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. De la Rosa et al. developed an in vivo CRISPR screening system to dissect macrophage regulation in multiple sclerosis models, revealing key cytokine signaling pathways that control myeloid cell behavior in neuroinflammation.
{"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":"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. De la Rosa et al. developed an in vivo CRISPR screening system to dissect macrophage regulation in multiple sclerosis models, revealing key cytokine signaling pathways that control myeloid cell behavior in neuroinflammation.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"493-509"},"PeriodicalIF":20.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02151-6.pdf","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":"OA","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}
Pub Date : 2025-12-03DOI: 10.1038/s41593-025-02181-0
Nature Neuroscience has introduced two initiatives to promote the quality, transparency and inclusivity of peer review. One enables the publication of peer review reports and authors’ responses, and the other facilitates the participation of early career researchers.
{"title":"Enhancing peer review at Nature Neuroscience","authors":"","doi":"10.1038/s41593-025-02181-0","DOIUrl":"10.1038/s41593-025-02181-0","url":null,"abstract":"Nature Neuroscience has introduced two initiatives to promote the quality, transparency and inclusivity of peer review. One enables the publication of peer review reports and authors’ responses, and the other facilitates the participation of early career researchers.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"28 12","pages":"2403-2403"},"PeriodicalIF":20.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02181-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145659790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1038/s41593-025-02178-9
William P. Olson
{"title":"Recurrence has it covered","authors":"William P. Olson","doi":"10.1038/s41593-025-02178-9","DOIUrl":"10.1038/s41593-025-02178-9","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":"145659784","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 : 2025-12-02DOI: 10.1038/s41593-025-02131-w
Margherita Zamboni, Adrián Martínez-Martín, Gabriel Rydholm, Timm Häneke, Laura Pintado Almeida, Deniz Seçilmiş, Christoph Ziegenhain, Enric Llorens-Bobadilla
Enhancer elements direct cell-type-specific gene expression programs. After injury, cells change their transcriptional state to adapt to stress and initiate repair. Here we investigate how injury-induced transcriptional programs are encoded within enhancers in the mammalian CNS. Leveraging single-nucleus transcriptomics and chromatin accessibility profiling, we identify thousands of injury-induced, cell-type-specific enhancers in the mouse spinal cord after a contusion injury. These are abundant in glial cells and retain cell-type specificity, even when regulating shared wound response genes. By modeling glial injury-responsive enhancers using deep learning, we reveal that their architecture encodes cell-type specificity by integrating generic stimulus response elements with cell identity programs. Finally, through in vivo enhancer screening, we demonstrate that injury-responsive enhancers can selectively target reactive astrocytes across the CNS using therapeutically relevant gene delivery vectors. Our decoding of the principles of injury-responsive enhancers enables the design of sequences that can be programmed to target disease-associated cell states. Zamboni et al. reveal how enhancers encode cell-type-specific responses to CNS injury. By combining multiomic profiling, deep learning and in vivo screening, they uncover injury-responsive enhancer logic and enable targeting of reactive astrocytes.
{"title":"The regulatory code of injury-responsive enhancers enables precision cell-state targeting in the CNS","authors":"Margherita Zamboni, Adrián Martínez-Martín, Gabriel Rydholm, Timm Häneke, Laura Pintado Almeida, Deniz Seçilmiş, Christoph Ziegenhain, Enric Llorens-Bobadilla","doi":"10.1038/s41593-025-02131-w","DOIUrl":"10.1038/s41593-025-02131-w","url":null,"abstract":"Enhancer elements direct cell-type-specific gene expression programs. After injury, cells change their transcriptional state to adapt to stress and initiate repair. Here we investigate how injury-induced transcriptional programs are encoded within enhancers in the mammalian CNS. Leveraging single-nucleus transcriptomics and chromatin accessibility profiling, we identify thousands of injury-induced, cell-type-specific enhancers in the mouse spinal cord after a contusion injury. These are abundant in glial cells and retain cell-type specificity, even when regulating shared wound response genes. By modeling glial injury-responsive enhancers using deep learning, we reveal that their architecture encodes cell-type specificity by integrating generic stimulus response elements with cell identity programs. Finally, through in vivo enhancer screening, we demonstrate that injury-responsive enhancers can selectively target reactive astrocytes across the CNS using therapeutically relevant gene delivery vectors. Our decoding of the principles of injury-responsive enhancers enables the design of sequences that can be programmed to target disease-associated cell states. Zamboni et al. reveal how enhancers encode cell-type-specific responses to CNS injury. By combining multiomic profiling, deep learning and in vivo screening, they uncover injury-responsive enhancer logic and enable targeting of reactive astrocytes.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"337-349"},"PeriodicalIF":20.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41593-025-02131-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1038/s41593-025-02160-5
Kianoush Banaie Boroujeni, Randolph F. Helfrich, Ian C. Fiebelkorn, J. Nicole Bentley, Peter Brunner, Jack J. Lin, Robert T. Knight, Sabine Kastner
Brain-wide communication supporting flexible behavior requires coordination between sensory and associative regions but how brain networks route sensory information at fast timescales to guide action remains unclear. Using human intracranial electrophysiology and spiking neural networks during spatial attention tasks, where participants detected targets at cued locations, we show that high-frequency activity bursts (HFAbs) mark temporal windows of elevated population firing that enable fast, long-range communications. HFAbs were evoked by sensory cues and targets, dynamically coupled to low-frequency rhythms. Notably, both the strength of cue-evoked HFAbs and their decoupling from slow rhythms predicted behavioral accuracy. HFAbs synchronized across the brain, revealing distinct cue- and target-activated subnetworks. These subnetworks exhibited lead–lag dynamics following target onset, with cue-activated subnetworks preceding target-activated subnetworks when cues were informative. Computational modeling suggested that HFAbs reflect transitions to population spiking, denoting temporal windows for network communications supporting attentional performance. These findings establish HFAbs as signatures of population state transitions, supporting information routing across distributed brain networks. Using intracranial electroencephalography from patients with epilepsy during spatial attention tasks, this study shows that high-frequency bursts facilitate fast communications in brain networks and support attentional information routing.
