Nature neuroscience最新文献_第2页

Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress 神经元老化导致剪接蛋白的错误定位和不受控制的细胞应激

IF 25 1区医学

Nature neuroscience Pub Date : 2025-06-02 DOI: 10.1038/s41593-025-01952-z

Kevin Rhine, Rachel Li, Hema M. Kopalle, Katherine Rothamel, Xuezhen Ge, Elle Epstein, Orel Mizrahi, Assael A. Madrigal, Hsuan-Lin Her, Trent A. Gomberg, Anita Hermann, Joshua L. Schwartz, Amanda J. Daniels, Uri Manor, John Ravits, Robert A. J. Signer, Eric J. Bennett, Gene W. Yeo

{"title":"Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress","authors":"Kevin Rhine, Rachel Li, Hema M. Kopalle, Katherine Rothamel, Xuezhen Ge, Elle Epstein, Orel Mizrahi, Assael A. Madrigal, Hsuan-Lin Her, Trent A. Gomberg, Anita Hermann, Joshua L. Schwartz, Amanda J. Daniels, Uri Manor, John Ravits, Robert A. J. Signer, Eric J. Bennett, Gene W. Yeo","doi":"10.1038/s41593-025-01952-z","DOIUrl":"https://doi.org/10.1038/s41593-025-01952-z","url":null,"abstract":"Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins—like the dementia- and ALS-associated protein TDP-43—mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity and the failure to respond to new stress events. Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"13 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192726","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

Egocentric value maps of the near-body environment 以自我为中心的近体环境价值图

IF 25 1区医学

Nature neuroscience Pub Date : 2025-06-02 DOI: 10.1038/s41593-025-01958-7

Rory John Bufacchi, Richard Somervail, Aoife Maria Fitzpatrick, Yusuke Murayama, Nikos Logothetis, Roberto Caminiti, Gian Domenico Iannetti

{"title":"Egocentric value maps of the near-body environment","authors":"Rory John Bufacchi, Richard Somervail, Aoife Maria Fitzpatrick, Yusuke Murayama, Nikos Logothetis, Roberto Caminiti, Gian Domenico Iannetti","doi":"10.1038/s41593-025-01958-7","DOIUrl":"https://doi.org/10.1038/s41593-025-01958-7","url":null,"abstract":"Body-part-centered response fields are pervasive in single neurons, functional magnetic resonance imaging, electroencephalography and behavior, but there is no unifying formal explanation of their origins and role. In the present study, we used reinforcement learning and artificial neural networks to demonstrate that body-part-centered fields do not simply reflect stimulus configuration, but rather action value: they naturally arise from the basic assumption that agents often experience positive or negative reward after contacting environmental objects. This perspective successfully reproduces experimental findings that are foundational in the peripersonal space literature. It also suggests that peripersonal fields provide building blocks that create a modular model of the world near the agent: an egocentric value map. This concept is strongly supported by the emergent modularity that we observed in our artificial networks. The short-term, close-range, egocentric map is analogous to the long-term, long-range, allocentric hippocampal map. This perspective fits empirical data from multiple experiments, provides testable predictions and accommodates existing explanations of peripersonal fields.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"5 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192889","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

Microglia eliminate inhibitory synapses and drive neuronal hyperexcitability in epilepsy 小胶质细胞消除抑制性突触并驱动癫痫中的神经元高兴奋性

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-30 DOI: 10.1038/s41593-025-01983-6

引用次数: 0

The transcriptomes, connections and development of submucosal neuron classes in the mouse small intestine 小鼠小肠粘膜下神经元类别的转录组、连接和发育

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-29 DOI: 10.1038/s41593-025-01962-x

Wei Li, Khomgrit Morarach, Ziwei Liu, Sanghita Banerjee, Yanan Chen, Ashley L. Harb, Joel M. Kosareff, Charles R. Hall, Fernando López-Redondo, Elham Jalalvand, Suad H. Mohamed, Anastassia Mikhailova, David R. Linden, Ulrika Marklund

