Nature neuroscience最新文献_第3页

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}

引用次数: 0

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

Microglia conduct the symphony of white matter degeneration in aging through T cell recruitment 小胶质细胞通过T细胞募集来指挥衰老过程中白质退化的交响乐

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-22 DOI: 10.1038/s41593-025-01929-y

Jonathan K. Monteiro, Veronique E. Miron

引用次数: 0

Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration 小胶质细胞激活协调cxcl10介导的CD8+ T细胞募集，促进衰老相关的白质变性

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-22 DOI: 10.1038/s41593-025-01955-w

Janos Groh, Ruoqing Feng, Xidi Yuan, Lu Liu, Dennis Klein, Gladis Hutahaean, Elisabeth Butz, Zhen Wang, Lisa Steinbrecher, Jonas Neher, Rudolf Martini, Mikael Simons

{"title":"Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration","authors":"Janos Groh, Ruoqing Feng, Xidi Yuan, Lu Liu, Dennis Klein, Gladis Hutahaean, Elisabeth Butz, Zhen Wang, Lisa Steinbrecher, Jonas Neher, Rudolf Martini, Mikael Simons","doi":"10.1038/s41593-025-01955-w","DOIUrl":"https://doi.org/10.1038/s41593-025-01955-w","url":null,"abstract":"Aging is the major risk factor for neurodegeneration and is associated with structural and functional alterations in white matter. Myelin is particularly vulnerable to aging, resulting in white matter-associated microglia activation. Here we used pharmacological and genetic approaches to investigate microglial functions related to aging-associated changes in myelinated axons of mice. Our results reveal that maladaptive microglia activation promotes the accumulation of harmful CD8+ T cells, leading to the degeneration of myelinated axons and subsequent impairment of brain function and behavior. We characterize glial heterogeneity and aging-related changes in white matter by single-cell and spatial transcriptomics and reveal elaborate glial–immune interactions. Mechanistically, we show that the CXCL10–CXCR3 axis is crucial for the recruitment and retention of CD8+ T cells in aged white matter, where they exert pathogenic effects. Our results indicate that myelin-related microglia dysfunction promotes adaptive immune reactions in aging and identify putative targets to mitigate their detrimental impact.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"154 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113740","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 dynamic and multimodal framework to define microglial states 一个动态和多模态框架来定义小胶质细胞状态

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-20 DOI: 10.1038/s41593-025-01978-3

Roman Sankowski, Marco Prinz

引用次数: 0

Bilateral integration in somatosensory cortex is controlled by behavioral relevance 躯体感觉皮层的双侧整合受行为关联控制

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-14 DOI: 10.1038/s41593-025-01960-z

Hyein Park, Hayagreev V. S. Keri, Chaeyoung Yoo, Chengyu Bi, Scott R. Pluta

{"title":"Bilateral integration in somatosensory cortex is controlled by behavioral relevance","authors":"Hyein Park, Hayagreev V. S. Keri, Chaeyoung Yoo, Chengyu Bi, Scott R. Pluta","doi":"10.1038/s41593-025-01960-z","DOIUrl":"https://doi.org/10.1038/s41593-025-01960-z","url":null,"abstract":"Sensory perception requires the processing of stimuli from both sides of the body. Yet, how neurons bind stimulus information across the hemispheres to create a unified percept remains unknown. Here we perform large-scale recordings from neurons in the left and right primary somatosensory cortex (S1) in mice performing a task requiring active whisker touch to coordinate stimulus features across hemispheres. When mice touched reward-associated stimuli, their whiskers moved with greater bilateral symmetry, and synchronous spiking and enhanced spike–field coupling emerged between the hemispheres. This coordinated activity was absent in stimulus-matched naive animals, indicating that interhemispheric coupling involves a goal-directed, internal process. In S1 neurons, the addition of ipsilateral touch primarily facilitated the contralateral principal whisker response. This facilitation primarily emerged for reward-associated stimuli and was lost on trials where mice failed to respond. Silencing of callosal S1 signaling reduced bilateral facilitation and interhemispheric synchrony. These results reveal a state-dependent logic that augments the flow of tactile information through the corpus callosum.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"43 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946018","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

Activity-driven myelin sheath growth is mediated by mGluR5 mGluR5介导活性驱动的髓鞘生长

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-14 DOI: 10.1038/s41593-025-01956-9

Philipp N. Braaker, Xuelong Mi, Daniel Soong, Jenea M. Bin, Katy Marshall-Phelps, Stephen Bradley, Silvia Benito-Kwiecinski, Julia Meng, Donia Arafa, Claire Richmond, Marcus Keatinge, Guoqiang Yu, Rafael G. Almeida, David A. Lyons

