-responsive enhancers using deep learning, we reveal that their architecture encodes cell-type specificity by integrating generic stimulus response elements with cell identity programs. Finally, through in vivo enhancer screening, we demonstrate that injury-responsive enhancers can selectively target reactive astrocytes across the CNS using therapeutically relevant gene delivery vectors. Our decoding of the principles of injury-responsive enhancers enables the design of sequences that can be programmed to target disease-associated cell states. Astrocyte Epigenetics and plasticity Molecular neuroscience Spinal cord injury biology mouse experiments
N Nature Neuroscience · Dec 02, 2025 High-frequency bursts facilitate fast communication for human spatial attention Brain-wide communication supporting flexible behavior requires coordination between sensory and associative regions but how brain networks route sensory information at fast timescales to guide action remains unclear. Using human intracranial electrophysiology and spiking neural networks during spatial attention tasks, where participants detected targets at cued locations, we show that high-frequency activity bursts (HFAbs) mark temporal windows of elevated population firing that enable fast, long-range communications. HFAbs were evoked by sensory cues and targets, dynamically coupled to low-frequency rhythms. Notably, both the strength of cue-evoked HFAbs and their decoupling from slow rhythms predicted behavioral accuracy. HFAbs synchronized across the brain, revealing distinct cue- and target-activated subnetworks. These subnetworks exhibited lead–lag dynamics following target onset, with cue-activated subnetworks preceding target-activated subnetworks when cues were informative. Computational modeling suggested that HFAbs reflect transitions to population spiking, denoting temporal windows for network communications supporting attentional performance. These findings establish HFAbs as signatures of population state transitions, supporting information routing across distributed brain networks. Attention Biophysical models Cognitive control Perception Sensory processing
N Nature Neuroscience · Dec 01, 2025 Oxidized phosphatidylcholines deposition drives chronic neurodegeneration in a mouse model of progressive multiple sclerosis via IL-1β signaling Oxidized phosphatidylcholines (OxPCs) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPCs contribute to the pathophysiology of P-MS is unclear. Here we show that stereotactic OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this model, we found that although microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte-derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology inCasp1/Casp4-deficient mice and by blockade of IL-1R1 indicate that IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPCs and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization could be effective for treating P-MS. Multiple sclerosis Neuroimmunology biology mouse experiments
N Nature Neuroscience · Nov 26, 2025 Increased neural excitability and glioma synaptic activity drives glioma proliferation in human cortex Adult gliomas are incurable primary brain cancers that infiltrate healthy brain and incorporate into neural networks. Gliomas can be classified as low grade or high grade based on histopathological and molecular features, which broadly predicts their aggressiveness. Here we performed patch-clamp electrophysiological recordings from pyramidal neurons and glioma cells from individuals with either low- or high-grade glioma. We find that the biophysical properties of human pyramidal neurons within glioma-infiltrated cortex differ according to tumor grade, with neurons from high-grade glioma being more excitable than those from low-grade glioma. Additionally, glioma cells within high-grade tumors have smaller, longer synaptic responses. Increased neuron–glioma network activity within human high-grade tumor tissue leads to increased glioma proliferation, suggesting that the hyperexcitability of pyramidal neurons in human high-grade glioma may drive tumor growth. Combined, our findings illustrate that high- and low-grade glioma differentially hijack neural networks. Cancer in the nervous system CNS cancer biology
N Nature Neuroscience · Nov 25, 2025 Trans-ancestry genome-wide analyses of bipolar disorder in East Asian and European populations improve genetic discovery Genome-wide association studies (GWASs) of bipolar disorder (BD) have predominantly included individuals of European (EUR) ancestry, underrepresenting non-EUR populations and limiting insight into disease mechanisms. Here we performed a GWAS of BD in Han Chinese individuals (5,164 cases and 13,460 controls) and conducted comparative and integrative analyses with independent East Asian (EAS, 4,479 cases and 75,725 controls) and EUR (59,287 cases and 781,022 controls) cohorts from the PGC4 GWAS. Our GWAS in EAS ancestry identified two genome-wide significant risk loci, including variants at the major histocompatibility complex (MHC) class II region. Incorporating EAS data into trans-ancestry GWAS revealed 93 significant loci (23 novel). Heritability enrichment analyses implicated a variety of neuronal cell types. Multidimensional post-GWAS prioritization identified 39 high-confidence risk genes, of which 15 were differentially expressed in the brains of patients with BD, 12 modulated BD-relevant behaviors in mice and 18 are pharmacologically tractable. This work advances understanding of the biological underpinnings of BD and provides direction for future research in underrepresented populations. Bipolar disorder Genome-wide association studies biology mouse experiments
N Nature Neuroscience · Nov 24, 2025 A myeloid trisomy 21-associated gene variant is protective from Alzheimer’s disease Alzheimer’s disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer’s disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience. Here, we introduce a myeloid DS-linkedCSF2RBA455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4–10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence.CSF2RBA455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies. Alzheimer's disease Induced pluripotent stem cells Microglia Neuroimmunology biology mouse experiments
N Nature Neuroscience · Nov 24, 2025 Munc18 modulates syntaxin phase separation to promote exocytosis The solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin mediates neuronal exocytosis and self-assembles into large clusters in the plasma membrane. The formation and function of these clusters, and whether they promote or inhibit synaptic-vesicle fusion, remain unclear. Here using optogenetic control of syntaxin clustering in vitro and in vivo, as a light-inducible gain-of-function assay, we show that light-enhanced clustering reduces both spontaneous and triggered vesicle fusion, and this impairs mouse hunting behavior. Cluster formation is induced by liquid–liquid phase separation (LLPS) of the SNARE domain of syntaxin. For the regulatory mechanism, Munc18, which is known to alter syntaxin conformation, acts to reduce LLPS for cluster formation, thereby promoting active syntaxin. These results suggest that exocytosis regulation involves LLPS-induced syntaxin clusters that serve as a syntaxin reservoir from which Munc18 captures syntaxin monomers to form a syntaxin–Munc18 complex, setting the stage for efficient fusion. Exocytosis Synaptic vesicle exocytosis biology mouse experiments
N Nature Neuroscience · Nov 24, 2025 The Alzheimer’s therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferonγgenes and antigen presentation. Finally, we identifySPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer’s disease. Alzheimer's disease Microglia biology mouse experiments
N Nature Neuroscience · Nov 24, 2025 A mouse brain atlas based on dendritic microenvironments Brain atlases map the spatial organization of neural tissue and serve as anatomical references. Current mouse brain atlases define regions based primarily on cell density patterns but overlook how neurons extend their branches (dendrites) to form local networks. Here we show that mapping dendrites enhanced by their local neighborhoods—which we call microenvironments—reveals a finer-grained brain organization. We analyzed dendrite patterns from more than 100,000 neurons across 111 mouse brains and discovered that neurons group into distinct microenvironments that subdivide known brain regions, nearly doubling the number of identifiable areas compared with the standard Allen Common Coordinate Framework. Remarkably, hippocampal neurons with similar local dendrite arrangements tend to form long-range connections to similar distant targets, suggesting that local structure predicts global connectivity. This microenvironment atlas complements existing resources by revealing previously hidden subdivisions and correlations that align with functional differences, offering new insights into how brain structure relates to function. Computational biology and bioinformatics Neuroscience Systems biology biology mouse experiments
