Nature neuroscience最新文献

Early lineage divergence segregates sensory and motor-associative identities in the thalamus. 早期谱系分化分离了丘脑的感觉和运动联合身份。

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-20 DOI: 10.1038/s41593-026-02485-9

Lorenzo Puche-Aroca, Belén Andrés-Bayón, Emily S Wilson, Awais Javed, Aurelia Torregrosa-Mira, Luis M Rodríguez-Malmierca, José P López-Atalaya, Guillermina López-Bendito

{"title":"Early lineage divergence segregates sensory and motor-associative identities in the thalamus.","authors":"Lorenzo Puche-Aroca, Belén Andrés-Bayón, Emily S Wilson, Awais Javed, Aurelia Torregrosa-Mira, Luis M Rodríguez-Malmierca, José P López-Atalaya, Guillermina López-Bendito","doi":"10.1038/s41593-026-02485-9","DOIUrl":"https://doi.org/10.1038/s41593-026-02485-9","url":null,"abstract":"The thalamus integrates sensory, motor and associative functions through distinct nuclei, yet the developmental principles driving their specification remain unclear. Here we generate a spatiotemporal single-cell multiomic and spatial transcriptomic atlas of the embryonic mouse thalamus, combined with barcoding-based lineage tracing. We identify two major glutamatergic lineages, sensory-related and motor-associative, each governed by different gene regulatory programs and temporal dynamics. These lineages arise from spatially and molecularly distinct progenitor domains, revealing an early segregation of functional identities. Within the sensory lineage, we resolve branching sensory trajectories leading to first-order visual and somatosensory neurons, both emerging from a shared higher-order-like state. Using in silico predictions and in vivo perturbation, we identify Sp9 as a key regulator of visual thalamic fate. Together, our findings define the molecular architecture and developmental trajectories that underpin thalamic modality specification, providing a framework to understand how functional circuits emerge in the mammalian brain.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dysregulated cholesterol trafficking through ABCA1 drives neurodegeneration in Parkinson's disease. 通过ABCA1介导的胆固醇运输失调驱动帕金森病的神经变性。

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-20 DOI: 10.1038/s41593-026-02487-7

Feng-Xia Ma, Xin-Xin Zhao, Xiao-Xin Wang, Shuo-Yan Fang, Shen-Han Xu, Min Wang, Yu-Xiao Liu, Cong Wang, Qiu-Ling Wang, Ming Lu, Lei Cao

{"title":"Dysregulated cholesterol trafficking through ABCA1 drives neurodegeneration in Parkinson's disease.","authors":"Feng-Xia Ma, Xin-Xin Zhao, Xiao-Xin Wang, Shuo-Yan Fang, Shen-Han Xu, Min Wang, Yu-Xiao Liu, Cong Wang, Qiu-Ling Wang, Ming Lu, Lei Cao","doi":"10.1038/s41593-026-02487-7","DOIUrl":"https://doi.org/10.1038/s41593-026-02487-7","url":null,"abstract":"Although brain cholesterol dysregulation is implicated in Parkinson's disease (PD), targeting cholesterol synthesis has shown limited efficacy. Here we identify ATP-binding cassette transporter A1 (ABCA1) as a critical regulator of cholesterol homeostasis in PD. We show that ABCA1 expression is elevated in the substantia nigra of postmortem PD brains and in a PD mouse model, with regional analyses revealing preferential alterations in nigral and striatal circuits. Mechanistically, astrocytic ABCA1 drives excessive cholesterol efflux in mice, promoting neuronal cholesterol overload. In neurons, ABCA1 localizes to lysosomes, where it facilitates cholesterol import, leading to cholesterol accumulation, autophagy impairment and α-synuclein pathology. Genetic silencing of Abca1 in either astrocytes or dopaminergic neurons attenuates neurodegeneration and behavioral deficits in vivo. Furthermore, we identify magnesium citrate as an ABCA1 inhibitor and show that it reduces dopaminergic neuronal loss in a PD mouse model. Our findings identify an ABCA1-dependent cholesterol pathway underlying PD pathogenesis and support ABCA1 inhibition as a potential disease-modifying strategy.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An amygdala-mediated simulation-to-decision cascade aligns interbrain dynamics to solve social dilemmas 一个杏仁核介导的模拟到决策级联对齐脑间动力学来解决社会困境