{"title":"Activity-driven myelin sheath growth is mediated by mGluR5","authors":"Philipp N. Braaker, Xuelong Mi, Daniel Soong, Jenea M. Bin, Katy Marshall-Phelps, Stephen Bradley, Silvia Benito-Kwiecinski, Julia Meng, Donia Arafa, Claire Richmond, Marcus Keatinge, Guoqiang Yu, Rafael G. Almeida, David A. Lyons","doi":"10.1038/s41593-025-01956-9","DOIUrl":"https://doi.org/10.1038/s41593-025-01956-9","url":null,"abstract":"Myelination by oligodendrocytes in the central nervous system is influenced by neuronal activity, but the molecular mechanisms by which this occurs have remained unclear. Here we employed pharmacological, genetic, functional imaging and optogenetic-stimulation approaches in zebrafish to assess activity-regulated myelination in vivo. Pharmacological inhibition and activation of metabotropic glutamate receptor 5 (mGluR5) impaired and promoted myelin sheath elongation, respectively, during development, without otherwise affecting the oligodendrocyte lineage. Correspondingly, mGluR5 loss-of-function mutants exhibit impaired myelin growth, while oligodendrocyte-specific mGluR5 gain of function promoted sheath elongation. Functional imaging and optogenetic-stimulation studies revealed that mGluR5 mediates activity-driven high-amplitude Ca2+ transients in myelin. Furthermore, we found that long-term stimulation of neuronal activity drives myelin sheath elongation in an mGluR5-dependent manner. Together these data identify mGluR5 as a mediator of the influence of neuronal activity on myelination by oligodendrocytes in vivo, opening up opportunities to assess the functional relevance of activity-regulated myelination.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946020","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

Aging and injury drive neuronal senescence in the dorsal root ganglia 衰老和损伤驱动背根神经节神经元衰老

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-14 DOI: 10.1038/s41593-025-01954-x

Lauren J. Donovan, Chelsie L. Brewer, Sabrina F. Bond, Alexander M. Laslavic, Aleishai Pena Lopez, Laura Colman, Claire E. Jordan, Linus H. Hansen, Oscar C. González, Akshay Pujari, Luis de Lecea, Marco Quarta, Julie A. Kauer, Vivianne L. Tawfik

{"title":"Aging and injury drive neuronal senescence in the dorsal root ganglia","authors":"Lauren J. Donovan, Chelsie L. Brewer, Sabrina F. Bond, Alexander M. Laslavic, Aleishai Pena Lopez, Laura Colman, Claire E. Jordan, Linus H. Hansen, Oscar C. González, Akshay Pujari, Luis de Lecea, Marco Quarta, Julie A. Kauer, Vivianne L. Tawfik","doi":"10.1038/s41593-025-01954-x","DOIUrl":"https://doi.org/10.1038/s41593-025-01954-x","url":null,"abstract":"Aging negatively impacts central nervous system function; however, there is limited information about the cellular impact of aging on peripheral nervous system function. Importantly, injury to vulnerable peripheral axons of dorsal root ganglion (DRG) neurons results in somatosensory dysfunction, such as pain, at higher rates in aged individuals. Cellular senescence is common to both aging and injury and contributes to the aged pro-inflammatory environment. We discovered DRG neuron senescence in the context of aging and pain-inducing peripheral nerve injury in young (~3 months) and aged (~24 months) male and female mice. Senescent neurons were dynamic and heterogeneous in their expression of multiple senescence markers, including pro-inflammatory factor IL6. Senescence marker-expressing neurons had nociceptor-like profiles, included high-firing phenotypes and displayed increased excitability after IL6 application. Furthermore, elimination of senescent cells resulted in improvement of nociceptive behaviors in nerve-injured mice. Finally, male and female post-mortem human DRG contained senescent neurons that increased with age (~32 years old versus 65 years old). Overall, we describe a susceptibility of the peripheral nervous system to neuronal senescence—a potential targetable mechanism to treat sensory dysfunction, such as chronic pain, particularly in aged populations.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"1 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946019","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

MeCP2 and non-CG DNA methylation stabilize the expression of long genes that distinguish closely related neuron types MeCP2和非cg DNA甲基化稳定了区分密切相关神经元类型的长基因的表达

IF 25 1区医学

Nature neuroscience Pub Date : 2025-05-12 DOI: 10.1038/s41593-025-01947-w

J. Russell Moore, Mati T. Nemera, Rinaldo D. D’Souza, Nicole Hamagami, Adam W. Clemens, Diana C. Beard, Alaina Urman, Yasmin Razia, Victoria Rodriguez Mendoza, Travis E. Law, John R. Edwards, Harrison W. Gabel

{"title":"MeCP2 and non-CG DNA methylation stabilize the expression of long genes that distinguish closely related neuron types","authors":"J. Russell Moore, Mati T. Nemera, Rinaldo D. D’Souza, Nicole Hamagami, Adam W. Clemens, Diana C. Beard, Alaina Urman, Yasmin Razia, Victoria Rodriguez Mendoza, Travis E. Law, John R. Edwards, Harrison W. Gabel","doi":"10.1038/s41593-025-01947-w","DOIUrl":"https://doi.org/10.1038/s41593-025-01947-w","url":null,"abstract":"The diversity of mammalian neurons is delineated by subtle gene expression differences that may require specialized mechanisms to be maintained. Neurons uniquely express the longest genes in the genome and use non-CG DNA methylation (mCA), together with the Rett syndrome protein methyl-CpG-binding protein 2 (MeCP2), to control gene expression. However, whether these distinctive gene structures and molecular machinery regulate neuronal diversity remains unexplored. Here, we use genomic and spatial transcriptomic analyses to show that MeCP2 maintains transcriptomic diversity across closely related neuron types. We uncover differential susceptibility of neuronal populations to MeCP2 loss according to global mCA levels and dissect methylation patterns driving shared and distinct MeCP2 gene regulation. We show that MeCP2 regulates long, mCA-enriched, ‘repeatedly tuned’ genes, that is, genes differentially expressed between many closely related neuron types, including across spatially distinct, vision-dependent gene programs in the visual cortex. Thus, MeCP2 maintains neuron type-specific gene programs to facilitate cellular diversity in the brain.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"5 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933509","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