N Nature Neuroscience · Nov 24, 2025 Preconfigured neuronal firing sequences in human brain organoids Neuronal firing sequences are thought to be the building blocks of information and broadcasting within the brain. Yet, it remains unclear when these sequences emerge during neurodevelopment. Here we demonstrate that structured firing sequences appear in spontaneous activity of human and murine brain organoids, both unguided and forebrain identity directed, as well as ex vivo neonatal murine cortical slices. We observed temporally rigid and flexible firing patterns in human and murine brain organoids and early postnatal murine somatosensory cortex, but not in dissociated primary cortical cultures. These results suggest that temporal sequences do not arise in an experience-dependent manner, but are rather constrained by a preconfigured architecture established during neurodevelopment. By demonstrating the developmental recapitulation of neural firing patterns, these findings highlight the potential of brain organoids as a model for neuronal circuit assembly. Developmental neurogenesis Extracellular recording Induced pluripotent stem cells Neurophysiology biology mouse experiments
N Nature Neuroscience · Nov 24, 2025 Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy Heterogeneous and predominantly sporadic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), remain highly challenging to model. Patient-derived induced pluripotent stem cell (iPSC) technologies offer great promise for these diseases; however, large-scale studies demonstrating accelerated neurodegeneration in patients with sporadic disease are limited. Here we generated an iPSC library from 100 patients with sporadic ALS (SALS) and conducted population-wide phenotypic screening. Motor neurons derived from patients with SALS recapitulated key aspects of the disease, including reduced survival, accelerated neurite degeneration correlating with donor survival, transcriptional dysregulation and pharmacological rescue by riluzole. Screening of drugs previously tested in ALS clinical trials revealed that 97% failed to mitigate neurodegeneration, reflecting trial outcomes and validating the SALS model. Combinatorial testing of effective drugs identified baricitinib, memantine and riluzole as a promising therapeutic combination for SALS. These findings demonstrate that patient-derived iPSC models can recapitulate sporadic disease features, paving the way for a new generation of disease modeling and therapeutic discovery in ALS. Amyotrophic lateral sclerosis Induced pluripotent stem cells biology
N Nature Neuroscience · Nov 21, 2025 Astrocytic Sox9 overexpression in Alzheimer’s disease mouse models promotes Aβ plaque phagocytosis and preserves cognitive function Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer’s disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes through the regulation of the phagocytic receptor MEGF10, which is sufficient to preserve cognitive function in AD models. Collectively, these studies highlight a role for astrocytic Sox9 during aging and AD while identifying Sox9−MEGF10 signaling as a prospective astrocyte-based therapeutic approach to ameliorate cognitive decline in neurodegenerative disease. Alzheimer's disease Astrocyte Cognitive ageing Glial biology biology mouse experiments
N Nature Neuroscience · Nov 20, 2025 Behavioral devaluation by local resistance to dopamine Repeated experiences can cause behavior-specific fatigue. We useDrosophilato study this common form of motivational change, finding that prior matings make males more likely to abandon future copulations when challenged. Here we show that, during mating, dopamine signals through the D2-like receptor (D2R) to promote resilience to challenges that might otherwise cause the male to switch behaviors. This motivating dopamine signal suppresses the output of the copulation decision neurons (CDNs), which can truncate matings when pushed past threshold. Repetition-induced devaluation of mating results from β-arrestin-dependent desensitization of the D2R on the CDNs, rendering them temporarily resistant to naturally released or experimentally supplied dopamine. When local desensitization to dopamine is prevented, the male shows no signs of fatigue, treating each mating as if it were his first. These findings explain a widespread motivational phenomenon and reveal a natural function for the notorious susceptibility of the D2R to drug-induced desensitization. Motivation Sexual behaviour
N Nature Neuroscience · Nov 18, 2025 Neural basis of concurrent deliberation toward a choice and confidence judgment Decision confidence plays a key role in flexible behavior and (meta)cognition, but its underlying neural mechanisms remain elusive. To uncover the latent dynamics of confidence formation at the level of single neurons and population activity, we trained nonhuman primates to report a perceptual choice and the associated level of confidence with a single eye movement on every trial. Monkey behavior was well fit by a bounded accumulator model, where choice and confidence are processed concurrently, but not by a serial model, where choice is resolved first, followed by postdecision accumulation for confidence. Neurons in the lateral intraparietal area (LIP) reflected concurrent accumulation, showing covariation of choice and confidence signals across the population, and within-trial dynamics consistent with parallel updating at near-zero time lag. The results demonstrate that the primate brain can process a single stream of evidence in service of two computational goals simultaneously and suggest area LIP as a candidate neural substrate for this ability. Decision Motion detection Neural decoding Psychology
N Nature Neuroscience · Nov 18, 2025 Brain-wide analysis reveals movement encoding structured across and within brain areas Movement-related activity has been detected across much of the brain, including sensory and motor regions. However, much remains unknown regarding the distribution of movement-related activity across brain regions, and how this activity relates to neural computation. Here we analyzed movement-related activity in brain-wide recordings of more than 50,000 neurons in mice performing a decision-making task. We used multiple machine learning methods to predict neural activity from videography and found that movement-related signals differed across areas, with stronger movement signals close to the motor periphery and in motor-associated subregions. Delineating activity that predicts or follows movement revealed fine-scale structure of sensory and motor encoding across and within brain areas. Through single-trial video-based predictions of behavior, we identified activity modulation by uninstructed movements and their impact on choice-related activity analysis. Our work provides a map of movement encoding across the brain and approaches for linking neural activity, uninstructed movements and decision-making. Computational neuroscience Motor control
N Nature Neuroscience · Nov 18, 2025 Spinal cord Tau pathology induces tactile deficits and cognitive impairment in Alzheimer’s disease via dysregulation of CCK neurons Somatosensory processing has been shown to be correlated with brain development and cognitive function, but whether and how tactile sensory deficits affect cognition decline remains unclear. Here we show that tactile function is impaired in individuals with Alzheimer’s disease (AD), and this impairment is inversely correlated with Montreal Cognitive Assessment scores and positively correlated with Tau pathology. We observed similar deficits in presymptomatic 3×Tg AD mice and find that cholecystokinin (CCK)-expressing neurons in the spinal cord are highly vulnerable to Tau pathology. Expressing mutant Tau-P301S in spinal cord CCK-expressing neurons aberrantly activates the transcription factor c-Maf, inhibits CCK neurons and induces tactile deficits, whereas silencing Tau or c-Maf restores tactile sensation and improves cognition in AD model mice. Together, these gain- and loss-of-function studies demonstrate that Tau pathology in spinal cord CCK neurons contributes to tactile dysfunction and cognitive function. Targeting tactile sensation may be a promising strategy for predicting the progression of cognitive impairment in AD. Alzheimer's disease Sensory processing Somatosensory system
N Nature Neuroscience · Nov 17, 2025 Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis Multiple sclerosis (MS) is a chronic autoimmune disease that targets mature oligodendrocytes (MOLs) and their myelin. MOLs are heterogeneous and can transition to immune-like states in MS. However, the dynamics of this process remain unclear. Here, we used single-cell multiome assay for transposase-accessible chromatin and RNA sequencing targeting oligodendroglia (OLG) from the experimental autoimmune encephalomyelitis (EAE) MS mouse model at multiple disease stages. We found that immune OLG states appear at early disease stages and persist to late stages, which can be consistent with epigenetic memory of previous neuroinflammation. Transcription factor activity suggested immunosuppression in OLG at early disease stages. Different MOLs exhibit differential responsiveness to EAE, with MOL2 exhibiting a stronger transcriptional immune response than MOL5/MOL6, and showed divergent responses at the epigenetic level during disease evolution. Our single-cell multiomic resource highlights dynamic and subtype-specific responses of OLG to EAE, which might be amenable to modulation in MS. Animal disease models Chromatin analysis Multiple sclerosis
