Nature neuroscience最新文献

{"title":"Neuromodulation for restoring and amplifying brain function.","authors":"Shrey Grover, Wen Wen, Robert M G Reinhart","doi":"10.1038/s41593-026-02434-6","DOIUrl":"https://doi.org/10.1038/s41593-026-02434-6","url":null,"abstract":"<p><p>Neuromodulation aims to improve brain function by altering neural activity. While many rehabilitation strategies seek to restore normal, healthy-like dynamics, some adopt a complementary strategy, using neuromodulation to strengthen repurposed processes that support function. Here we formalize these approaches as 'restorative normalization' (RN) and 'compensatory amplification' (CA), respectively. Drawing on cognitive neurophysiology, we evaluate the following four factors that enable CA to be effective: multiple realizability, multiscale neuroplasticity, precision readiness and activity selectivity. We analyze the interplay between RN and CA across clinical goals, such as stroke rehabilitation, and identify opportunities in neurodegeneration, psychiatry and aging where CA could delay decline, facilitate remission or increase neural processing capacity. We propose that positioning CA alongside RN as a core design principle can sharpen target selection, guide stratified treatments and translate known compensatory signatures into testable neuromodulation protocols.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892176","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}

{"title":"Author Correction: 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/s41593-026-02463-1","DOIUrl":"https://doi.org/10.1038/s41593-026-02463-1","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892201","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}

{"title":"Neural geometry guides learning.","authors":"Aaron P Batista","doi":"10.1038/s41593-026-02442-6","DOIUrl":"https://doi.org/10.1038/s41593-026-02442-6","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892174","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}

{"title":"Structured experience shapes strategy learning and neural dynamics in the medial entorhinal cortex.","authors":"John C Bowler, Dua B Azhar, Cambria M Jensen, Hyun-Woo Lee, James G Heys","doi":"10.1038/s41593-026-02409-7","DOIUrl":"https://doi.org/10.1038/s41593-026-02409-7","url":null,"abstract":"<p><p>Animals solve new, complex tasks by reusing and adapting prior knowledge. This flexibility depends not only on the content of experience but also on its structure. Early training curricula are especially important: poorly structured experiences can hinder abstraction and limit generalization. However, the neural mechanisms through which experience shapes future learning remain unclear. Here, we trained recurrent neural networks (RNNs) on an odor timing task used to study complex timing behavior in mice and then tested the model predictions with mouse behavior and medial entorhinal cortex recordings. Without structured early experience, both RNNs and mice developed rigid, error-prone strategies, whereas structured training promoted neural activity reflecting the task's temporal structure. Using dynamical systems analysis, we examined how different training curricula shaped network dynamics and whether these dynamics supported abstraction and generalization as task complexity increased. These findings demonstrate that the structure of prior experience governs how flexible, generalizable knowledge emerges in biological systems and computational models.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888249","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}

{"title":"Priming of CD8⁺ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration.","authors":"Hao Hu, Peter Bor-Chian Lin, Carisa Zeng, Yongyi Li, Megan E Bosch, Joshua T Emmerson, Prabal Sharma, Ray A Ohara, Wendy Dong, Tong Wu, Siling Du, Wenqing Gao, Hong Jiang, Liya Yuan, Xin Bao, Shasha Li, Anthony N Vomund, Petra Erdmann-Gilmore, Yichen Gu, Miwei Hu, Jonathan Nulman, Timothy M Miller, Wayne M Yokoyama, Cheryl F Lichti, Jeffrey Milbrandt, Richard J Perrin, Jonathan Kipnis, Maxim N Artyomov, Kenneth M Murphy, Jason D Ulrich, David M Holtzman","doi":"10.1038/s41593-026-02427-5","DOIUrl":"https://doi.org/10.1038/s41593-026-02427-5","url":null,"abstract":"<p><p>Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8⁺ T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8⁺ T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8⁺ T cell infiltration and glial activation. The remaining CD8⁺ T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8⁺ T cell accumulation in the brain and tau-mediated neurodegeneration.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888262","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}

