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Human CLOCK enhances neocortical function 人体时钟增强新皮层功能
IF 25 1区 医学
Nature neuroscience Pub Date : 2025-06-30 DOI: 10.1038/s41593-025-01993-4
Yuxiang Liu, Miles R. Fontenot, Ashwinikumar Kulkarni, Nitin Khandelwal, Seon Hye E. Voth Park, Connor Criswell, Matthew Harper, Pin Xu, Nisha Gupta, Jay R. Gibson, Joseph S. Takahashi, Genevieve Konopka
{"title":"Human CLOCK enhances neocortical function","authors":"Yuxiang Liu, Miles R. Fontenot, Ashwinikumar Kulkarni, Nitin Khandelwal, Seon Hye E. Voth Park, Connor Criswell, Matthew Harper, Pin Xu, Nisha Gupta, Jay R. Gibson, Joseph S. Takahashi, Genevieve Konopka","doi":"10.1038/s41593-025-01993-4","DOIUrl":"https://doi.org/10.1038/s41593-025-01993-4","url":null,"abstract":"<p>The transcription factor CLOCK is ubiquitously expressed and important for circadian rhythms, while its human-specific expression in neocortex suggests additional functions. Here, we generated a mouse model (HU) that recapitulates human cortical expression of CLOCK. The HU mice show enhanced cognitive flexibility, which might be associated with alteration in spatiotemporal expression of CLOCK. Cell-type-specific genomic profiling identified upregulated genes related to dendritic growth and spine formation in excitatory neurons of HU mice. We also found that excitatory neurons in HU mice have increased dendritic complexity and spine density, and a greater frequency of excitatory postsynaptic currents, suggesting a greater abundance of neural connectivity. In contrast, CLOCK knockout in human induced pluripotent stem cell-derived neurons showed reduced complexity of dendrites and lower density of presynaptic puncta. Together, our data demonstrate that CLOCK might have evolved brain-relevant gains of function via altered spatiotemporal gene expression and that these functions may underlie human brain specializations.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"36 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515426","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
Fine-mapping genomic loci refines bipolar disorder risk genes 精细定位基因组位点细化双相情感障碍风险基因
IF 25 1区 医学
Nature neuroscience Pub Date : 2025-06-25 DOI: 10.1038/s41593-025-01998-z
Maria Koromina, Ashvin Ravi, Georgia Panagiotaropoulou, Brian M. Schilder, Jack Humphrey, Alice Braun, Tim Bidgeli, Chris Chatzinakos, Brandon J. Coombes, Jaeyoung Kim, Xiaoxi Liu, Chikashi Terao, Kevin S. O’Connell, Mark J. Adams, Rolf Adolfsson, Martin Alda, Lars Alfredsson, Till F. M. Andlauer, Ole A. Andreassen, Anastasia Antoniou, Bernhard T. Baune, Susanne Bengesser, Joanna Biernacka, Michael Boehnke, Rosa Bosch, Murray J. Cairns, Vaughan J. Carr, Miquel Casas, Stanley Catts, Sven Cichon, Aiden Corvin, Nicholas Craddock, Konstantinos Dafnas, Nina Dalkner, Udo Dannlowski, Franziska Degenhardt, Arianna Di Florio, Dimitris Dikeos, Frederike Tabea Fellendorf, Panagiotis Ferentinos, Andreas J. Forstner, Liz Forty, Mark Frye, Janice M. Fullerton, Micha Gawlik, Ian R. Gizer, Katherine Gordon-Smith, Melissa J. Green, Maria Grigoroiu-Serbanescu, José Guzman-Parra, Tim Hahn, Frans Henskens, Jan Hillert, Assen V. Jablensky, Lisa Jones, Ian Jones, Lina Jonsson, John R. Kelsoe, Tilo Kircher, George Kirov, Sarah Kittel-Schneider, Manolis Kogevinas, Mikael Landén, Marion Leboyer, Melanie Lenger, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Donald J. MacIntyre, Nicholas G. Martin, Eirini Maratou, Carol A. Mathews, Fermin Mayoral, Susan L. McElroy, Nathaniel W. McGregor, Andrew McIntosh, Andrew McQuillin, Patricia Michie, Philip B. Mitchell, Paraskevi Moutsatsou, Bryan Mowry, Bertram Müller-Myhsok, Richard M. Myers, Igor Nenadić, Caroline M. Nievergelt, Markus M. Nöthen, John Nurnberger, Michael O. ’Donovan, Claire O. ’Donovan, Roel A. Ophoff, Michael J. Owen, Christos Pantelis, Carlos Pato, Michele T. Pato, George