Pub Date : 2025-12-10DOI: 10.1038/s41593-025-02134-7
Henrike Planert, Franz Xaver Mittermaier, Sabine Grosser, Pawel Fidzinski, Ulf Christoph Schneider, Helena Radbruch, Julia Onken, Martin Holtkamp, Dietmar Schmitz, Henrik Alle, Imre Vida, Jörg Rolf Paul Geiger, Yangfan Peng
Understanding the functional principles of the human brain requires deep insight into its neuronal and network physiology. In superficial layers of temporal cortex, molecular and morphological subtypes of glutamatergic excitatory pyramidal neurons have been described, but subtyping based on electrophysiological parameters has not been performed. The extent to which pyramidal neuron subtypes contribute to the specialization of physiological interactions by forming synaptic subnetworks remains unclear. Here we performed whole-cell patch-clamp recordings of more than 1,400 layer 2–3 (L2–3) pyramidal neurons and 1,400 identified monosynaptic connections in acute slices of human temporal cortex. We extract principles of neuronal and synaptic physiology along with anatomy and functional synaptic connectivity. We also show robust classification of pyramidal neurons into four electrophysiological subtypes, corroborated by differences in morphology and decipher subtype-specific synaptic interactions. Principles of microcircuit organization are found to be conserved at the individual level. Such a fine network structure suggests that the functional diversity of pyramidal neurons translates into differential computations within the L2–3 microcircuit of the human cortex.
{"title":"Electrophysiological classification of human layer 2–3 pyramidal neurons reveals subtype-specific synaptic interactions","authors":"Henrike Planert, Franz Xaver Mittermaier, Sabine Grosser, Pawel Fidzinski, Ulf Christoph Schneider, Helena Radbruch, Julia Onken, Martin Holtkamp, Dietmar Schmitz, Henrik Alle, Imre Vida, Jörg Rolf Paul Geiger, Yangfan Peng","doi":"10.1038/s41593-025-02134-7","DOIUrl":"https://doi.org/10.1038/s41593-025-02134-7","url":null,"abstract":"Understanding the functional principles of the human brain requires deep insight into its neuronal and network physiology. In superficial layers of temporal cortex, molecular and morphological subtypes of glutamatergic excitatory pyramidal neurons have been described, but subtyping based on electrophysiological parameters has not been performed. The extent to which pyramidal neuron subtypes contribute to the specialization of physiological interactions by forming synaptic subnetworks remains unclear. Here we performed whole-cell patch-clamp recordings of more than 1,400 layer 2–3 (L2–3) pyramidal neurons and 1,400 identified monosynaptic connections in acute slices of human temporal cortex. We extract principles of neuronal and synaptic physiology along with anatomy and functional synaptic connectivity. We also show robust classification of pyramidal neurons into four electrophysiological subtypes, corroborated by differences in morphology and decipher subtype-specific synaptic interactions. Principles of microcircuit organization are found to be conserved at the individual level. Such a fine network structure suggests that the functional diversity of pyramidal neurons translates into differential computations within the L2–3 microcircuit of the human cortex.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"13 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711552","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}
Pub Date : 2025-12-09DOI: 10.1038/s41593-025-02112-z
Andrew M. Shafik, Yong Peng, Zijie Zhang, Chen Chang, Pingluan Wang, Junghwa Lim, Hongjun Song, Chuan He, Mengjie Chen, Peng Jin
N6-methyladenosine (m6A) is a major RNA modification in the brain, regulating neural processes and contributing to disease mechanisms. Despite its importance, regional, age-specific and sex-specific m6A patterns in the human brain are still poorly described. Here, we profiled m6A mRNA modifications in five human brain regions (Brodmann areas 9 and 24, and the caudate, hippocampus and thalamus) across 25 individuals of different ages, ranging from 0 to 71 years old. We uncovered widespread regional differences for m6A patterns in the brain, notably in disease-risk genes, while age-related changes were most prominent in the prefrontal cortex. Integrating m6A data with whole-genome sequencing revealed that m6A modifications are associated with disease-related genetic loci. Our work identifies the spatial and temporal variation in m6A modifications and suggests how they could contribute to neurological disorders.