{"title":"Glutamate concentration tunes AMPA receptor function through conductance-state occupancy.","authors":"Gokulakrishna Banumurthy, Reagan L Pennock, Luke T Coddington, Xiaohui Yan, Gabrielle N Smith, Linda Overstreet-Wadiche, Jacques I Wadiche","doi":"10.1038/s41593-026-02414-w","DOIUrl":"https://doi.org/10.1038/s41593-026-02414-w","url":null,"abstract":"<p><p>α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate excitatory synaptic transmission across the brain and exhibit distinct modes of opening depending on how much glutamate is bound. Despite extensive work on AMPAR conductance states and subunit composition, whether changes in glutamate levels at and around synapses regulate AMPAR function is unknown. Here we show that glutamate concentration ([glutamate]) at mouse interneuron synapses governs key biophysical features of AMPARs that are commonly used to infer subunit composition. Lower [glutamate] reduces hallmark AMPAR properties, including current-voltage rectification, polyamine block and Ca²⁺ permeability, highlighting a strong dependence of receptor function on synaptic [glutamate]. Recordings from isolated AMPARs combined with numerical simulations reveal differential spermine affinity across distinct conductance states and establish [glutamate], rather than solely subunit composition, as a key determinant of receptor behavior. These findings uncover a previously unrecognized mechanism through which the synaptic glutamate landscape dynamically shapes AMPAR signaling, broadening the framework for how excitatory input is encoded within neural circuits.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880928","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}

{"title":"Mitochondrial calcium influx-driven bioenergetics selectively enable drug addiction.","authors":"Jun Gao, Haixin Zhao, Xiao Han, Lingmin Zeng, Jingqi Pan, Guangqin Liu, Xuechen Wei, Changwei Liu, Wenjun Wu, Siqi Chen, Jiayi Chen, Ting Li, Jiye Yin, Tao Zhou, Xue-Min Zhang, Ai-Ling Li, Teng Li, Xin Pan","doi":"10.1038/s41593-026-02421-x","DOIUrl":"https://doi.org/10.1038/s41593-026-02421-x","url":null,"abstract":"<p><p>Addictive substances hijack the brain's reward system, driving pathological dopamine surges that underlie compulsive behavior and addiction. However, directly targeting dopamine signaling for treatment risks disrupting natural reward processes. Here we identify a bioenergetic mechanism that selectively promotes addiction-related dopamine release and behaviors. Opioids and methamphetamine, but not natural rewards, induce mitochondrial calcium (Ca²⁺) influx via the mitochondrial calcium uniporter (MCU) in dopaminergic terminals of the nucleus accumbens. Optogenetic stimulation reveals that this mitochondrial Ca²⁺ influx occurs exclusively during high-intensity dopaminergic neuronal activation. This Ca²⁺ influx drives rapid ATP production, compensating for energy deficits caused by neuronal hyperactivity and enabling sustained dopamine release. Genetic deletion or pharmacological inhibition of MCU in dopaminergic neurons selectively reduces drug-induced dopamine release and prevents addictive behaviors while sparing natural reward processing. These findings uncover a distinct mitochondrial bioenergetic mechanism underlying drug reward and propose MCU as a therapeutic target for addiction treatment.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881144","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}

{"title":"Stressing out astrocyte cilia","authors":"Leonie Welberg","doi":"10.1038/s41593-026-02441-7","DOIUrl":"10.1038/s41593-026-02441-7","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 9","pages":"2056-2056"},"PeriodicalIF":20.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872198","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}