IF 25 1区医学

Nature neuroscience Pub Date : 2026-10-19 DOI: 10.1038/s41593-026-02473-z

Jun Ni, Fangang Meng, Chao Zhang, Huixin Tan, Xiaoyu Zeng, Jiaxin Yang, HuanJia Li, Yuan Qi, Yuchi Yan, Yanyang Zhang, Kai Zhang, Yina Ma

{"title":"An amygdala-mediated simulation-to-decision cascade aligns interbrain dynamics to solve social dilemmas","authors":"Jun Ni, Fangang Meng, Chao Zhang, Huixin Tan, Xiaoyu Zeng, Jiaxin Yang, HuanJia Li, Yuan Qi, Yuchi Yan, Yanyang Zhang, Kai Zhang, Yina Ma","doi":"10.1038/s41593-026-02473-z","DOIUrl":"https://doi.org/10.1038/s41593-026-02473-z","url":null,"abstract":"Mutual cooperation (MC) requires independent decision-makers to coordinate under uncertainty about each other’s intentions. Using simultaneous intracranial electroencephalography from epilepsy–patient dyads playing a real-time iterated prisoner’s dilemma, we identified neurocognitive mechanisms that enable interacting brains to align during mutual cooperation. Amygdala interbrain representational alignment (IBRA), similarity in fine-grained neural spectral patterns across partners, emerged selectively during MC and predicted trial-by-trial outcomes. Early θ-suppression-characterized IBRA reflected rapid, history-sensitive alignment, whereas later IBRA, characterized by low-frequency suppression and γ increases, supported coordinated commitment and action. Furthermore, mutual cooperation relied on an amygdala-mediated, simulation-to-decision cascade, operationalized here as a model-based prospective estimate of partner cooperation that guided self-choice. Amygdala low-frequency suppression tracked this prospective estimate of partner cooperation and θ–γ coupling linked this partner estimate to self-decision processes. Conditional cooperators strategically relied on partner tracking, whereas unconditional cooperators leveraged dispositional tolerance of uncertainty to transition into anticipatory neural alignment. These findings reveal the neural interdependency underpinning MC, redefining cooperation not as isolated decision-making but as a dynamic, interbrain, cognitive alignment.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"73 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatiotemporal remodeling in habenula marks the onset of depression-related phenotypes 缰带的时空重塑标志着抑郁症相关表型的开始

IF 25 1区医学

Nature neuroscience Pub Date : 2026-10-19 DOI: 10.1038/s41593-026-02488-6

Patricia Molina, Denys Osypenko, Josep Garnica, Quentin Amossé, Farha Bouteldja, Léa Camelot, Sarah Mondoloni, Mauro Congiu, Claudia Kathe, Manuel Mameli

{"title":"Spatiotemporal remodeling in habenula marks the onset of depression-related phenotypes","authors":"Patricia Molina, Denys Osypenko, Josep Garnica, Quentin Amossé, Farha Bouteldja, Léa Camelot, Sarah Mondoloni, Mauro Congiu, Claudia Kathe, Manuel Mameli","doi":"10.1038/s41593-026-02488-6","DOIUrl":"https://doi.org/10.1038/s41593-026-02488-6","url":null,"abstract":"Chronic stress has lasting adverse consequences that can lead, over time, to depression, yet the optimal timeframe for effective therapies remains unclear. The lateral habenula (LHb) has been implicated in stress-related behavioral repercussions, but the precise timing of its contribution is not understood. Here, using spatial transcriptomics, we generated a spatially resolved molecular atlas of the LHb of male mice, revealing a topographically organized and temporally defined remodeling of gene expression after chronic stress. Longitudinal in vivo two-photon calcium imaging of individual LHb neurons revealed progressively heightened excitatory responses to aversive stimuli. These neuronal adaptations mirrored both the progression of transcriptional changes and the emergence of depression-related behavioral phenotypes and were reversed by the antidepressant ketamine. Moreover, chemogenetically limiting LHb neuronal activity or administering ketamine at the onset of these changes exerted antidepressant effects. These findings link spatiotemporal signatures of LHb neuronal ensembles and genetic landscape with the onset of stress-induced depression-related states.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"42 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatiotemporal AI-based modeling of gene regulation and variant effects in the developing human brain using Seal. 基于ai的人类大脑发育过程中基因调控和变异效应的时空建模