{"title":"Multi-region m6A epitranscriptome profiling of the human brain reveals spatial and temporal variation and enrichment of disease-associated loci","authors":"Andrew M. Shafik, Yong Peng, Zijie Zhang, Chen Chang, Pingluan Wang, Junghwa Lim, Hongjun Song, Chuan He, Mengjie Chen, Peng Jin","doi":"10.1038/s41593-025-02112-z","DOIUrl":"https://doi.org/10.1038/s41593-025-02112-z","url":null,"abstract":"N6-methyladenosine (m6A) is a major RNA modification in the brain, regulating neural processes and contributing to disease mechanisms. Despite its importance, regional, age-specific and sex-specific m6A patterns in the human brain are still poorly described. Here, we profiled m6A mRNA modifications in five human brain regions (Brodmann areas 9 and 24, and the caudate, hippocampus and thalamus) across 25 individuals of different ages, ranging from 0 to 71 years old. We uncovered widespread regional differences for m6A patterns in the brain, notably in disease-risk genes, while age-related changes were most prominent in the prefrontal cortex. Integrating m6A data with whole-genome sequencing revealed that m6A modifications are associated with disease-related genetic loci. Our work identifies the spatial and temporal variation in m6A modifications and suggests how they could contribute to neurological disorders.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"5 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705136","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}
Pub Date : 2025-12-08DOI: 10.1038/s41593-025-02127-6
Mingzheng Wu, Yiyuan Yang, Jinglan Zhang, Andrew I Efimov, Xiuyuan Li, Kaiqing Zhang, Yue Wang, Kevin L Bodkin, Mohammad Riahi, Jianyu Gu, Glingna Wang, Minsung Kim, Liangsong Zeng, Jiaqi Liu, Lauren H Yoon, Haohui Zhang, Sara N Freda, Minkyu Lee, Jiheon Kang, Joanna L Ciatti, Kaila Ting, Stephen Cheng, Xincheng Zhang, He Sun, Wenming Zhang, Yi Zhang, Anthony Banks, Cameron H Good, Julia M Cox, Lucas Pinto, Abraham Vázquez-Guardado, Yonggang Huang, Yevgenia Kozorovitskiy, John A Rogers
Synthesizing perceivable artificial neural inputs independent of typical sensory channels remains a fundamental challenge in developing next-generation brain-machine interfaces. Establishing a minimally invasive, wirelessly effective and miniaturized platform with long-term stability is crucial for creating research methods and clinically meaningful biointerfaces capable of mediating artificial perceptual feedback. Here we demonstrate a miniaturized, fully implantable transcranial optogenetic neural stimulator designed to generate artificial perceptions by patterning large cortical ensembles wirelessly in real time. Experimentally validated numerical simulations characterized light and heat propagation, whereas neuronal responses were assessed by in vivo electrophysiology and molecular methods. Cue discrimination during operant learning demonstrated the wireless genesis of artificial percepts sensed by mice, where spatial distance across large cortical networks and sequential order-based analyses of discrimination predicted performance. These conceptual and technical advances expand understanding of artificially patterned neural activity and its perception by the brain to guide the evolution of next-generation all-optical brain-machine communication.