N Nature Neuroscience · Nov 11, 2025 Genetic targeting of premyelinating oligodendrocytes reveals activity-dependent myelination mechanisms To myelinate axons, oligodendrocyte precursor cells (OPCs) must stop dividing and differentiate into premyelinating oligodendrocytes (preOLs), a transient cell stage during myelination that is often stalled at human demyelinating lesions. PreOLs extend processes, surveying nearby axons to begin ensheathment. The lack of genetic tools to visualize and manipulate preOLs has hindered their in-depth study. Here we present a CreERT2knockin mouse line that enables genetic labeling, lineage tracing, manipulation and multimodal profiling of preOL subsets across the central nervous system. Genetically labeled preOLs are postmitotic, with distinct morphology and unique transcriptomic, epigenetic and electrophysiological features. PreOL lineage tracing revealed spatiotemporal dynamics of oligodendrogenesis across the mouse brain. Moreover, fate mapping of preOLs under sensory deprivation revealed that neuronal activity influences preOLs within a narrow maturation window, promoting their survival and successful integration. Together, our work presents a genetic tool to study preOL biology and axon−oligodendrocyte interactions in health and disease. Myelin biology and repair Oligodendrocyte
N Nature Neuroscience · Nov 11, 2025 Estrogen modulates reward prediction errors and reinforcement learning Gonadal hormones act throughout the brain and modulate psychiatric symptoms. Yet how hormones influence cognitive processes is unclear. Exogenous 17β-estradiol, the most potent estrogen, modulates dopamine in the nucleus accumbens core, which instantiates reward prediction errors (RPEs), the difference between received and expected reward. Here we show that following endogenous increases in 17β-estradiol, dopamine RPEs and behavioral sensitivity to previous rewards are enhanced, and nucleus accumbens core dopamine reuptake proteins are reduced. Rats adjusted how quickly they initiated trials in a task with varying reward states, balancing effort against expected rewards. Nucleus accumbens core dopamine reflected RPEs that influenced rats’ initiation times. Higher 17β-estradiol predicted greater sensitivity to reward states and larger RPEs. Proteomics revealed reduced dopamine transporter expression following 17β-estradiol increases. Finally, knockdown of midbrain estrogen receptors suppressed sensitivity to reward states. Therefore, endogenous 17β-estradiol predicts dopamine reuptake and RPE signaling, and causally dictates the impact of previous rewards on behavior. Motivation Neural circuits Reward
N Nature Neuroscience · Nov 11, 2025 A genome-wide analysis of the shared genetic risk architecture of complex neurological and psychiatric disorders Although neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathophysiological mechanisms. However, the extent to which these heritable disorders share genetic influences remains unclear. Here we performed a comprehensive analysis of genome-wide association study data, involving nearly 1 million cases across ten neurological diseases and ten psychiatric disorders, to compare their common genetic signal and biological associations. Using complementary statistical tools, we demonstrate that a large set of common genetic variants impacts the risk of multiple neurological and psychiatric disorders, even in the absence of genetic correlations. Furthermore, genome-wide association studies on psychiatric disorders consistently implicate neuronal biology, whereas neurological diseases are associated with diverse neurobiological processes. Together, this study elucidates the genetic relationship between complex neurological and psychiatric disorders, indicating a larger degree of genetic pleiotropy than previously recognized. The findings have implications for disease classification, precision medicine and clinical practice. Genome-wide association studies Neurological disorders Psychiatric disorders
N Nature Neuroscience · Nov 11, 2025 APOE4toAPOE2allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition Compared to individuals carrying two copies of the ε4 allele of apolipoprotein E (APOE), ε2 homozygotes have an approximate 99% reduction in late-onset Alzheimer’s disease (AD) risk. Here we develop a knock-in model that allows for an inducible ‘switch’ between risk and protective alleles (APOE4s2). Gene expression and proteomic analyses confirm that APOE4s2 mice synthesize E4 at baseline and E2 after tamoxifen administration. A whole-body allelic switch results in a metabolic profile resembling E2/E2 humans and drives AD-relevant alterations in the lipidome and single-cell transcriptome, particularly in astrocytes. Finally, when crossed to the 5xFAD background, astrocyte-specific E4 to E2 switching improves cognition, decreases amyloid pathology, lowers gliosis and reduces plaque-associated apolipoprotein E. Together, these data show that a short-term transition fromAPOE4toAPOE2can broadly affect the cerebral transcriptome and lipidome, and that astrocyte-specificAPOEreplacement may be a viable strategy for future gene editing approaches to simultaneously reduce multiple AD-associated pathologies. Alzheimer's disease Astrocyte Genetic engineering Metabolism
N Nature Neuroscience · Nov 10, 2025 Subsecond dopamine fluctuations do not specify the vigor of ongoing actions Dopamine (DA) is essential for the production of vigorous actions, but how DA modifies the gain of motor commands remains unclear. Here we show that subsecond DA transients in the striatum of mice are neither required nor sufficient for specifying the vigor of ongoing forelimb movements. Our findings have important implications for our understanding of how DA contributes to motor control under physiological conditions and in Parkinson’s disease. Basal ganglia Neural circuits
N Nature Neuroscience · Nov 06, 2025 Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer’s disease Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer’s disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([18F]AZD4694), tau aggregation ([18F]MK-6240) and microglial activation ([11C]PBR28), along with plasma biomarkers for astrocyte reactivity (GFAP) and tau phosphorylation (p-tau217). We further evaluated 251 individuals with cerebrospinal fluid levels of the microglial marker sTREM2. We found that Aβ pathology was associated with astrocyte reactivity across cortical brain regions only in the presence of microglial activation. The microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Our results suggest that microglial activation plays a key role in Aβ-related astrocyte reactivity, which, in turn, contributes to downstream pathological features of AD. Alzheimer's disease Astrocyte Biomarkers Microglia
N Nature Neuroscience · Nov 06, 2025 Selective direct influence of motor cortex on limb muscle activity during naturalistic climbing in mice When and how motor cortical output directly influences limb muscle activity through descending projections remain poorly resolved, impeding a mechanistic understanding of motor control. Here we addressed this in mice performing an ethologically inspired climbing behavior. We quantified the direct influence of forelimb primary motor cortex (caudal forelimb area) on muscles across the muscle activity states expressed during climbing. We found that the caudal forelimb area instructs muscle activity pattern by selectively activating certain muscles, while less frequently activating or suppressing their antagonists. From Neuropixels recordings, we identified linear combinations (components) of motor cortical activity that covary with these effects. These components differ partially from those that covary with muscle activity and differ almost completely from those that covary with kinematics. Collectively, our results reveal an instructive direct motor cortical influence on limb muscles that is selective within a motor behavior and reliant on a distinct neural activity subspace. Motor cortex Neural circuits
N Nature Neuroscience · Nov 03, 2025 Connectome caricatures remove large-amplitude coactivation patterns in resting-state fMRI to emphasize individual differences High-amplitude coactivation patterns are sparsely present during resting-state functional magnetic resonance imaging (fMRI), yet they drive functional connectivity and resemble task activation patterns. However, little research has characterized the remaining majority of the resting-state signal. Here, we introduce caricaturing, a method for projecting resting-state data onto a subspace orthogonal to a manifold of coactivation patterns estimated from task fMRI data. This removes linear combinations of these coactivation patterns from resting-state data to create caricatured connectomes. We used task data from two large-scale neuroimaging datasets to construct a manifold of task coactivation patterns and created caricatured connectomes. These connectomes exhibit lower between-individual similarity and higher identifiability and could be used to predict phenotypic measures, representing individual differences in behavior, often to a greater degree than standard connectomes. Our results show that there is a useful signal beyond the dominant coactivations that drive resting-state functional connectivity, which may better characterize the brain’s intrinsic functional architecture. Cognitive neuroscience Computational neuroscience