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-15 DOI: 10.1038/s41593-026-02470-2

Yun Hao, Christopher Y Park, Chandra L Theesfeld, Olga G Troyanskaya

{"title":"Spatiotemporal AI-based modeling of gene regulation and variant effects in the developing human brain using Seal.","authors":"Yun Hao, Christopher Y Park, Chandra L Theesfeld, Olga G Troyanskaya","doi":"10.1038/s41593-026-02470-2","DOIUrl":"https://doi.org/10.1038/s41593-026-02470-2","url":null,"abstract":"Understanding how genetic variation shapes gene regulation in the developing human brain remains a central challenge in neuroscience, particularly in transient cell types and developmental stages where data are limited. We present Seal, an interpretable artificial intelligence (AI) transfer learning framework for genome-based modeling of gene expression and variant effects with spatiotemporal resolution across 26 regions, 30 cell types and 7 developmental stages. Seal predictions provide mechanistic interpretation by linking variants to transcriptional regulators in a spatiotemporal context. Applying Seal to genome-wide association studies, we identify shared and distinct regulatory architectures across six neuropsychiatric conditions that align with clinical trajectories. In the Simons Simplex Collection autism cohort whole-genome data, Seal uncovers a significant burden of de novo regulatory variants in transient fetal excitatory neurons, revealing cell-type-specific and stage-specific effects. By connecting genetic variation to spatiotemporal regulatory programs, Seal offers a general framework for uncovering mechanisms of human brain development and disease.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

5-HT_2A receptors in layer 5 pyramidal neurons mediate the neuroplastic but not the hallucinogenic effects of psilocybin. 第5层锥体神经元中的5- ht2a受体介导裸盖菇素的神经可塑性作用，但不介导致幻作用。

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-15 DOI: 10.1038/s41593-026-02490-y

Jacob J Baker, Emily Kogan, Shaorong Ma, Ju Lu, Yi Zuo

引用次数: 0

Periventricular gradient pathology is linked to ependymal reactivity and cell adhesion disruption in multiple sclerosis. 在多发性硬化症中，心室周围梯度病理与室管膜反应性和细胞粘附破坏有关。

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-15 DOI: 10.1038/s41593-026-02461-3

Adam M R Groh, Elia Afanasiev, Risavarshni Thevakumaran, Finn Creeggan, Liam Callahan-Martin, Maxime Bigotte, Moein Yaqubi, Joshua Gertsvolf, Junze Pei, Hayden Wu, Judith de Vos, Maurice C G Aalders, Stephanie Zandee, Alexandre Prat, David A Rudko, Jo Anne Stratton

{"title":"Periventricular gradient pathology is linked to ependymal reactivity and cell adhesion disruption in multiple sclerosis.","authors":"Adam M R Groh, Elia Afanasiev, Risavarshni Thevakumaran, Finn Creeggan, Liam Callahan-Martin, Maxime Bigotte, Moein Yaqubi, Joshua Gertsvolf, Junze Pei, Hayden Wu, Judith de Vos, Maurice C G Aalders, Stephanie Zandee, Alexandre Prat, David A Rudko, Jo Anne Stratton","doi":"10.1038/s41593-026-02461-3","DOIUrl":"https://doi.org/10.1038/s41593-026-02461-3","url":null,"abstract":"Cerebrospinal fluid (CSF)-adjacent brain areas are especially vulnerable to diffuse degeneration in multiple sclerosis (MS). Surface-in gradients arising from CSF-borne cytotoxic factors have been proposed to predict disease relapses independent of white matter lesions. Yet, whether such factors disrupt ependymal cells to penetrate the ventricular border in MS remains unknown. Here, using ultra-high-field magnetic resonance imaging-guided histology, electron microscopy and single-nucleus multiomics, we found that ependymal pathology correlates with periventricular gradients and involves an immune-reactive state marked by transporter and junctional protein dysregulation. We further defined the gene regulatory networks underpinning the MS ependymal state and predicted ligands known to be enriched in MS CSF that could drive the emergence of this state. One of the candidates, IFNγ, increased murine ependymal permeability in vivo, indicating that CSF ligands can modulate ependymal function and regional inflammation. These findings identify CSF-driven ependymal dysfunction as a contributor to periventricular pathology in MS.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A half-center oscillator regulates sleep pressure. 半中心振荡器调节睡眠压力。