{"title":"Patterned wireless transcranial optogenetics generates artificial perception.","authors":"Mingzheng Wu, Yiyuan Yang, Jinglan Zhang, Andrew I Efimov, Xiuyuan Li, Kaiqing Zhang, Yue Wang, Kevin L Bodkin, Mohammad Riahi, Jianyu Gu, Glingna Wang, Minsung Kim, Liangsong Zeng, Jiaqi Liu, Lauren H Yoon, Haohui Zhang, Sara N Freda, Minkyu Lee, Jiheon Kang, Joanna L Ciatti, Kaila Ting, Stephen Cheng, Xincheng Zhang, He Sun, Wenming Zhang, Yi Zhang, Anthony Banks, Cameron H Good, Julia M Cox, Lucas Pinto, Abraham Vázquez-Guardado, Yonggang Huang, Yevgenia Kozorovitskiy, John A Rogers","doi":"10.1038/s41593-025-02127-6","DOIUrl":"10.1038/s41593-025-02127-6","url":null,"abstract":"<p><p>Synthesizing perceivable artificial neural inputs independent of typical sensory channels remains a fundamental challenge in developing next-generation brain-machine interfaces. Establishing a minimally invasive, wirelessly effective and miniaturized platform with long-term stability is crucial for creating research methods and clinically meaningful biointerfaces capable of mediating artificial perceptual feedback. Here we demonstrate a miniaturized, fully implantable transcranial optogenetic neural stimulator designed to generate artificial perceptions by patterning large cortical ensembles wirelessly in real time. Experimentally validated numerical simulations characterized light and heat propagation, whereas neuronal responses were assessed by in vivo electrophysiology and molecular methods. Cue discrimination during operant learning demonstrated the wireless genesis of artificial percepts sensed by mice, where spatial distance across large cortical networks and sequential order-based analyses of discrimination predicted performance. These conceptual and technical advances expand understanding of artificially patterned neural activity and its perception by the brain to guide the evolution of next-generation all-optical brain-machine communication.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.0,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708672","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}
Pub Date : 2025-12-08DOI: 10.1038/s41593-025-02128-5
Domenico Guarino,Anton Filipchuk,Alain Destexhe
Cortical population events, short-lived patterns of neuronal activity that recur with consistency, are central to sensorimotor coordination. These reproducible firing patterns are often attributed to attractor dynamics, supported by strong mutual connectivity. However, by using multimodal datasets-including two-photon imaging, electrophysiology and electron microscopy-we show that these reproducible patterns do not involve strongly interconnected neurons. Instead, we show that cortical networks exhibit hierarchical modularity, with core neurons serving as high-information-flow nodes at module interfaces. These cores funnel activity but lack the structural signatures of pattern-completion units that are typically found in attractor networks. Using computational models, we find that distance-dependent connectivity is necessary and sufficient to produce the modularity and transient reproducible events observed in cortex. Our findings suggest that cortical networks are preconfigured to support sensorimotor coordination. This work redefines the structural and dynamical basis of cortical activity, with a focus on the relationship between modular structure and function.
{"title":"Convergent information flows explain recurring firing patterns in cerebral cortex.","authors":"Domenico Guarino,Anton Filipchuk,Alain Destexhe","doi":"10.1038/s41593-025-02128-5","DOIUrl":"https://doi.org/10.1038/s41593-025-02128-5","url":null,"abstract":"Cortical population events, short-lived patterns of neuronal activity that recur with consistency, are central to sensorimotor coordination. These reproducible firing patterns are often attributed to attractor dynamics, supported by strong mutual connectivity. However, by using multimodal datasets-including two-photon imaging, electrophysiology and electron microscopy-we show that these reproducible patterns do not involve strongly interconnected neurons. Instead, we show that cortical networks exhibit hierarchical modularity, with core neurons serving as high-information-flow nodes at module interfaces. These cores funnel activity but lack the structural signatures of pattern-completion units that are typically found in attractor networks. Using computational models, we find that distance-dependent connectivity is necessary and sufficient to produce the modularity and transient reproducible events observed in cortex. Our findings suggest that cortical networks are preconfigured to support sensorimotor coordination. This work redefines the structural and dynamical basis of cortical activity, with a focus on the relationship between modular structure and function.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"6 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704669","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}
Pub Date : 2025-12-05DOI: 10.1038/s41593-025-02135-6
