Nature neuroscience最新文献_第3页

Genome-wide analysis of common structural variants in Alzheimer's disease identifies a risk-associated regulatory CCG repeat in FAM193B. 阿尔茨海默病常见结构变异的全基因组分析确定了FAM193B中风险相关的调节CCG重复序列。

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-12 DOI: 10.1038/s41593-026-02481-z

Han Cao, Yifan Fu, Xiaopu Zhou, Yangyang Duan, Fanny C F Ip, Yu Chen, Shenyuan Hu, Si Chai Liu, Timothy C Y Kwok, Kin Y Mok, Tom H Cheung, John Hardy, Amy K Y Fu, Nancy Y Ip

{"title":"Genome-wide analysis of common structural variants in Alzheimer's disease identifies a risk-associated regulatory CCG repeat in FAM193B.","authors":"Han Cao, Yifan Fu, Xiaopu Zhou, Yangyang Duan, Fanny C F Ip, Yu Chen, Shenyuan Hu, Si Chai Liu, Timothy C Y Kwok, Kin Y Mok, Tom H Cheung, John Hardy, Amy K Y Fu, Nancy Y Ip","doi":"10.1038/s41593-026-02481-z","DOIUrl":"https://doi.org/10.1038/s41593-026-02481-z","url":null,"abstract":"Although Alzheimer's disease (AD) has a polygenic architecture, with numerous associated single-nucleotide polymorphisms (SNPs) identified, the contribution of structural variants (SVs) is unclear. In this study, using long-read (n = 11) and short-read (n = 3,190) sequencing data from the Chinese population, we show that common SVs contribute to AD heritability beyond common SNPs. We identify an expanded CCG repeat in the FAM193B promoter that shows a genome-wide significant association with increased AD risk (odds ratio = 2.20 per 10-repeat increase, P = 5.5 × 10-13). The expanded FAM193B-CCG repeat increases FAM193B expression and mediates the pleiotropic association between brain FAM193B expression and AD risk. Analyses of postmortem human brains and cultured neuronal cells show that elevated neuronal FAM193B expression is associated with DNA damage and cell death-related pathways. These findings establish the common FAM193B-CCG repeat as an AD risk genetic factor and highlight the contribution of common SVs to AD heritability.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166587","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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Alzheimer's disease target and drug discovery by leveraging multiomics and electronic health data. 利用多组学和电子健康数据发现阿尔茨海默病靶点和药物。

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-08 DOI: 10.1038/s41593-026-02472-0

Yuan Hou, Yichen Li, Pengyue Zhang, Noah Lorincz-Comi, Dhruv Gohel, Fan Fan, Yunguang Qiu, Jun Yang, Xin Chen, Wenqiang Song, Xiaoyu Yang, Zhibing Tan, Zhigang Liu, Xing Fang, Isabela Rivera Paz, William Martin, Yayan Feng, Yadi Zhou, Jielin Xu, Lijun Dou, Jane Border, Huawei Zhang, Jena' N Mazique, Sung Hee Hwang, Richard J Roman, Tousi Babak, Lynn Bekris, Ehud Karavani, Michael Danziger, Michal Rosen-Zvi, Jonathan L Haines, Haiyuan Yu, Bruce D Hammock, James B Leverenz, Andrew A Pieper, Jeffrey Cummings, Feixiong Cheng

{"title":"Alzheimer's disease target and drug discovery by leveraging multiomics and electronic health data.","authors":"Yuan Hou, Yichen Li, Pengyue Zhang, Noah Lorincz-Comi, Dhruv Gohel, Fan Fan, Yunguang Qiu, Jun Yang, Xin Chen, Wenqiang Song, Xiaoyu Yang, Zhibing Tan, Zhigang Liu, Xing Fang, Isabela Rivera Paz, William Martin, Yayan Feng, Yadi Zhou, Jielin Xu, Lijun Dou, Jane Border, Huawei Zhang, Jena' N Mazique, Sung Hee Hwang, Richard J Roman, Tousi Babak, Lynn Bekris, Ehud Karavani, Michael Danziger, Michal Rosen-Zvi, Jonathan L Haines, Haiyuan Yu, Bruce D Hammock, James B Leverenz, Andrew A Pieper, Jeffrey Cummings, Feixiong Cheng","doi":"10.1038/s41593-026-02472-0","DOIUrl":"10.1038/s41593-026-02472-0","url":null,"abstract":"Despite prolific genomic data from individuals with Alzheimer's disease (AD), translation into treatments has lagged. Here we applied Mendelian randomization to multiple AD genome-wide association studies and functional multiomics datasets to nominate druggable targets, identifying 19 targets for individuals of European ancestry and 7 for African ancestry. This included epoxide hydrolase 2 (EPHX2), for which we identified a protective missense variant (p.Arg287Gln). Experiments in induced pluripotent stem cell-derived neurons and cerebral organoids from patients with AD validated the protective role of p.Arg287Gln via reduced levels of EPHX2 and phosphorylated tau (pTau-181). Pharmacological inhibition of EPHX2 improved cognitive performance in the 5xFAD mouse model of AD. Finally, by leveraging electronic health data from 111,680 patients with mild cognitive impairment, we identified 12 drugs associated with reduced AD incidence, including trazodone (targeting ADRA1A) and baclofen (targeting GABBR1). Thus, integrating multiomics data, functional validation and electronic health data identifies new approaches for treating AD.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137844","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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Modality-specific reactive and predictive responses in the human superior colliculus 人类上丘的模式特异性反应性和预测性反应