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-15 DOI: 10.1038/s41593-026-02431-9

Peter S Hasenhuetl, Raffaele Sarnataro, Eleftheria Vrontou, H Olof Rorsman, Clifford B Talbot, Ruth Brain, Gero Miesenböck

{"title":"A half-center oscillator regulates sleep pressure.","authors":"Peter S Hasenhuetl, Raffaele Sarnataro, Eleftheria Vrontou, H Olof Rorsman, Clifford B Talbot, Ruth Brain, Gero Miesenböck","doi":"10.1038/s41593-026-02431-9","DOIUrl":"https://doi.org/10.1038/s41593-026-02431-9","url":null,"abstract":"Changes in oscillatory neural dynamics reflect-but may not necessarily determine-transitions between sleep stages and variations in sleep pressure. Here we show that sleep-control neurons innervating the dorsal fan-shaped body of Drosophila (dFBNs) produce slow-wave activity (SWA) that is causally linked to sleep. The dFBN ensemble contains bistable cells whose membrane voltages oscillate between hyperpolarized DOWN and depolarized UP states. The oscillations rely on interhemispheric competition of two half-centers connected by inhibitory glutamatergic synapses. dFBN-restricted interference with glutamate release disrupts SWA and baseline as well as rebound sleep, whereas the optogenetic replay of SWA induces sleep. dFBNs generate SWA throughout the sleep-wake cycle (despite mutual antagonism with arousing dopaminergic neurons) and adjust its power to sleep need via sleep history-dependent increases in excitability and homeostatic synaptic depression. The oscillatory format permits a continuous encoding of sleep pressure but requires mechanisms that convert the amplitude-modulated signal into binary sleep-wake states.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience. 衰老敏感分泌磷脂酶赋予神经保护和认知弹性。

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-15 DOI: 10.1038/s41593-026-02465-z

Cinzia Vicidomini, Travis D Goode, Ruilin Yu, Iyanah Mehta, Kathleen M McAvoy, Connor H Beveridge, Caitlin E Randolph, Sanjay N Iyer, Matheus B Victor, Noelle Leary, Liam Evans, Michael J Steinbaugh, Zon Weng Lai, Marina C Lyon, Manuel Rico Fernández San Silvestre, Giorgia Tosoni, Dilara Ayyildiz, Shannan Ho Sui, Kei Yamamoto, Makoto Murakami, Evgenia Salta, Li-Huei Tsai, Gaurav Chopra, Amar Sahay

{"title":"An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience.","authors":"Cinzia Vicidomini, Travis D Goode, Ruilin Yu, Iyanah Mehta, Kathleen M McAvoy, Connor H Beveridge, Caitlin E Randolph, Sanjay N Iyer, Matheus B Victor, Noelle Leary, Liam Evans, Michael J Steinbaugh, Zon Weng Lai, Marina C Lyon, Manuel Rico Fernández San Silvestre, Giorgia Tosoni, Dilara Ayyildiz, Shannan Ho Sui, Kei Yamamoto, Makoto Murakami, Evgenia Salta, Li-Huei Tsai, Gaurav Chopra, Amar Sahay","doi":"10.1038/s41593-026-02465-z","DOIUrl":"10.1038/s41593-026-02465-z","url":null,"abstract":"Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging and is associated with cognitive resilience in humans. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes, including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation, lipid droplet accumulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to prevent these pathophysiological alterations in hippocampal-cortical circuits, protect memory and prophylactically modify trajectory of cognitive decline. Mutagenesis of the catalytic site of PLA2G2F prevented lipid droplet mobilization and reduction of reactive gliosis and inflammatory microglia. Neuronal PLA2G2F mediates intercellular signaling to decrease lipid droplet and cholesterol ester load in human induced pluripotent stem cell-derived microglia. Our findings implicate PLA2G2F as a compensatory neuroprotective broadcast signal that maintains lipid homeostasis to counteract aging-associated cognitive decline.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Symmetries and continuous attractors in disordered neural circuits. 无序神经回路中的对称性和连续吸引子。

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-14 DOI: 10.1038/s41593-026-02452-4

David G Clark, L F Abbott, Haim Sompolinsky

引用次数: 0