Matthew A. Geramita, Susanne E. Ahmari, Eric A. Yttri
{"title":"The striatal indirect pathway mediates hesitation","authors":"Matthew A. Geramita, Susanne E. Ahmari, Eric A. Yttri","doi":"10.1038/s41593-025-02135-6","DOIUrl":"https://doi.org/10.1038/s41593-025-02135-6","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"1 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680202","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}
Pub Date : 2025-12-04DOI: 10.1038/s41593-025-02126-7
Vinh Nguyen, Capucine Gros, Brandon M. Stell
{"title":"Rapid motor skill adjustment is associated with population-level modulation of cerebellar error signals","authors":"Vinh Nguyen, Capucine Gros, Brandon M. Stell","doi":"10.1038/s41593-025-02126-7","DOIUrl":"https://doi.org/10.1038/s41593-025-02126-7","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"153 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664512","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}
Pub Date : 2025-12-04DOI: 10.1038/s41593-025-02151-6
Clara de la Rosa, Arek Kendirli, Seren Baygün, Franz Bauernschmitt, Anna S. Thomann, Ilgin Kisioglu, Daniela Beckmann, Yves Carpentier Solorio, Veronika Pfaffenstaller, Yi-Heng Tai, Niel Mehraein, Paula Sanchez, Lena Spieth, Lisa Ann Gerdes, Eduardo Beltran, Klaus Dornmair, Mikael Simons, Anneli Peters, Marc Schmidt-Supprian, Martin Kerschensteiner
Here we established an in vivo CRISPR screening pipeline using genetically editable progenitor cells to dissect macrophage regulation in mouse models of multiple sclerosis (MS). Screening over 100 cytokine receptors and signaling molecules identified interferon-γ, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor and transforming growth factor-β as essential regulators of macrophage polarization in vivo. Single-cell transcriptomics confirmed that transferred progenitor cells generate all blood-derived CNS myeloid cell populations, enabling Perturb-seq analysis of cytokine actions in neuroinflammation. Combined with biosensor expression, our approach allows monitoring cytokine effects on myeloid cell migration, debris phagocytosis and oxidative activity in vivo. Comparative transcriptomic analyses revealed conserved neuroinflammatory cytokine signatures across myeloid populations, CNS compartments and species, elucidating cytokine cues shaping myeloid function in the cerebrospinal fluid and parenchyma of individuals with MS. This versatile pipeline thus provides a scalable framework for high-resolution analysis of macrophage states and uncovers the cytokine signals that underlie their regulation in MS and MS models.
{"title":"In vivo CRISPR screen reveals regulation of macrophage states in neuroinflammation","authors":"Clara de la Rosa, Arek Kendirli, Seren Baygün, Franz Bauernschmitt, Anna S. Thomann, Ilgin Kisioglu, Daniela Beckmann, Yves Carpentier Solorio, Veronika Pfaffenstaller, Yi-Heng Tai, Niel Mehraein, Paula Sanchez, Lena Spieth, Lisa Ann Gerdes, Eduardo Beltran, Klaus Dornmair, Mikael Simons, Anneli Peters, Marc Schmidt-Supprian, Martin Kerschensteiner","doi":"10.1038/s41593-025-02151-6","DOIUrl":"https://doi.org/10.1038/s41593-025-02151-6","url":null,"abstract":"Here we established an in vivo CRISPR screening pipeline using genetically editable progenitor cells to dissect macrophage regulation in mouse models of multiple sclerosis (MS). Screening over 100 cytokine receptors and signaling molecules identified interferon-γ, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor and transforming growth factor-β as essential regulators of macrophage polarization in vivo. Single-cell transcriptomics confirmed that transferred progenitor cells generate all blood-derived CNS myeloid cell populations, enabling Perturb-seq analysis of cytokine actions in neuroinflammation. Combined with biosensor expression, our approach allows monitoring cytokine effects on myeloid cell migration, debris phagocytosis and oxidative activity in vivo. Comparative transcriptomic analyses revealed conserved neuroinflammatory cytokine signatures across myeloid populations, CNS compartments and species, elucidating cytokine cues shaping myeloid function in the cerebrospinal fluid and parenchyma of individuals with MS. This versatile pipeline thus provides a scalable framework for high-resolution analysis of macrophage states and uncovers the cytokine signals that underlie their regulation in MS and MS models.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"115 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664510","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}
Pub Date : 2025-12-03DOI: 10.1038/s41593-025-02177-w
Ioana A. Marin
{"title":"When protein turns toxic","authors":"Ioana A. Marin","doi":"10.1038/s41593-025-02177-w","DOIUrl":"10.1038/s41593-025-02177-w","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 12","pages":"2406-2406"},"PeriodicalIF":20.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145659783","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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