P. Patrinos, Joanna M. Pawlak, Roy H. Perlis, Evgenia Porichi, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z. Reininghaus, Marta Ribasés, Marcella Rietschel, Ulrich Schall, Peter R. Schofield, Thomas G. Schulze, Laura Scott, Rodney J. Scott, Alessandro Serretti, Jordan W. Smoller, Beata Świątkowska, Maria Soler Artigas, Dan J. Stein, Fabian Streit, Claudio Toma, Paul Tooney, Marquis P. Vawter, Eduard Vieta, John B. Vincent, Irwin D. Waldman, Cynthia Shannon Weickert, Thomas Weickert, Stephanie H. Witt, Kyung Sue Hong, Masashi Ikeda, Nakao Iwata, Hong-Hee Won, Howard J. Edenberg, Stephan Ripke, Towfique Raj, Jonathan R. I. Coleman, Niamh Mullins
{"title":"Fine-mapping genomic loci refines bipolar disorder risk genes","authors":"Maria Koromina, Ashvin Ravi, Georgia Panagiotaropoulou, Brian M. Schilder, Jack Humphrey, Alice Braun, Tim Bidgeli, Chris Chatzinakos, Brandon J. Coombes, Jaeyoung Kim, Xiaoxi Liu, Chikashi Terao, Kevin S. O’Connell, Mark J. Adams, Rolf Adolfsson, Martin Alda, Lars Alfredsson, Till F. M. Andlauer, Ole A. Andreassen, Anastasia Antoniou, Bernhard T. Baune, Susanne Bengesser, Joanna Biernacka, Michael Boehnke, Rosa Bosch, Murray J. Cairns, Vaughan J. Carr, Miquel Casas, Stanley Catts, Sven Cichon, Aiden Corvin, Nicholas Craddock, Konstantinos Dafnas, Nina Dalkner, Udo Dannlowski, Franziska Degenhardt, Arianna Di Florio, Dimitris Dikeos, Frederike Tabea Fellendorf, Panagiotis Ferentinos, Andreas J. Forstner, Liz Forty, Mark Frye, Janice M. Fullerton, Micha Gawlik, Ian R. Gizer, Katherine Gordon-Smith, Melissa J. Green, Maria Grigoroiu-Serbanescu, José Guzman-Parra, Tim Hahn, Frans Henskens, Jan Hillert, Assen V. Jablensky, Lisa Jones, Ian Jones, Lina Jonsson, John R. Kelsoe, Tilo Kircher, George Kirov, Sarah Kittel-Schneider, Manolis Kogevinas, Mikael Landén, Marion Leboyer, Melanie Lenger, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Donald J. MacIntyre, Nicholas G. Martin, Eirini Maratou, Carol A. Mathews, Fermin Mayoral, Susan L. McElroy, Nathaniel W. McGregor, Andrew McIntosh, Andrew McQuillin, Patricia Michie, Philip B. Mitchell, Paraskevi Moutsatsou, Bryan Mowry, Bertram Müller-Myhsok, Richard M. Myers, Igor Nenadić, Caroline M. Nievergelt, Markus M. Nöthen, John Nurnberger, Michael O. ’Donovan, Claire O. ’Donovan, Roel A. Ophoff, Michael J. Owen, Christos Pantelis, Carlos Pato, Michele T. Pato, George P. Patrinos, Joanna M. Pawlak, Roy H. Perlis, Evgenia Porichi, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z. Reininghaus, Marta Ribasés, Marcella Rietschel, Ulrich Schall, Peter R. Schofield, Thomas G. Schulze, Laura Scott, Rodney J. Scott, Alessandro Serretti, Jordan W. Smoller, Beata Świątkowska, Maria Soler Artigas, Dan J. Stein, Fabian Streit, Claudio Toma, Paul Tooney, Marquis P. Vawter, Eduard Vieta, John B. Vincent, Irwin D. Waldman, Cynthia Shannon Weickert, Thomas Weickert, Stephanie H. Witt, Kyung Sue Hong, Masashi Ikeda, Nakao Iwata, Hong-Hee Won, Howard J. Edenberg, Stephan Ripke, Towfique Raj, Jonathan R. I. Coleman, Niamh Mullins","doi":"10.1038/s41593-025-01998-z","DOIUrl":"https://doi.org/10.1038/s41593-025-01998-z","url":null,"abstract":"<p>Bipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder. We mapped these SNPs to genes and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci and results from rare variant exome sequencing in bipolar disorder. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment, including <i>SCN2A</i>, <i>TRANK1</i>, <i>DCLK3</i>, <i>INSYN2B</i>, <i>SYNE1</i>, <i>THSD7A</i>, <i>CACNA1B</i>, <i>TUBBP5</i>, <i>FKBP2</i>, <i>RASGRP1</i>, <i>FURIN</i>, <i>FES</i>, <i>MED24</i> and <i>THRA</i> among others in bipolar disorder. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of bipolar disorder polygenic risk scores across diverse populations and present a high-throughput fine-mapping pipeline.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"270 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478967","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