N Nature Neuroscience · Oct 31, 2025 Specialized structure of neural population codes in parietal cortex outputs Cortical neurons projecting to the same target area may form specialized population codes to transmit information, but whether and how they do so remains unclear. We used calcium imaging in mouse posterior parietal cortex, retrograde labeling and statistical multivariate models to address this question during a delayed match-to-sample task in virtual reality. We found that neurons projecting to the same area have elevated pairwise activity correlations. These correlations are structured as information-limiting and information-enhancing motifs that shape interaction networks and collectively enhance information about the mouse’s choice beyond what is contributed by pairwise interactions. This network structure is unique to subpopulations that project to the same target and was not observed in surrounding neural populations with unidentified projections. Furthermore, this structure is only present when mice make correct, but not incorrect, behavioral choices. Therefore, cortical neurons comprising an output pathway form a population code with a unique correlation structure that enhances population-level information to guide accurate behavior. Computational neuroscience Sensorimotor processing
N Nature Neuroscience · Oct 31, 2025 TDP-43-dependent mis-splicing ofKCNQ2triggers intrinsic neuronal hyperexcitability in ALS/FTD Motor neuron hyperexcitability is a broadly observed yet poorly understood feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Nuclear depletion and cytoplasmic aggregation of the RNA splicing protein TAR DNA-binding protein 43 (TDP-43) are observed in most ALS and FTD patients. Here we show that TDP-43 dysfunction causes mis-splicing ofKCNQ2, which encodes a voltage-gated potassium channel (Kv7.2) that regulates neuronal excitability. Using iPSC-derived neurons and postmortem ALS/FTD brain and spinal cord tissue we find widespread, disease-specific and TDP-43-specific skipping of an exon encoding the KCNQ2 pore domain. The mis-spliced mRNA escapes degradation and is translated into a nonfunctional protein with severely reduced ion conductance that aggregates in the endoplasmic reticulum and causes intrinsic hyperexcitability in ALS neuronal models. This event, which correlates with higher phosphorylated TDP-43 levels and earlier age of disease onset in patients, can be rescued by splice-modulating antisense oligonucleotides that dampen hyperexcitability in induced pluripotent stem cell cortical neurons and spinal motor neurons with TDP-43 depletion. Our work reveals that nuclear TDP-43 maintains the fidelity ofKCNQ2expression and function and provides a mechanistic link between established excitability disruption in ALS/FTD patients and TDP-43 dysfunction. Amyotrophic lateral sclerosis Ion channels in the nervous system
N Nature Neuroscience · Oct 31, 2025 Dendritome mapping reveals the spatial organization of striatal neuron morphology Dendritic arbors are essential for neuronal computation and signal propagation, yet large-scale single-neuron morphology studies remain challenging. Here we present a systems biology approach, termed ‘dendritome mapping’, to profile the dendritic morphology of genetically defined single neurons in mice, unveiling striatal medium spiny neuron (MSN) morphological territories and aging-associated or disease-associated alterations. We generated 3,762 three-dimensional-reconstructed and reference-atlas-mapped striatal D1-type and D2-type MSNs, revealing distinct impacts of D1/D2 genotypes and striatal locations on MSN morphology. To analyze dendritic variation at a finer resolution than known anatomical landmarks permit, we assigned MSNs to latticed cubic boxes within the reference brain atlas, summarized a morphometric representation (‘eigen-morph’) for each box and clustered boxes with shared morphometry. This identified six modules with characteristic dendritic features and spanning contiguous striatal territories, each receiving distinct corticostriatal inputs. Finally, we found that aging confers dendritic atrophy in both D1-MSNs and D2-MSNs, whereas Huntington’s disease mice exhibit MSN-type and regional-specific defects. Cellular neuroscience Genetics
N Nature Neuroscience · Oct 31, 2025 Laser-engineered PRIME fiber for panoramic reconfigurable control of neural activity Understanding the neural basis of behavior requires tools to flexibly control neural activity across distributed circuits. Optical methods enable precise, cell-type-specific control, but current fiber-based approaches deliver light to only a few fixed sites, limiting versatility. To address this, we developed ‘panoramically reconfigurable illuminative’ (PRIME), a single-fiber probe with over a thousand light-emitting sites distributed along its length and circumference, enabling panoramic and reconfigurable illumination from a single implant. We equipped a 160-μm multicore fiber with laser-engineered grating light emitters at designated axial and radial positions. By modulating input light patterns, PRIME dynamically switched illumination at 60 Hz among 1,200 sites spanning 5 mm and 360°. By integrating PRIME with high-density recording arrays, including Neuropixels, we demonstrated spatially targeted optogenetic activation alongside simultaneous electrophysiological recording in vivo. In freely moving mice, stimulation at different depths and locations within the superior colliculus evoked distinct defensive behaviors. PRIME’s scalable and reconfigurable light delivery across large volumes offers a powerful platform for optical control of neural circuits across the brain. Biotechnology Optogenetics
N Nature Neuroscience · Oct 29, 2025 Attentional failures after sleep deprivation are locked to joint neurovascular, pupil and cerebrospinal fluid flow dynamics Sleep deprivation rapidly disrupts cognitive function and in the long term contributes to neurological disease. Why sleep deprivation has such profound effects on cognition is not well understood. Here we use simultaneous fast fMRI–EEG to test how sleep deprivation modulates cognitive, neural and fluid dynamics in the human brain. We demonstrate that attentional failures during wakefulness after sleep deprivation are tightly orchestrated in a series of brain–body changes, including neuronal shifts, pupil constriction and cerebrospinal fluid (CSF) flow pulsations, pointing to a coupled system of fluid dynamics and neuromodulatory state. CSF flow and hemodynamics are coupled to attentional function within the awake state, with CSF pulsations following attentional impairment. The timing of these dynamics is consistent with a vascular mechanism regulated by neuromodulatory state. The attentional costs of sleep deprivation may thus reflect an irrepressible need for rest periods driven by a central neuromodulatory system that regulates both neuronal and fluid physiology. Neuro–vascular interactions Sleep deprivation
N Nature Neuroscience · Oct 28, 2025 Falling asleep follows a predictable bifurcation dynamic Sleep is a fundamental part of our lives; yet, how our brain falls asleep remains one of the most enduring mysteries of neuroscience. Here we report a new conceptual framework to analyze and model this phenomenon. The framework represents the changes in brain electroencephalogram activity during the transition into sleep as a trajectory in a normalized feature space. We use the framework to show that the brain’s wake-to-sleep transition follows bifurcation dynamics with a distinct tipping point preceded by a critical slowing down. We validate the bifurcation dynamics in two independent datasets, which include more than 1,000 human participants. Finally, we demonstrate the framework’s utility by predicting a person’s progression into sleep in real time with seconds temporal resolution and over 0.95 average accuracy. Dynamical systems Sleep
N Nature Neuroscience · Oct 27, 2025 Longitudinal measures of monkey brain structure and activity through adolescence predict cognitive maturation In humans and other primates, adolescence is associated with improvement in cognitive abilities and with changes in brain structure and connectivity. However, how these changes affect neural activity underlying cognitive performance remains unknown. Here we conducted a multilevel, longitudinal study of monkey adolescent neurocognitive development by tracking behavior, neuronal activity and anatomical imaging measures. The trajectory of prefrontal neural activity accounted well for working memory improvements. Complex aspects of activity changed progressively during adolescence, but even simpler attributes, such as baseline rate and variability, had predictive power over behavior. Trajectories of neural activity and cognitive performance were well predicted by maturation of long-distance white matter tracts linking the frontal lobe with other brain areas but, surprisingly, not by decreases in brain volume and thickness, which underlie cognitive changes in humans. Our results link white matter maturation to neural activity changes in adolescent cognitive development. Development of the nervous system Learning and memory