{"title":"The transcriptomes, connections and development of submucosal neuron classes in the mouse small intestine","authors":"Wei Li, Khomgrit Morarach, Ziwei Liu, Sanghita Banerjee, Yanan Chen, Ashley L. Harb, Joel M. Kosareff, Charles R. Hall, Fernando López-Redondo, Elham Jalalvand, Suad H. Mohamed, Anastassia Mikhailova, David R. Linden, Ulrika Marklund","doi":"10.1038/s41593-025-01962-x","DOIUrl":"https://doi.org/10.1038/s41593-025-01962-x","url":null,"abstract":"The enteric submucosal plexus regulates essential digestive functions, yet its neuronal composition remains incompletely understood. We identified two putative secretomotor neuron classes and a previously unrecognized submucosal intrinsic primary afferent neuron class through single-cell RNA sequencing in the mouse small intestine. Using viral-mediated labeling of each class, we uncovered their morphologies and neural projections in the submucosa–mucosa context, finding connections among all classes and an unexpected close association with enterochromaffin cells. Further transcriptome analysis at the postnatal stage and lineage tracing revealed that neuron identities in the submucosal plexus emerge through an initial binary fate split at neurogenesis, followed by phenotypic diversification, akin to the developmental process of the myenteric plexus. We propose a unified developmental framework for neuronal diversification across the gut wall. Our study offers comprehensive molecular, developmental and morphological insights into submucosal neurons, opening new avenues for exploring physiological functions, circuit dynamics and formation of the submucosal plexus.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"8 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164788","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

Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development 小鼠脑发育过程中脉络丛大汗液分泌影响脑脊液蛋白质组

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-28 DOI: 10.1038/s41593-025-01972-9

Ya’el Courtney, Joshua P. Head, Neil Dani, Olga V. Chechneva, Frederick B. Shipley, Yong Zhang, Michael J. Holtzman, Cameron Sadegh, Towia A. Libermann, Maria K. Lehtinen

{"title":"Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development","authors":"Ya’el Courtney, Joshua P. Head, Neil Dani, Olga V. Chechneva, Frederick B. Shipley, Yong Zhang, Michael J. Holtzman, Cameron Sadegh, Towia A. Libermann, Maria K. Lehtinen","doi":"10.1038/s41593-025-01972-9","DOIUrl":"https://doi.org/10.1038/s41593-025-01972-9","url":null,"abstract":"The choroid plexus (ChP) regulates cerebrospinal fluid (CSF) composition, providing essential molecular cues for brain development; yet, embryonic ChP secretory mechanisms remain poorly defined. Here we identify apocrine secretion by embryonic ChP epithelial cells as a key regulator of the CSF proteome and neurodevelopment in male and female mice. We demonstrate that the activation of serotonergic 5-HT2C receptors (by WAY-161503) triggers sustained Ca2+ signaling, driving high-volume apocrine secretion in mouse and human ChP. This secretion alters the CSF proteome, stimulating neural progenitors lining the brain’s ventricles and shifting their developmental trajectory. Inducing ChP secretion in utero in mice disrupts neural progenitor dynamics, cerebral cortical architecture and offspring behavior. Additionally, illness or lysergic acid diethylamide exposure during pregnancy provokes coordinated ChP secretion in the mouse embryo. Our findings reveal a fundamental secretory pathway in the ChP that shapes brain development, highlighting how its disruption can have lasting consequences for brain health.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"4 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153581","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 hypothalamus–brainstem circuit governs the prioritization of safety over essential needs 下丘脑-脑干回路控制着安全优先于基本需求

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-28 DOI: 10.1038/s41593-025-01975-6

Nathalie Krauth, Lara K. Sach, Giacomo Sitzia, Christoffer Clemmensen, Ole Kiehn

引用次数: 0

What dopamine teaches depends on what the brain believes 多巴胺教什么取决于大脑相信什么

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-28 DOI: 10.1038/s41593-025-01980-9

Eleonora Bano, Steven Ryu, Adam Kepecs

引用次数: 0

GABA-dependent microglial elimination of inhibitory synapses underlies neuronal hyperexcitability in epilepsy gaba依赖性的抑制性突触的小胶质消除是癫痫中神经元高兴奋性的基础

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-27 DOI: 10.1038/s41593-025-01979-2

Zhang-Peng Chen, Xiansen Zhao, Suji Wang, Ruolan Cai, Qiangqiang Liu, Haojie Ye, Meng-Ju Wang, Shi-Yu Peng, Wei-Xuan Xue, Yang-Xun Zhang, Wei Li, Hua Tang, Tengfei Huang, Qipeng Zhang, Liang Li, Lixia Gao, Hong Zhou, Chunhua Hang, Jing-Ning Zhu, Xinjian Li, Xiangyu Liu, Qifei Cong, Chao Yan