Large-scale high-density brain-wide neural recording in nonhuman primates 非人类灵长类动物的大规模高密度全脑神经记录
IF 25 1区 医学
Nature neuroscience Pub Date : 2025-06-23 DOI: 10.1038/s41593-025-01976-5
Eric M. Trautmann, Janis K. Hesse, Gabriel M. Stine, Ruobing Xia, Shude Zhu, Daniel J. O’Shea, Bill Karsh, Jennifer Colonell, Frank F. Lanfranchi, Saurabh Vyas, Andrew Zimnik, Elom Amematsro, Natalie A. Steinemann, Daniel A. Wagenaar, Marius Pachitariu, Alexandru Andrei, Carolina Mora Lopez, John O’Callaghan, Jan Putzeys, Bogdan C. Raducanu, Marleen Welkenhuysen, Mark Churchland, Tirin Moore, Michael Shadlen, Krishna Shenoy, Doris Tsao, Barundeb Dutta, Timothy Harris
{"title":"Large-scale high-density brain-wide neural recording in nonhuman primates","authors":"Eric M. Trautmann, Janis K. Hesse, Gabriel M. Stine, Ruobing Xia, Shude Zhu, Daniel J. O’Shea, Bill Karsh, Jennifer Colonell, Frank F. Lanfranchi, Saurabh Vyas, Andrew Zimnik, Elom Amematsro, Natalie A. Steinemann, Daniel A. Wagenaar, Marius Pachitariu, Alexandru Andrei, Carolina Mora Lopez, John O’Callaghan, Jan Putzeys, Bogdan C. Raducanu, Marleen Welkenhuysen, Mark Churchland, Tirin Moore, Michael Shadlen, Krishna Shenoy, Doris Tsao, Barundeb Dutta, Timothy Harris","doi":"10.1038/s41593-025-01976-5","DOIUrl":"https://doi.org/10.1038/s41593-025-01976-5","url":null,"abstract":"<p>High-density silicon probes have transformed neuroscience by enabling large-scale neural recordings at single-cell resolution. However, existing technologies have provided limited functionality in nonhuman primates (NHPs) such as macaques. In the present report, we describe the design, fabrication and performance of Neuropixels 1.0 NHP, a high-channel electrode array designed to enable large-scale acute recording throughout large animal brains. The probe features 4,416 recording sites distributed along a 45-mm shank. Experimenters can programmably select 384 recording channels, enabling simultaneous multi-area recording from thousands of neurons with single or multiple probes. This technology substantially increases scalability and recording access relative to existing technologies and enables new classes of experiments that involve electrophysiological mapping of brain areas at single-neuron and single-spike resolution, measurement of spike–spike correlations between cells and simultaneous brain-wide recordings at scale.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"4 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144341178","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
Closed-loop electrical stimulation prevents focal epilepsy progression and long-term memory impairment 闭环电刺激可预防局灶性癫痫进展和长期记忆障碍
IF 25 1区 医学
Nature neuroscience Pub Date : 2025-06-23 DOI: 10.1038/s41593-025-01988-1
Jose J. Ferrero, Ahnaf R. Hassan, Zelin Yu, Zifang Zhao, Liang Ma, Cynthia Wu, Shan Shao, Takeshi Kawano, Judah Engel, Werner Doyle, Orrin Devinsky, Dion Khodagholy, Jennifer N. Gelinas
{"title":"Closed-loop electrical stimulation prevents focal epilepsy progression and long-term memory impairment","authors":"Jose J. Ferrero, Ahnaf R. Hassan, Zelin Yu, Zifang Zhao, Liang Ma, Cynthia Wu, Shan Shao, Takeshi Kawano, Judah Engel, Werner Doyle, Orrin Devinsky, Dion Khodagholy, Jennifer N. Gelinas","doi":"10.1038/s41593-025-01988-1","DOIUrl":"https://doi.org/10.1038/s41593-025-01988-1","url":null,"abstract":"<p>Interictal epileptiform discharges (IEDs) are expressed in epileptic networks and disrupt cognitive functions. It is unclear whether addressing IED-induced dysfunction could improve epilepsy outcomes, as most therapeutic approaches target seizures. We show, in a kindling model of progressive focal epilepsy, that IEDs produce pathological oscillatory coupling associated with prolonged, hypersynchronous neural spiking in synaptically connected cortex and expand the brain territory capable of generating IEDs. A similar relationship between IED-mediated oscillatory coupling and temporal organization of IEDs across brain regions was identified in human participants with refractory focal epilepsy. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing the spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. These findings suggest that stimulation-based network interventions that normalize interictal dynamics may be an effective treatment of epilepsy and its comorbidities, with a low barrier to clinical translation.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"19 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144341290","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
Heat shock proteins function as signaling molecules to mediate neuron–glia communication in C. elegans during aging 热休克蛋白作为信号分子介导秀丽隐杆线虫衰老过程中神经元-胶质细胞间的通讯
IF 25 1区 医学
Nature neuroscience Pub Date : 2025-06-18 DOI: 10.1038/s41593-025-01989-0
Jieyu Wu, Victoria R. Yarmey, Olivia Jiaming Yang, Erik J. Soderblom, Adriana San-Miguel, Dong Yan
{"title":"Heat shock proteins function as signaling molecules to mediate neuron–glia communication in C. elegans during aging","authors":"Jieyu Wu, Victoria R. Yarmey, Olivia Jiaming Yang, Erik J. Soderblom, Adriana San-Miguel, Dong Yan","doi":"10.1038/s41593-025-01989-0","DOIUrl":"https://doi.org/10.1038/s41593-025-01989-0","url":null,"abstract":"<p>The nervous system is primarily composed of neurons and glia, and the communication between them has profound roles in regulating the development and function of the brain. Neuron–glia signal transduction is known to be mediated by secreted signals through ligand–receptor interactions on the cell membrane. Here we show a new mechanism for neuron–glia signal transduction, wherein neurons transmit proteins to glia through extracellular vesicles, activating glial signaling pathways. We find that in the amphid sensory organ of <i>Caenorhabditis elegans</i>, different sensory neurons exhibit varying aging rates. This discrepancy in aging is governed by the cross-talk between neurons and glia. We demonstrate that early aged neurons can transmit heat shock proteins to glia via extracellular vesicles. These neuronal heat shock proteins activate the glial IRE1–XBP1 pathway, leading to the transcriptional regulation of chondroitin synthases to protect glia-embedded neurons from aging-associated functional decline. Therefore, our studies unveil a new mechanism for neuron–glia communication in the nervous system and provide new insights into our understanding of brain aging.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"93 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312249","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
Challenges of the inconsistent neurorights framework in Latin America 拉丁美洲不一致的神经权利框架的挑战
IF 25 1区 医学
Nature neuroscience Pub Date : 2025-06-18 DOI: 10.1038/s41593-025-02001-5
Diego Borbón
{"title":"Challenges of the inconsistent neurorights framework in Latin America","authors":"Diego Borbón","doi":"10.1038/s41593-025-02001-5","DOIUrl":"https://doi.org/10.1038/s41593-025-02001-5","url":null,"abstract":"<p>The integration of neurotechnology into society has prompted urgent discussions on neurorights (new lists of human rights to regulate neurotechnology) and has led to varied legislative responses across the region that leads this debate: Latin America. Although some countries have responded by pursuing constitutional amendments, others have proposed varied legal reforms, adopted different principles or adopted non-binding soft-law approaches, such as recommendations and guidelines. This diversity of responses has resulted in a fragmented landscape of neurorights protections that poses challenges for regional coherence. This Comment briefly discusses the divergent strategies of Latin American countries for integrating neurorights into their respective legal frameworks, highlighting inconsistencies and proposing ways to navigate these complexities alongside informed scholarship.