N Nature Neuroscience · Oct 27, 2025 The neuronal chromatin landscape in brains from individuals with schizophrenia is linked to early fetal development Noncoding variants increase neuropsychiatric disease risk, but our understanding of their cell-type-specific role remains incomplete. We conducted large-scale chromatin accessibility profiling of neurons and non-neurons from 2 neocortical regions in 1,393 libraries. We observed substantial differences in neuronal chromatin accessibility between schizophrenia (SCZ) cases and controls, with upregulated open chromatin regions (OCRs) in neurons associated with SCZ risk loci. A comparison of SCZ-associated OCRs with fetal brain-specific OCRs revealed a strong correlation between upregulated changes in SCZ chromatin and openness in fetal cortical brains, linking disease-related chromatin alterations to neurodevelopment. Here we show that a prominent neuronaltrans-regulatory domain containing upregulated OCRs consolidates key neurodevelopmental chromatin signatures and is enriched for immature glutamatergic neurons. These findings link altered adult cortical chromatin states to early developmental mechanisms in SCZ. This study provides a comprehensive cell-type-resolved chromatin accessibility resource for the human cortex and offers insights into the regulatory architecture underlying SCZ risk. Epigenomics Schizophrenia
N Nature Neuroscience · Oct 27, 2025 Prediction of neural activity in connectome-constrained recurrent networks Recent technological advances have enabled measurement of the synaptic wiring diagram, or ‘connectome’, of large neural circuits or entire brains. However, the extent to which such data constrain models of neural dynamics and function is debated. In this study, we developed a theory of connectome-constrained neural networks in which a ‘student’ network is trained to reproduce the activity of a ground truth ‘teacher’, representing a neural system for which a connectome is available. Unlike standard paradigms with unconstrained connectivity, the two networks have the same synaptic weights but different biophysical parameters, reflecting uncertainty in neuronal and synaptic properties. We found that a connectome often does not substantially constrain the dynamics of recurrent networks, illustrating the difficulty of inferring function from connectivity alone. However, recordings from a small subset of neurons can remove this degeneracy, producing dynamics in the student that agree with the teacher. Our theory demonstrates that the solution spaces of connectome-constrained and unconstrained models are qualitatively different and determines when activity in such networks can be well predicted. It can also prioritize which neurons to record to most effectively inform such predictions. The authors show that connectome datasets alone are generally not sufficient to predict neural activity. However, pairing connectivity information with neural recordings can produce accurate predictions of activity in unrecorded neurons. Dynamical systems Network models Neural circuits Population dynamics
N Nature Neuroscience · Oct 23, 2025 A glial circadian gene expression atlas reveals cell-type and disease-specific reprogramming in response to amyloid pathology or aging While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer’s disease risk genes, displayed circadian oscillations, many of which were altered by pathology. Microglial oxidative stress and amyloid phagocytosis showed temporal variation in gene expression and function. Thus, circadian rhythms in gene expression are cell-dependent and context dependent, and provide important insights into glial function in health, Alzheimer’s disease and aging. Alzheimer's disease Astrocyte Circadian mechanisms Microglia
N Nature Neuroscience · Oct 23, 2025 Cortical and subcortical mapping of the human allostatic–interoceptive system using 7 Tesla fMRI The brain continuously anticipates the body’s energetic needs and prepares to meet them before they arise—a process called allostasis. To support allostasis, the brain continually models the body’s sensory state, a process known as interoception. Here we replicate and extend a large-scale system that supports allostasis and interoception in the human brain using ultrahigh precision 7 Tesla functional magnetic resonance imaging (n= 90), improving precision in subgenual and pregenual anterior cingulate topography and expanding brainstem nuclei mapping. Our functional connectivity analyses provide corroborating evidence for more than 96% of the anatomical connections documented in nonhuman animal tract-tracing studies. This system also includes regions of dense intrinsic connectivity throughout the system, some of which were identified previously as part of the backbone of neural communication across the brain. These results reinforce the existing evidence for a whole-brain system that supports the modeling and regulation of the body’s internal milieu. Neural circuits Psychology
N Nature Neuroscience · Oct 21, 2025 TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus of neurons in the brain and spinal cord. A key function of TDP-43 has emerged as a repressor of cryptic exon inclusion during pre-mRNA splicing, but a role for TDP-43 in other RNA-processing events remains unresolved. Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA). Using high-resolution polyadenylation site mapping, we comprehensively defined TDP-43-regulated APA events in human stem cell-derived neurons and found that both the strength and position of TDP-43 binding influence polyA site usage. APA events caused by loss of TDP-43 impact expression of disease-relevant genes (for example,SFPQ,NEFLandTMEM106B). These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology. Alternative splicing Amyotrophic lateral sclerosis Transcriptomics
N Nature Neuroscience · Oct 21, 2025 TDP-43 loss induces cryptic polyadenylation in ALS/FTD Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 are cellular hallmarks of amyotrophic lateral sclerosis (ALS). TDP-43 nuclear loss causes de-repression of cryptic exons, yet cryptic alternative polyadenylation (APA) events have been largely overlooked. In this study, we developed a bioinformatic pipeline to reliably identify alternative last exons, 3’ untranslated region (3’UTR) extensions and intronic polyadenylation APA event types, and we identified cryptic APA sites induced by TDP-43 loss in induced pluripotent stem cell (iPSC)-derived neurons. TDP-43 binding sites are enriched at sites of these cryptic events, and TDP-43 can both repress and enhance APA. All categories of cryptic APA were also identified in ALS and frontotemporal dementia (FTD) postmortem brain tissue. RNA sequencing (RNA-seq), thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) and ribosome profiling (Ribo-seq) revealed that distinct cryptic APA categories have different downstream effects on transcript levels and that cryptic 3’UTR extensions can increase RNA stability, leading to increased translation. In summary, we demonstrate that TDP-43 nuclear depletion induces cryptic APA, expanding the palette of known consequences of TDP-43. Amyotrophic lateral sclerosis Cellular neuroscience Computational biology and bioinformatics RNA splicing
N Nature Neuroscience · Oct 20, 2025 Oxytocin modulates respiratory heart rate variability through a hypothalamus–brainstem–heart neuronal pathway The variation in heart rate in phase with breathing is called respiratory heart rate variability (RespHRV). Relaxation and positive socio-emotional states can amplify RespHRV, yet the underlying mechanism remains largely unknown. Here we identify a hypothalamus–brainstem neuronal pathway in rodents through which oxytocin (OT) amplifies RespHRV during calming behavior. OT neurons from the caudal paraventricular nucleus in the hypothalamus regulate the activity of a subgroup of inhibitory neurons in the pre-Bötzinger complex, the brainstem nucleus that generates the inspiratory rhythm. Specifically, OT enhances the glycinergic input from OT-receptor-expressing neurons in the pre-Bötzinger complex to cardiac-innervating parasympathetic neurons in the nucleus ambiguus during inspiration. This leads to amplified respiratory modulation of parasympathetic activity to the heart, thereby enhancing RespHRV. We show that OT neurons participate in the restoration of RespHRV amplitude during recovery from stress in mice, indicating that OT acts centrally to regulate cardiac activity during a calming behavior. Autonomic nervous system Cardiovascular biology Neural circuits Respiration