{"title":"High-frequency bursts facilitate fast communication for human spatial attention","authors":"Kianoush Banaie Boroujeni, Randolph F. Helfrich, Ian C. Fiebelkorn, J. Nicole Bentley, Peter Brunner, Jack J. Lin, Robert T. Knight, Sabine Kastner","doi":"10.1038/s41593-025-02160-5","DOIUrl":"10.1038/s41593-025-02160-5","url":null,"abstract":"Brain-wide communication supporting flexible behavior requires coordination between sensory and associative regions but how brain networks route sensory information at fast timescales to guide action remains unclear. Using human intracranial electrophysiology and spiking neural networks during spatial attention tasks, where participants detected targets at cued locations, we show that high-frequency activity bursts (HFAbs) mark temporal windows of elevated population firing that enable fast, long-range communications. HFAbs were evoked by sensory cues and targets, dynamically coupled to low-frequency rhythms. Notably, both the strength of cue-evoked HFAbs and their decoupling from slow rhythms predicted behavioral accuracy. HFAbs synchronized across the brain, revealing distinct cue- and target-activated subnetworks. These subnetworks exhibited lead–lag dynamics following target onset, with cue-activated subnetworks preceding target-activated subnetworks when cues were informative. Computational modeling suggested that HFAbs reflect transitions to population spiking, denoting temporal windows for network communications supporting attentional performance. These findings establish HFAbs as signatures of population state transitions, supporting information routing across distributed brain networks. Using intracranial electroencephalography from patients with epilepsy during spatial attention tasks, this study shows that high-frequency bursts facilitate fast communications in brain networks and support attentional information routing.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 2","pages":"435-444"},"PeriodicalIF":20.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656991","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 : 2025-12-01DOI: 10.1038/s41593-025-02113-y
Ruoqi Yu, Brian M. Lozinski, Ally Seifert, Khanh Ta, Stephanie Zandee, Deepak K. Kaushik, Jian Park, Wendy Klement, Sandra Larouche, Sotirios Tsimikas, Joseph L. Witztum, Dorian B. McGavern, Alexandre Prat, Yifei Dong
Oxidized phosphatidylcholines (OxPCs) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPCs contribute to the pathophysiology of P-MS is unclear. Here we show that stereotactic OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this model, we found that although microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte-derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology in Casp1/Casp4-deficient mice and by blockade of IL-1R1 indicate that IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPCs and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization could be effective for treating P-MS. In this study, Yu et al. found that a positive feedback loop between oxidized phosphatidylcholine and IL-1β promotes chronic neurodegeneration in the central nervous system and could be a contributing mechanism to progressive multiple sclerosis.
{"title":"Oxidized phosphatidylcholines deposition drives chronic neurodegeneration in a mouse model of progressive multiple sclerosis via IL-1β signaling","authors":"Ruoqi Yu, Brian M. Lozinski, Ally Seifert, Khanh Ta, Stephanie Zandee, Deepak K. Kaushik, Jian Park, Wendy Klement, Sandra Larouche, Sotirios Tsimikas, Joseph L. Witztum, Dorian B. McGavern, Alexandre Prat, Yifei Dong","doi":"10.1038/s41593-025-02113-y","DOIUrl":"10.1038/s41593-025-02113-y","url":null,"abstract":"Oxidized phosphatidylcholines (OxPCs) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPCs contribute to the pathophysiology of P-MS is unclear. Here we show that stereotactic OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this model, we found that although microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte-derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology in Casp1/Casp4-deficient mice and by blockade of IL-1R1 indicate that IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPCs and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization could be effective for treating P-MS. In this study, Yu et al. found that a positive feedback loop between oxidized phosphatidylcholine and IL-1β promotes chronic neurodegeneration in the central nervous system and could be a contributing mechanism to progressive multiple sclerosis.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"29 1","pages":"67-80"},"PeriodicalIF":20.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145645167","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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