</p><p>Neurorights have emerged as ethical necessities in response to advanced neurotechnology, with varied propositions by leading scholars. Marcello Ienca and Roberto Andorno in 2017 defined four key neurorights: cognitive liberty, mental privacy, mental integrity, and psychological continuity<sup>1</sup>, each designed to protect individuals from unethical uses of neurotechnology. Concurrently, the Neurorights Foundation led by Rafael Yuste emphasized the importance of creating novel neurorights to mental privacy, personal identity, free will, equitable access to cognitive augmentation, and bias protection (https://neurorightsfoundation.org/mission). These new rights aim to address ethical issues by setting regulatory and protective standards to govern the application of emerging neurotechnologies<sup>2</sup>.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"26 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311939","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
Myelin–axon interface vulnerability in Alzheimer’s disease revealed by subcellular proteomics and imaging of human and mouse brain 亚细胞蛋白质组学和人和小鼠脑成像揭示阿尔茨海默病髓磷脂-轴突界面易感性
IF 25 1区 医学
Nature neuroscience Pub Date : 2025-06-13 DOI: 10.1038/s41593-025-01973-8
Yifei Cai, Iguaracy Pinheiro-de-Sousa, Mykhaylo Slobodyanyuk, Fuyi Chen, Tram Huynh, Jean Kanyo, Peiyang Tang, Lukas A. Fuentes, Amber Braker, Rachel Welch, Anita Huttner, Lei Tong, Peng Yuan, TuKiet T. Lam, Evangelia Petsalaki, Jüri Reimand, Angus C. Nairn, Jaime Grutzendler
{"title":"Myelin–axon interface vulnerability in Alzheimer’s disease revealed by subcellular proteomics and imaging of human and mouse brain","authors":"Yifei Cai, Iguaracy Pinheiro-de-Sousa, Mykhaylo Slobodyanyuk, Fuyi Chen, Tram Huynh, Jean Kanyo, Peiyang Tang, Lukas A. Fuentes, Amber Braker, Rachel Welch, Anita Huttner, Lei Tong, Peng Yuan, TuKiet T. Lam, Evangelia Petsalaki, Jüri Reimand, Angus C. Nairn, Jaime Grutzendler","doi":"10.1038/s41593-025-01973-8","DOIUrl":"https://doi.org/10.1038/s41593-025-01973-8","url":null,"abstract":"<p>Myelin ensheathment is essential for rapid axonal conduction, metabolic support and neuronal plasticity. In Alzheimer’s disease (AD), disruptions in myelin and axonal structures occur, although the underlying mechanisms remain unclear. We implemented proximity labeling subcellular proteomics of the myelin–axon interface in postmortem human brains from AD donors and 15-month-old male and female 5XFAD mice. We uncovered multiple dysregulated signaling pathways and ligand–receptor interactions, including those linked to amyloid-β processing, axonal outgrowth and lipid metabolism. Expansion microscopy confirmed the subcellular localization of top proteomic hits and revealed amyloid-β aggregation within the internodal periaxonal space and paranodal/juxtaparanodal channels. Although overall myelin coverage is preserved, we found reduced paranode density, aberrant myelination and altered paranode positioning around amyloid-plaque-associated dystrophic axons. These findings suggest that the myelin–axon interface is a critical site of protein aggregation and disrupted neuro-glial signaling in AD.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"53 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278506","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
The brain works at more than 10 bits per second 大脑的工作速度超过每秒10比特
IF 25 1区 医学
Nature neuroscience Pub Date : 2025-06-13 DOI: 10.1038/s41593-025-01997-0
Britton A. Sauerbrei, J. Andrew Pruszynski