N Nature Neuroscience · Oct 20, 2025 A lateral hypothalamic neuronal population expressing leptin receptors counteracts anxiety to enable adaptive behavioral responses Neuronal mechanisms that facilitate adaptive strategies to enable an animal to overcome anxiety in threatening situations remain unknown. Using single-cell calcium imaging and cell-type-specific activity manipulations in behaving mice, we identified leptin-sensitive neuronal subpopulations in the lateral hypothalamus (LH; LepRLH) that encode anxiogenic stimuli. In high-anxiety animals, LepRLHneurons differentiated poorly among anxiogenic stimuli and were inhibited by input from the prefrontal cortex. The activity of LepRLHneurons predicted the anxiety level of individual animals, and the activation of LepRLHneurons enabled adaptive responses under anxiogenic conditions—exploration of new terrain, eating despite anxiogenic environment and limiting maladaptive excessive locomotion in an anorexia nervosa disease model. Thus, leptin-sensitive neuronal subpopulations in the LH enable adaptive fulfillment of vital needs despite anxiogenic conditions, both in healthy and pathological states. Anxiety Hypothalamus Neural circuits Prefrontal cortex
N Nature Neuroscience · Oct 16, 2025 Differential synaptic depression mediates the therapeutic effect of deep brain stimulation Deep 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. Parkinson's disease
N Nature Neuroscience · Oct 14, 2025 C9orf72 hexanucleotide repeat expansions impair microglial response in ALS Microglia and neuroinflammation are involved in amyotrophic lateral sclerosis (ALS), but the precise underlying molecular mechanisms remain elusive. We generated single-nuclei transcriptomes from the spinal cord and motor cortex of patients with sporadic ALS (sALS) andC9orf72ALS (C9-ALS). Here we confirmed thatC9orf72is highly expressed in microglia and observed that the hexanucleotide repeat expansion (HRE) results in haploinsufficiency. Whereas sALS microglia transitioned toward disease-associated cell states,C9orf72HRE microglia exhibited a diminished response, with alterations in endolysosomal pathways. We confirmed these observations using a human microglia xenograft model, in whichC9orf72mutations led to a reduced activation. We also confirmed the endolysosomal alterations inC9orf72HRE andC9orf72-deficient induced pluripotent stem cell (iPSC)-derived microglia. We also found a diminished response ofC9orf72HRE astrocytes and provided a map of dysregulated ligand−receptor pairs in microglia and astrocytes. Our data highlight variations in the cellular substrate of sporadic and inherited forms of ALS, which have implications for patient stratification and selection of appropriate treatments. Amyotrophic lateral sclerosis Microglia
N Nature Neuroscience · Oct 14, 2025 Region-specific drivers of CSF mobility measured with MRI in humans Many 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. Magnetic resonance imaging Neuro–vascular interactions Neurodegeneration
N Nature Neuroscience · Oct 13, 2025 Astrocytic Ca2+prevents synaptic depotentiation by limiting repetitive activity in dendrites during motor learning Astrocytic Ca2+activity regulates activity-dependent synaptic plasticity, but its role in learning-related synaptic changes in the living brain remains unclear. We found that motor training induced synaptic potentiation on apical dendrites of layer 5 pyramidal neurons, as well as astrocytic Ca2+rises in the mouse motor cortex. Reducing astrocytic Ca2+led to synaptic depotentiation during motor training and subsequent impairment in performance improvement. Notably, synaptic depotentiation occurred on a fraction of dendrites with repetitive dendritic Ca2+activity. On those dendrites, dendritic spines that were active before dendritic Ca2+activity underwent CaMKII-dependent size reduction. In addition, the activation of adenosine receptors prevented repetitive dendritic Ca2+activity and synaptic depotentiation caused by the reduction of astrocytic Ca2+, suggesting the involvement of ATP released from astrocytes and adenosine signaling in the processes. Together, these findings reveal the function of astrocytic Ca2+in preventing synaptic depotentiation by limiting repetitive dendritic activity during learning. Glial biology Physiology
N Nature Neuroscience · Oct 13, 2025 Psychedelic 5-HT2Areceptor agonism alters neurovascular coupling and differentially affects neuronal and hemodynamic measures of brain function Human neuroimaging studies report that psychedelics induce serotonin-2A receptor-dependent changes in functional brain reorganization, presumably reflecting neuromodulation. However, these studies often overlook the potent vasoactive effects of serotonin. Here we identified psilocybin-induced alterations in hemodynamic response functions during human functional magnetic resonance imaging, suggesting potential disruptions in neurovascular coupling. We then used wide-field optical imaging in awake Thy1-jRGECO1a mice to determine whether psychedelic-induced changes in hemodynamics arise from neuronal, vascular or neurovascular effects. Exposure to the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) differentially altered coupling between cortical excitatory neuronal versus hemodynamic activity, both during whisker stimulation and in the resting state. Furthermore, DOI resulted in discordant changes between neuronal-based versus hemodynamic-based assessments of functional connectivity. A selective serotonin-2A receptor antagonist (MDL100907) reversed many of the effects of DOI. Our results demonstrate a dissociation between DOI-induced neuronal and hemodynamic signals, indicating a need to consider neurovascular effects of psychedelics when interpreting blood-based measures of brain function. Neural circuits Neuro–vascular interactions
N Nature Neuroscience · Oct 03, 2025 Brain tumors induce widespread disruption of calvarial bone and alteration of skull marrow immune landscape The skull marrow niche has recently been identified as a reservoir that supplies the brain with monocytes and neutrophils in the context of disease and injury, but its role in brain cancers remains unknown. Here we show that glioblastoma, the most malignant type of brain tumor, induces calvarial bone abnormalities in murine models and patients with glioblastoma, altering osteoclast activities and increasing the number of skull channels in mice. Single-cell RNA sequencing revealed glioblastoma-mediated alterations in the immune landscape of skull marrow and femoral bone marrow, including expansion of neutrophils and deterioration of various B cell subsets. In vivo inhibition of bone resorption reduced bone abnormalities, but promoted tumor progression in mesenchymal subtype tumors. This also abolished the survival benefit of the checkpoint inhibitor anti-PD-L1, by reducing activated T cell and increasing inflammatory neutrophil numbers. Together, these data provide insight into how brain tumors affect skull bone and the immune environment. CNS cancer Mechanisms of disease Neuroimmunology
N Nature Neuroscience · Oct 03, 2025 Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models Amyotrophic lateral sclerosis (ALS) is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Recent findings highlight a pivotal role for TAR DNA-binding protein 43 (TDP-43) in forming axonal pathological condensates and facilitating NMJ disruption through inhibition of local protein synthesis. However, the mechanisms that drive local TDP-43 accumulation remain unknown. Here we identify that the TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice stems from its aberrant local synthesis. This is a non-cell-autonomous process driven by muscle-derived miR-126a-5p extracellular vesicles (EVs). Inhibiting muscle secretion of miR-126a-5p prompts presynaptic TDP-43 synthesis and accumulation, which disrupts axonal translation and causes NMJ degeneration. Introducing miR-126 to SOD1G93Amice, primary co-cultures and human induced pluripotent stem cell (iPSC)-derived co-cultures with ALS mutations exhibits neuroprotective effects and delays motor decline. These findings identify a transcellular communication axis between muscles and motor neurons that regulates axonal local synthesis and NMJ maintenance, offering insights into ALS onset and progression. Amyotrophic lateral sclerosis Cellular neuroscience
N Nature Neuroscience · Oct 02, 2025 Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain Chronic pain and mood disorders co-occur, exacerbate one another and share neurobiological mechanisms, but whether a single intervention could promptly alleviate both conditions remains unclear. Here, in two chronic pain models, we show that a single dose of psilocybin induces a rapid and sustained reversal of both mechanical allodynia and anxiodepression-like states in adult male and female mice. Using local psilocin injections, the key active metabolite of psilocybin, we show that the engagement of prefrontal cortical circuits is critical for the concurrent alleviation of both conditions. Two-photon calcium imaging reveals that psilocin rapidly normalizes chronic pain-associated hyperactivity in anterior cingulate cortex layer 2/3 pyramidal neurons. Pharmacologic manipulations with full agonists of 5-HT2Aand 5-HT1Areceptors replicated some, but not all, of psilocin’s cellular and behavioral effects, suggesting that psilocin’s actions arise from partial agonism at these receptors within shared circuits governing pain and mood processing. Chronic pain Experimental models of disease