{"title":"GABA-dependent microglial elimination of inhibitory synapses underlies neuronal hyperexcitability in epilepsy","authors":"Zhang-Peng Chen, Xiansen Zhao, Suji Wang, Ruolan Cai, Qiangqiang Liu, Haojie Ye, Meng-Ju Wang, Shi-Yu Peng, Wei-Xuan Xue, Yang-Xun Zhang, Wei Li, Hua Tang, Tengfei Huang, Qipeng Zhang, Liang Li, Lixia Gao, Hong Zhou, Chunhua Hang, Jing-Ning Zhu, Xinjian Li, Xiangyu Liu, Qifei Cong, Chao Yan","doi":"10.1038/s41593-025-01979-2","DOIUrl":"https://doi.org/10.1038/s41593-025-01979-2","url":null,"abstract":"Neuronal hyperexcitability is a common pathophysiological feature of many neurological diseases. Neuron–glia interactions underlie this process but the detailed mechanisms remain unclear. Here, we reveal a critical role of microglia-mediated selective elimination of inhibitory synapses in driving neuronal hyperexcitability. In epileptic mice of both sexes, hyperactive inhibitory neurons directly activate surveilling microglia via GABAergic signaling. In response, these activated microglia preferentially phagocytose inhibitory synapses, disrupting the balance between excitatory and inhibitory synaptic transmission and amplifying network excitability. This feedback mechanism depends on both GABA–GABAB receptor-mediated microglial activation and complement C3–C3aR-mediated microglial engulfment of inhibitory synapses, as pharmacological or genetic blockage of both pathways effectively prevents inhibitory synapse loss and ameliorates seizure symptoms in mice. Additionally, putative cell–cell interaction analyses of brain tissues from males and females with temporal lobe epilepsy reveal that inhibitory neurons induce microglial phagocytic states and inhibitory synapse loss. Our findings demonstrate that inhibitory neurons can directly instruct microglial states to control inhibitory synaptic transmission through a feedback mechanism, leading to the development of neuronal hyperexcitability in temporal lobe epilepsy.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"133 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145590","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}

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Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy Lemborexant改善tau介导的睡眠缺失和雄性小鼠tau病模型中的神经变性

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-27 DOI: 10.1038/s41593-025-01966-7

Samira Parhizkar, Xin Bao, Wei Chen, Nicholas Rensing, Yun Chen, Michal Kipnis, Sihui Song, Grace Gent, Eric Tycksen, Melissa Manis, Choonghee Lee, Javier Remolina Serrano, Megan E. Bosch, Emily Franke, Carla M. Yuede, Eric C. Landsness, Michael Wong, David M. Holtzman

{"title":"Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy","authors":"Samira Parhizkar, Xin Bao, Wei Chen, Nicholas Rensing, Yun Chen, Michal Kipnis, Sihui Song, Grace Gent, Eric Tycksen, Melissa Manis, Choonghee Lee, Javier Remolina Serrano, Megan E. Bosch, Emily Franke, Carla M. Yuede, Eric C. Landsness, Michael Wong, David M. Holtzman","doi":"10.1038/s41593-025-01966-7","DOIUrl":"https://doi.org/10.1038/s41593-025-01966-7","url":null,"abstract":"Sleep disturbances are associated with the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and primary tauopathies. Here we demonstrate that administration of the dual orexin receptor antagonist lemborexant in the P301S/E4 mouse model of tauopathy improves tau-associated impairments in sleep–wake behavior. It also protects against chronic reactive microgliosis and brain atrophy in male P301S/E4 mice by preventing abnormal phosphorylation of tau. These neuroprotective effects in males were not observed after administration of the nonorexinergic drug zolpidem that similarly promoted nonrapid eye movement sleep. Furthermore, both genetic ablation of orexin receptor 2 and lemborexant treatment reduced wakefulness and decreased seeding and spreading of phosphorylated tau in the brain of wild-type mice. These findings raise the therapeutic potential of targeting sleep by orexin receptor antagonism to prevent abnormal tau phosphorylation and limit tau-induced damage.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"33 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145589","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

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles 裸盖菇素增强的恐惧消退与皮质集合的双向调节有关

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-26 DOI: 10.1038/s41593-025-01964-9

Sophie A. Rogers, Elizabeth A. Heller, Gregory Corder

{"title":"Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles","authors":"Sophie A. Rogers, Elizabeth A. Heller, Gregory Corder","doi":"10.1038/s41593-025-01964-9","DOIUrl":"https://doi.org/10.1038/s41593-025-01964-9","url":null,"abstract":"The psychedelic drug psilocybin demonstrates rapid and long-lasting efficacy across neuropsychiatric disorders that are characterized by behavioral inflexibility. However, its impact on the neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test whether psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the mouse retrosplenial cortex across a 5-day trace fear learning and extinction assay. We found that a single dose of psilocybin altered cortical ensemble turnover and oppositely modulated fear- and extinction-active neurons. Suppression of fear-active neurons and recruitment of extinction-active neurons predicted psilocybin-enhanced fear extinction. In a computational model of this microcircuit, inhibition of simulated fear-active units modulated recruitment of extinction-active units and behavioral variability in freezing, aligning with experimental results. These results suggest that psilocybin enhances behavioral flexibility by recruiting new neuronal populations and suppressing fear-active populations in the retrosplenial cortex.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"48 8 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137160","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