{"title":"The brain works at more than 10 bits per second","authors":"Britton A. Sauerbrei, J. Andrew Pruszynski","doi":"10.1038/s41593-025-01997-0","DOIUrl":"https://doi.org/10.1038/s41593-025-01997-0","url":null,"abstract":"A recent article makes a claim with far-reaching implications for neuroscience, technology, and society: that the human brain is subject to an information processing ‘speed limit’ of 10 bits per second. Although this speed limit appears to hold for high-level cognitive functions, we argue that unconscious processing for real-time control of movement, which occupies a majority of neurons in the central nervous system and accounts for most of the information throughput of humans, substantially exceeds this limit.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"22 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279001","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
Protective exercise responses in the dentate gyrus of Alzheimer’s disease mouse model revealed with single-nucleus RNA-sequencing 单核rna测序揭示阿尔茨海默病小鼠齿状回的保护性运动反应
IF 25 1区 医学
Nature neuroscience Pub Date : 2025-06-12 DOI: 10.1038/s41593-025-01971-w
Joana F. da Rocha, Michelle L. Lance, Renhao Luo, Pius Schlachter, Luis Moreira, Mohamed Ariff Iqbal, Paula Kuhn, Robert S. Gardner, Sophia Valaris, Mohammad R. Islam, Gabriele M. Gassner, Sofia Mazuera, Kaela Healy, Sanjana Shastri, Nathaniel B. Hibbert, Kristen V. Moran-Figueroa, Erin B. Haley, Ryan D. Pfeiffer, Sema Aygar, Ksenia V. Kastanenka, Logan Brase, Oscar Harari, Bruno A. Benitez, Nathan R. Tucker, Christiane D. Wrann
{"title":"Protective exercise responses in the dentate gyrus of Alzheimer’s disease mouse model revealed with single-nucleus RNA-sequencing","authors":"Joana F. da Rocha, Michelle L. Lance, Renhao Luo, Pius Schlachter, Luis Moreira, Mohamed Ariff Iqbal, Paula Kuhn, Robert S. Gardner, Sophia Valaris, Mohammad R. Islam, Gabriele M. Gassner, Sofia Mazuera, Kaela Healy, Sanjana Shastri, Nathaniel B. Hibbert, Kristen V. Moran-Figueroa, Erin B. Haley, Ryan D. Pfeiffer, Sema Aygar, Ksenia V. Kastanenka, Logan Brase, Oscar Harari, Bruno A. Benitez, Nathan R. Tucker, Christiane D. Wrann","doi":"10.1038/s41593-025-01971-w","DOIUrl":"https://doi.org/10.1038/s41593-025-01971-w","url":null,"abstract":"<p>Exercise’s protective effects in Alzheimer’s disease (AD) are well recognized, but cell-specific contributions to this phenomenon remain unclear. Here we used single-nucleus RNA sequencing (snRNA-seq) to dissect the response to exercise (free-wheel running) in the neurogenic stem-cell niche of the hippocampal dentate gyrus in male APP/PS1 transgenic AD model mice. Transcriptomic responses to exercise were distinct between wild-type and AD mice, and most prominent in immature neurons. Exercise restored the transcriptional profiles of a proportion of AD-dysregulated genes in a cell type-specific manner. We identified a neurovascular-associated astrocyte subpopulation, the abundance of which was reduced in AD, whereas its gene expression signature was induced with exercise. Exercise also enhanced the gene expression profile of disease-associated microglia. Oligodendrocyte progenitor cells were the cell type with the highest proportion of dysregulated genes recovered by exercise. Last, we validated our key findings in a human AD snRNA-seq dataset. Together, these data present a comprehensive resource for understanding the molecular mediators of neuroprotection by exercise in AD.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"90 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268647","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 flexible hippocampal population code for experience relative to reward 一个灵活的海马体群体编码相对于奖励的经验
IF 25 1区 医学
Nature neuroscience Pub Date : 2025-06-11 DOI: 10.1038/s41593-025-01985-4
Marielena Sosa, Mark H. Plitt, Lisa M. Giocomo
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