IF 25 1区医学

Nature neuroscience Pub Date : 2026-10-07 DOI: 10.1038/s41593-026-02480-0

Danlei Chen,Maya Barton-Zuckerman,Zoe Kross,Philip A. Kragel,Paul W. Savoca,Lawrence L. Wald,Marta Bianciardi,Tor D. Wager,Ji-Kyung Choi,Jiahe Zhang,Karen S. Quigley,Ajay B. Satpute,Lisa Feldman Barrett,Jordan E. Theriault-Brown

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Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons 星形胶质细胞调节C9ORF72肌萎缩侧索硬化症运动神经元轴突线粒体运输缺陷

IF 25 1区医学

Nature neuroscience Pub Date : 2026-10-07 DOI: 10.1038/s41593-026-02464-0

Maria Stavrou,Áine Bríd Heffernan,Roderick N. Carter,Owen Dando,Zoeb Jiwaji,Karen Burr,Jyoti Nanda,David Villarroel-Campos,Alya Masoud Abdelhafid,Justyna Cholewa-Waclaw,Daniel Soong,David Story,Giampietro Schiavo,Giles E. Hardingham,Siddharthan Chandran,Bhuvaneish T. Selvaraj

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Publisher Correction: A population code for semantics in human hippocampus 出版者更正：人类海马体语义的群体代码

IF 25 1区医学

Nature neuroscience Pub Date : 2026-10-06 DOI: 10.1038/s41593-026-02501-y

Melissa Franch,Elizabeth A. Mickiewicz,James L. Belanger,Brad Joiner,Kalman A. Katlowitz,Hanlin Zhu,Ana G. Chavez,Assia Chericoni,Alica M. Goldman,Vaishnav Krishnan,Atul Maheshwari,Danika L. Paulo,Eleonora Bartoli,Suzanne Kemmer,Steven T. Piantadosi,Nicole R. Provenza,Jay A. Hennig,Sameer A. Sheth,Benjamin Y. Hayden

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Human claustrum neurons encode uncertainty and prediction errors during aversive learning 人类屏状核神经元在厌恶学习过程中编码不确定性和预测错误

IF 25 1区医学

Nature neuroscience Pub Date : 2026-10-06 DOI: 10.1038/s41593-026-02475-x

Mingyue Hu, Rodrigo Dalvit, Mauricio Medina-Pizarro, Maximilian Dougherty, Yajun Zhou, Jonathan Barreto-Nieves, Sami Obaid, Arman Afrasiyabi, Smita Krishnaswamy, Alfred P. Kaye, Murat Günel, John H. Krystal, Kevin N. Sheth, Xiaosi Gu, Christopher P. Pittenger, Toby Wise, Eyiyemisi C. Damisah

{"title":"Human claustrum neurons encode uncertainty and prediction errors during aversive learning","authors":"Mingyue Hu, Rodrigo Dalvit, Mauricio Medina-Pizarro, Maximilian Dougherty, Yajun Zhou, Jonathan Barreto-Nieves, Sami Obaid, Arman Afrasiyabi, Smita Krishnaswamy, Alfred P. Kaye, Murat Günel, John H. Krystal, Kevin N. Sheth, Xiaosi Gu, Christopher P. Pittenger, Toby Wise, Eyiyemisi C. Damisah","doi":"10.1038/s41593-026-02475-x","DOIUrl":"https://doi.org/10.1038/s41593-026-02475-x","url":null,"abstract":"Flexible behavior depends on continuous updating of internal models, yet the neural circuits coordinating this process remain poorly understood. The claustrum, which is reciprocally connected to nearly the entire neocortex, is uniquely positioned to influence cortical processing. Here we report single-neuron recordings from the human claustrum during aversive learning, with anterior cingulate cortex and amygdala recordings for comparison. Claustrum and anterior cingulate neurons displayed structured, task-related responses. Distinct subpopulations encoded stimulus onset and action-contingent outcomes, with outcome representations diverging between regions. Critically, both regions encoded model-derived latent variables, including uncertainty and prediction error, but with different temporal profiles; only the anterior cingulate carried uncertainty signals during the intertrial period, whereas both regions encoded uncertainty and prediction error during the active-avoidance period. By contrast, the amygdala showed minimal latent-variable modulation. These findings provide evidence that human claustrum neurons track higher-order cognitive variables not directly observable from sensory input and reveal dissociable roles for the claustrum and anterior cingulate cortex in tracking latent task states.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"45 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087841","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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Glioblastoma treatment gels 胶质母细胞瘤治疗凝胶

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-02 DOI: 10.1038/s41593-026-02479-7

Shari Wiseman

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Brain stimulation boosts CSF flow 脑刺激促进脑脊液流动

IF 20.3 1区医学

Nature neuroscience Pub Date : 2026-10-01 DOI: 10.1038/s41593-026-02477-9

Ioana A. Marin

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In conversation with Richard Andersen 在与理查德·安德森的谈话中