{"title":"Whole-exome sequencing in individuals with obsessive-compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes.","authors":"Belinda Wang, Matthew N Tran, Sheng Wang, Yuting Liu, Emily Olfson, George Wang, Nawei Sun, Jeanselle Dea, Charles Ochieng' Olwal, Lyvia Bertolace, Michael H Bloch, Carolina Cappi, Yi-Chieh Chang, Denise Chavira, Barbara J Coffey, Martha J Falkenstein, Adam C Frank, Martin E Franklin, Stephanie Garayalde, Helena Garrido, Marco Grados, Rami Hatem, Allyna-London Howell, Starlette Khim, Jennie M Kuckertz, Mindy M Le, Allison Libby, Ryan J McCarty, Mary E McNamara, Daniel McNeil, Euripedes C Miguel, Cara Nasello, Binh Nguyen, Tenzin Norbu, Lauren Oh, Ashley Ordway, Catherine Paciotti, Viviana A Peskin, Christopher Pittenger, Helen Blair Simpson, Heather Simpson Martin, Max A Tischfield, Jinchuan Xing, Jessica J Zakrzewski, Andrea Dietrich, Donald L Gilbert, Pieter J Hoekstra, Young Shin Kim, Samuel Kuperman, Alyssa Rosen, Samuel H Zinner, Mehdi Bouhaddou, Robert A King, Guy Rouleau, Kerry J Ressler, Carol A Mathews, Nevan J Krogan, Nenad Sestan, Jay A Tischfield, A Moses Lee, Gary A Heiman, Thomas V Fernandez, A Jeremy Willsey, Matthew W State","doi":"10.1038/s41593-026-02419-5","DOIUrl":"https://doi.org/10.1038/s41593-026-02419-5","url":null,"abstract":"<p><p>Obsessive-compulsive disorder (OCD) and chronic tic disorders (CTDs) are highly heritable. Rare mutations confer large risks for OCD and CTDs but only four high-confidence (hc) genes have been identified. Here we analyzed whole-exome sequencing data from 3,964 individuals with OCD, CTDs or both, including 2,418 trios. We found an excess in cases of de novo and rare protein-damaging mutations and identified 36 hc genes (false discovery rate < 0.1), including four previously identified hc genes (CELSR3, CHD8, SCUBE1 and WWC1) and four genes that overlap with OCD genome-wide association study loci (BRWD1, CELSR3, QRICH1 and SYNE1). Risk genes are shared among OCD, CTDs and other neurodevelopmental conditions. Transcriptomic and network analyses highlight mechanistic convergence and increased risk gene expression in postnatal cerebellum, prenatal and postnatal cortex and striatum. Dozens of large-effect OCD and CTD genes offer insights into pathogenesis and a path forward for illuminating pathophysiology and identifying novel treatment targets.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875490","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}

{"title":"State-dependent signal flow hierarchy in the human cerebral cortex.","authors":"Younghyun Oh, Yejin Ann, Jae-Joong Lee, Takuya Ito, Sean Froudist-Walsh, Casey Paquola, Michael Milham, R Nathan Spreng, Daniel Margulies, Boris Bernhardt, Choong-Wan Woo, Seok-Jun Hong","doi":"10.1038/s41593-026-02389-8","DOIUrl":"https://doi.org/10.1038/s41593-026-02389-8","url":null,"abstract":"<p><p>Understanding how information flows across distributed brain networks is central to linking brain structure, dynamics and function. Here we present a neuroimaging framework that combines integrated effective connectivity (iEC) and unconstrained signal flow mapping for data-driven identification of human cerebral functional hierarchies. Simulations and empirical validation show that iEC recovers connectome directionality and aligns with histologically defined feedforward and feedback pathways. The iEC-derived hierarchy exhibits a monotonically increasing level along the axis where the sensorimotor, association and paralimbic areas are sequentially ordered, consistent with predictions from the structural model of laminar connectivity. This hierarchy is not fixed but flexibly reorganizes across brain states; it becomes flatter during externally oriented processing and steeper during internally focused conditions, reflecting increased engagement of interoceptive regions. Our study indicates that macroscale directed functional connectivity can reveal biologically grounded, state-dependent principles of signal flow in the human brain.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875463","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}