N Nature Neuroscience · Sep 30, 2025 Facial expressions in mice reveal latent cognitive variables and their neural correlates Brain activity controls adaptive behavior but also drives unintentional incidental movements. Such movements could potentially be used to read out internal cognitive variables that are also neurally computed. Establishing this would require ruling out that incidental movements reflect cognition merely because they are coupled with task-related responses through the biomechanics of the body. Here we addressed this issue in a foraging task for mice, where multiple decision variables are simultaneously encoded even if, at any given time, only one of them is used. We found that characteristic features of the face simultaneously encode not only the currently used decision variables but also independent and unexpressed ones, and we show that these features partially originate from neural activity in the secondary motor cortex. Our results suggest that facial movements reflect ongoing computations above and beyond those related to task demands and demonstrate the ability of noninvasive monitoring to expose otherwise latent cognitive states. Decision Neural decoding
N Nature Neuroscience · Sep 26, 2025 Hormonal milieu influences whole-brain structural dynamics across the menstrual cycle using dense sampling in multiple individuals Gonadal hormone receptors are widely distributed across the brain, yet their influence on brain structure remains understudied. Here, using precision imaging, we examined four females, including one with endometriosis and one using oral contraceptives (OC), across a monthly period. Whole-brain analyses revealed spatiotemporal patterns of brain volume changes, with substantial variations across the monthly period. In typical cycles, spatiotemporal patterns were associated with serum progesterone levels, while in cycles with endometriosis and during OC intake, patterns were associated with serum estradiol levels. The volume changes were widely distributed rather than region-specific, suggesting a widespread but coordinated influence of hormonal fluctuations. These findings underscore the importance of considering diverse hormonal milieus beyond typical menstrual cycles in understanding structural brain dynamics and suggest that hormonal rhythms may drive widespread structural brain changes. Brain Neuroendocrine diseases Neuroscience
N Nature Neuroscience · Sep 22, 2025 A bottom-up septal inhibitory circuit mediates anticipatory control of drinking Drinking behavior is not only homeostatically regulated but also rapidly adjusted before any changes in blood osmolality occur, known as anticipatory thirst satiation. Homeostatic and anticipatory signals converge in the subfornical organ (SFO); however, the neural pathways conveying peripheral information to the SFO before changes in blood composition are incompletely understood. Here we reveal an inhibitory pathway from the medial septum (MS) to the SFO that is involved in the control of anticipatory drinking behavior in mice. MS γ-aminobutyric acid (GABA)ergic neurons encode water-satiation signals by integrating cues from the oral cavity and tracking gastrointestinal signals. These neurons receive inputs from the parabrachial nucleus and relay to SFOCaMKIIneurons, forming a bottom-up pathway with activity that prevents overhydration. Disruption of this circuit leads to excessive water intake and hyponatremia. Our findings reveal a septal pathway that integrates multiple layers of presystemic signals to fine-tune drinking behavior. Neural circuits Neurophysiology
N Nature Neuroscience · Sep 18, 2025 Temporal integration in human auditory cortex is predominantly yoked to absolute time Sound structures such as phonemes and words have highly variable durations. Therefore, there is a fundamental difference between integrating across absolute time (for example, 100 ms) versus sound structure (for example, phonemes). Auditory and cognitive models have traditionally cast neural integration in terms of time and structure, respectively, but the extent to which cortical computations reflect time or structure remains unknown. Here, to answer this question, we rescaled the duration of all speech structures using time stretching and compression and measured integration windows in the human auditory cortex using a new experimental and computational method applied to spatiotemporally precise intracranial recordings. We observed slightly longer integration windows for stretched speech, but this lengthening was very small (~5%) relative to the change in structure durations, even in non-primary regions strongly implicated in speech-specific processing. These findings demonstrate that time-yoked computations dominate throughout the human auditory cortex, placing important constraints on neurocomputational models of structure processing. Cortex Neural encoding
N Nature Neuroscience · Sep 17, 2025 Rapid learning of neural circuitry from holographic ensemble stimulation enabled by model-based compressed sensing Discovering how computations are implemented in the brain at the level of monosynaptic connectivity requires probing for connections from potentially thousands of presynaptic candidate neurons. Two-photon optogenetics is a promising technology for mapping such connectivity via sequential stimulation of individual neurons while recording postsynaptic responses intracellularly. However, this technique is currently not scalable because stimulating neurons one by one requires prohibitively long experiments. Here we developed novel computational tools that, when combined, enable learning of monosynaptic connectivity from high-speed holographic ensemble stimulation. First, we developed a model-based compressed sensing algorithm that identifies connections from postsynaptic responses evoked by stimulating many neurons at once, greatly increasing mapping efficiency. Second, we developed a deep-learning method that isolates the postsynaptic response to each stimulus, allowing stimulation to rapidly switch between ensembles without waiting for the postsynaptic response to return to baseline. Together, our system increases the throughput of connectivity mapping by an order of magnitude, facilitating discovery of the circuitry underlying neural computations. Computational neuroscience Neural circuits
N Nature Neuroscience · Sep 17, 2025 High-throughput synaptic connectivity mapping using in vivo two-photon holographic optogenetics and compressive sensing Characterizing synaptic connectivity in living neural circuits is key to understanding the interplay between network structure and function during behavior. However, the throughput of current in vivo synaptic mapping methods remains very limited. Here, we present a framework for increasing mapping throughput and speed that combines two-photon holographic optogenetic stimulation of presynaptic neurons, whole-cell recordings of postsynaptic responses and compressive sensing reconstruction of sparse connectivity. Under sequential single-cell stimulation, the method enables rapid probing of connectivity across up to 100 potential presynaptic cells within ~5 min in the visual cortex of anesthetized mice, identifying synaptic pairs along with their strength and spatial distribution. Furthermore, in sparsely connected populations, holographic multi-cell stimulation combined with a compressive sensing approach further improved sampling efficiency and recovered most connections found using the sequential approach, with up to a threefold reduction in the number of required measurements. Overall, these results highlight the potential for higher throughput in vivo circuit analysis and deeper insights into brain structure–function relationships. Neural circuits Neurophysiology
N Nature Neuroscience · Sep 15, 2025 Augmenting AMPA receptor signaling after spinal cord injury increases ependymal-derived neural stem/progenitor cell migration and promotes functional recovery Ependymal cells in the adult spinal cord become activated after spinal cord injury (SCI), gaining stem/progenitor cell properties. Although growing evidence has implicated these cells as potential players in the endogenous repair process after injury, their activation to a stem-cell-like state is transient and insufficient for adequate regeneration. Moreover, the drivers of their activation state remain largely unknown. Previous work suggested that AMPA receptors (AMPARs) regulate cultured ependymal-derived neural stem/progenitor cells (epNSPCs). In this study, we identified an AMPAR-dependent mechanism of epNSPC regulation after SCI. Using lineage tracing in adult mice, we demonstrate that conditional knockout of GluA1–GluA3 AMPAR subunits in epNSPCs abolishes glutamate-induced AMPA currents and impairs the acute activation of these cells after SCI. Augmenting AMPAR signaling with the ampakine CX546 alters the transcriptional profile of epNSPCs, maintaining their acute maturation reversal after SCI into the chronic injury period, increasing connexin-43 signaling, promoting their migratory capacity and enhancing ependymal–glial cell contacts, which may contribute to the spatial distribution and migratory pattern of ependymal cells after injury. CX546 treatment ameliorates the subacute decrease in corticospinal tract excitability after SCI and leads to long-term functional improvements. Together, this work identifies a neurotransmitter receptor-dependent mechanism of epNSPC activation after injury, which may be targeted to harness the regenerative potential of the spinal cord. Spinal cord injury Stem cells in the nervous system
N Nature Neuroscience · Sep 15, 2025 Recurrent pattern completion drives the neocortical representation of sensory inference When sensory information is incomplete, the brain relies on prior expectations to infer perceptual objects. Despite the centrality of this process to perception, the neural mechanisms of sensory inference are not understood. Here we used illusory contours (ICs), multi-Neuropixels measurements, mesoscale two-photon (2p) calcium imaging and 2p holographic optogenetics in mice to reveal the neural codes and circuits of sensory inference. We discovered a specialized subset of neurons in primary visual cortex (V1) that respond emergently to illusory bars but not to component image segments. Selective holographic photoactivation of these ‘IC-encoders’ recreated the visual representation of ICs in V1 in the absence of any visual stimulus. These data imply that neurons that encode sensory inference are specialized for receiving and locally broadcasting top-down information. More generally, pattern completion circuits in lower cortical areas may selectively reinforce activity patterns that match prior expectations, constituting an integral step in perceptual inference. Extrastriate cortex Neural decoding Sensory processing Striate cortex
N Nature Neuroscience · Sep 10, 2025 Grid cells accurately track movement during path integration-based navigation despite switching reference frames Grid cells, with their periodic firing fields, are fundamental units in neural networks that perform path integration. It is widely assumed that grid cells encode movement in a single, global reference frame. In this study, by recording grid cell activity in mice performing a self-motion-based navigation task, we discovered that grid cells did not have a stable grid pattern during the task. Instead, grid cells track the animal movement in multiple reference frames within single trials. Specifically, grid cells reanchor to a task-relevant object through a translation of the grid pattern. Additionally, the internal representation of movement direction in grid cells drifted during self-motion navigation, and this drift predicted the mouse’s homing direction. Our findings reveal that grid cells do not operate as a global positioning system but rather estimate position within multiple local reference frames. Neural circuits Neural decoding Spatial memory
N Nature Neuroscience · Aug 27, 2025 Large-scale cortical functional networks are organized in structured cycles The human brain cycles through a repertoire of brain networks on a 1-second timescale during rest and tasks. This cycling appears to allow periodic engagement of essential cognitive functions, with the speed of cycling linked to genetics and age.
N Nature Neuroscience · Aug 26, 2025 Allothetic and idiothetic spatial cues control the multiplexed theta phase coding of place cells Theta oscillation is considered a temporal scaffold for hippocampal computations that organizes the activity of spatially tuned cells known as place cells. Late phases of theta support prospective spatial representation via phase ‘precession’. In contrast, some studies have hypothesized that early phases of theta may subserve both retrospective spatial representation via phase ‘procession’ and the encoding of new associations. Here, combining virtual reality, electrophysiology and computational modeling, we provide experimental evidence for such a functionally multiplexed phase code and describe how distinct spatial inputs control its manifestation. Specifically, when rats continuously learned new associations between external landmark (allothetic) cues and self-motion (idiothetic) cues, phase ‘precession’ remained intact, allowing continuous prediction of future positions. Conversely, phase ‘procession’ was diminished, matching the putative role in encoding at the early theta phase. This multiplexed phase code may serve as a general circuit logic for alternating different computations at a sub-second scale. Learning and memory Neural circuits
N Nature Neuroscience · Aug 22, 2025 CRISPR screening by AAV episome-sequencing (CrAAVe-seq): a scalable cell-type-specific in vivo platform uncovers neuronal essential genes There is a substantial need for scalable CRISPR-based genetic screening methods that can be applied in mammalian tissues in vivo while enabling cell-type-specific analysis. Here we developed an adeno-associated virus (AAV)-based CRISPR screening platform, CrAAVe-seq, that incorporates a Cre-sensitive sgRNA construct for pooled screening within targeted cell populations in mouse tissues. We used this approach to screen two large sgRNA libraries, which collectively target over 5,000 genes, in mouse brains and uncovered genes essential for neuronal survival, of which we validatedRabggtaandHspa5. We highlight the reproducibility and scalability of the platform and show that it is sufficiently sensitive for screening in a restricted subset of neurons. We systematically characterize the impact of sgRNA library size, mouse cohort size, the size of the targeted cell population, viral titer, and coinfection rate on screen performance to establish general guidelines for large-scale in vivo screens. Functional genomics Genetics of the nervous system High-throughput screening Molecular neuroscience
N Nature Neuroscience · Aug 21, 2025 Stable cortical body maps before and after arm amputation The adult brain’s capacity for cortical reorganization remains debated. Using longitudinal neuroimaging in three adults, followed before and up to 5 years after arm amputation, we compared cortical activity elicited by movement of the hand (before amputation) versus phantom hand (after amputation) and lips (before and after amputation). We observed stable cortical representations of both hand and lips in primary sensorimotor regions. By directly quantifying activity changes across amputation, we demonstrate that amputation does not trigger large-scale cortical reorganization. Cognitive neuroscience Cortex Motor control Sensorimotor processing
N Nature Neuroscience · Aug 21, 2025 Toxoplasma gondiiinfection and chronic IL-1 elevation drive hippocampal DNA double-strand break signaling, leading to cognitive deficits Chronic inflammation, resulting from infections, is characterized by increased levels of cytokines including interleukin-1 (IL-1), but little is known about how IL-1 contributes to cognitive impairment, potentially via epigenetic processes. Here we demonstrate that mice chronically infected with the parasiteToxoplasma gondiiexhibit impaired spatial memory, which is dependent on neuronal IL-1 signaling and mimicked by chronic exposure to IL-1β. BothT. gondiiinfection and chronic IL-1β drive H2A.X-dependent DNA double-strand break signaling in hippocampal neurons and invalidating neuronal H2A.X-dependent signaling blocks memory impairments caused by either exposure. Our results highlight the instrumental role of cytokine-induced double-strand-break-dependent signaling in spatial memory defects, which may be relevant to multiple brain diseases. Consolidation Cytokines Infectious diseases Inflammatory diseases Neuroimmunology
N Nature Neuroscience · Aug 18, 2025 FOXPgenes regulate Purkinje cell diversity and cerebellar morphogenesis Cerebellar Purkinje cells (PCs), the sole output neurons of the cerebellar cortex, are essential for motor coordination, learning and circuit formation. While functionally diverse, the extent of PC heterogeneity and the molecular drivers of this diversity remain unclear. Using single-cell RNA sequencing, we identified at least 11 molecularly distinct PC subtypes in the embryonic mouse cerebellum. Spatial reconstruction revealed that these subtypes are organized in embryonic patterns that predict key features of adult cerebellar architecture, including longitudinal stripes and lobular specificities. PC-subtype identity is defined by the combinatorial expression ofFoxp1,Foxp2andFoxp4. Genetic deletion ofFoxp1andFoxp2disrupts PC diversification and cerebellar patterning, including the loss of aFoxp1+subtype and the failure of cerebellar hemisphere formation.Foxp1+PCs are enriched in the fetal human cerebellum but are rare in chick, suggesting a role in cerebellar evolution. These findings uncover early PC diversification and identify Foxp1+PCs as critical regulators of cerebellar hemispheric development. Cell type diversity Cerebellum Differentiation
