Pub Date : 2025-12-17DOI: 10.1038/s41593-025-02157-0
William A. Eimer, Alex S. Rodriguez, Michael T. DeFao, Simon Ehricke, Joseph Park, Deepak K. Vijaya Kumar, Nanda K. Navalpur Shanmugam, Sanjana Singh, Tara Sawhney, Robert D. Moir, Rudolph E. Tanzi
Tau is a microtubule-associated cytoskeletal protein, which, when hyperphosphorylated and aggregated, can result in a myriad of different tauopathies, including Alzheimer’s disease (AD). We previously showed that the principal component of senile plaques, amyloid beta (Aβ), is an antimicrobial peptide capable of binding and entrapping microbial pathogens. Here we show that tau is hyperphosphorylated in neurons in response to viral infection and can neutralize herpes simplex virus 1 (HSV-1) infectivity by directly binding to viral capsids. Our data suggest that the ‘pathogenic’ characteristics of tau hyperphosphorylation, microtubule destabilization and aggregation are part of an antiviral response, in which tau serves as a host defense protein in the innate immune system of the brain. The combined antimicrobial activities of Aβ and phosphorylated tau resulting in Aβ plaques and neurofibrillary tangles, along with neuroinflammation, suggest that AD neuropathology may have evolved as an orchestrated innate immune host defense response to microbial infection in the brain.
{"title":"Phosphorylated tau exhibits antimicrobial activity capable of neutralizing herpes simplex virus 1 infectivity in human neurons","authors":"William A. Eimer, Alex S. Rodriguez, Michael T. DeFao, Simon Ehricke, Joseph Park, Deepak K. Vijaya Kumar, Nanda K. Navalpur Shanmugam, Sanjana Singh, Tara Sawhney, Robert D. Moir, Rudolph E. Tanzi","doi":"10.1038/s41593-025-02157-0","DOIUrl":"https://doi.org/10.1038/s41593-025-02157-0","url":null,"abstract":"Tau is a microtubule-associated cytoskeletal protein, which, when hyperphosphorylated and aggregated, can result in a myriad of different tauopathies, including Alzheimer’s disease (AD). We previously showed that the principal component of senile plaques, amyloid beta (Aβ), is an antimicrobial peptide capable of binding and entrapping microbial pathogens. Here we show that tau is hyperphosphorylated in neurons in response to viral infection and can neutralize herpes simplex virus 1 (HSV-1) infectivity by directly binding to viral capsids. Our data suggest that the ‘pathogenic’ characteristics of tau hyperphosphorylation, microtubule destabilization and aggregation are part of an antiviral response, in which tau serves as a host defense protein in the innate immune system of the brain. The combined antimicrobial activities of Aβ and phosphorylated tau resulting in Aβ plaques and neurofibrillary tangles, along with neuroinflammation, suggest that AD neuropathology may have evolved as an orchestrated innate immune host defense response to microbial infection in the brain.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"12 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765580","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 : 2025-12-16DOI: 10.1038/s41593-025-02132-9
Samira M Epp,Gabriel Castrillón,Beijia Yuan,Jessica Andrews-Hanna,Christine Preibisch,Valentin Riedl
Functional magnetic resonance imaging measures brain activity indirectly by monitoring changes in blood oxygenation levels, known as the blood-oxygenation-level-dependent (BOLD) signal, rather than directly measuring neuronal activity. This approach crucially relies on neurovascular coupling, the mechanism that links neuronal activity to changes in cerebral blood flow. However, it remains unclear whether this relationship is consistent for both positive and negative BOLD responses across the human cortex. Here we found that about 40% of voxels with significant BOLD signal changes during various tasks showed reversed oxygen metabolism, particularly in the default mode network. These 'discordant' voxels differed in baseline oxygen extraction fraction and regulated oxygen demand via oxygen extraction fraction changes, whereas 'concordant' voxels depended mainly on cerebral blood flow changes. Our findings challenge the canonical interpretation of the BOLD signal, indicating that quantitative functional magnetic resonance imaging provides a more reliable assessment of both absolute and relative changes in neuronal activity.
{"title":"BOLD signal changes can oppose oxygen metabolism across the human cortex.","authors":"Samira M Epp,Gabriel Castrillón,Beijia Yuan,Jessica Andrews-Hanna,Christine Preibisch,Valentin Riedl","doi":"10.1038/s41593-025-02132-9","DOIUrl":"https://doi.org/10.1038/s41593-025-02132-9","url":null,"abstract":"Functional magnetic resonance imaging measures brain activity indirectly by monitoring changes in blood oxygenation levels, known as the blood-oxygenation-level-dependent (BOLD) signal, rather than directly measuring neuronal activity. This approach crucially relies on neurovascular coupling, the mechanism that links neuronal activity to changes in cerebral blood flow. However, it remains unclear whether this relationship is consistent for both positive and negative BOLD responses across the human cortex. Here we found that about 40% of voxels with significant BOLD signal changes during various tasks showed reversed oxygen metabolism, particularly in the default mode network. These 'discordant' voxels differed in baseline oxygen extraction fraction and regulated oxygen demand via oxygen extraction fraction changes, whereas 'concordant' voxels depended mainly on cerebral blood flow changes. Our findings challenge the canonical interpretation of the BOLD signal, indicating that quantitative functional magnetic resonance imaging provides a more reliable assessment of both absolute and relative changes in neuronal activity.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"4 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765284","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 : 2025-12-15DOI: 10.1038/s41593-025-02123-w
Judit González-Gallego, Katalin Todorov-Völgyi, Stephan A. Müller, Sophie Antesberger, Mihail Ivilinov Todorov, Rainer Malik, Rita Grimalt-Mirada, Carolina Cardoso Gonçalves, Martina Schifferer, Georg Kislinger, Isabel Weisheit, Barbara Lindner, Dennis Crusius, Joseph Kroeger, Mila Borri, Ali Erturk, Mark Nelson, Thomas Misgeld, Stefan F. Lichtenthaler, Martin Dichgans, Dominik Paquet
Blood–brain barrier (BBB) integrity is critical for brain homeostasis, with malfunctions contributing to neurovascular and neurodegenerative disorders. Mechanistic studies on BBB function have been mostly conducted in rodent and in vitro models, which recapitulate some disease features, but have limited translatability to humans and pose challenges for drug discovery. Here we report on a fully human induced pluripotent stem (iPS)-cell-derived, microfluidic three-dimensional (3D) BBB model consisting of endothelial cells (ECs), mural cells and astrocytes. Our model expresses typical fate markers, forms a barrier in vessel-like tubes and enables perfusion, including with human blood. Deletion of FOXF2 in ECs, a major risk gene for cerebral small vessel disease, induced key features of BBB dysfunction, including compromised cell junction integrity and enhanced caveolae formation. Proteomic analysis revealed dysregulated endocytosis and cell junction pathways. Disease features phenocopied those seen in mice with EC-specific Foxf2 deficiency. Moreover, lipid-nanoparticle-based treatment with Foxf2 mRNA rescued BBB deficits, demonstrating the potential for drug development.
{"title":"A fully iPS-cell-derived 3D model of the human blood–brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions","authors":"Judit González-Gallego, Katalin Todorov-Völgyi, Stephan A. Müller, Sophie Antesberger, Mihail Ivilinov Todorov, Rainer Malik, Rita Grimalt-Mirada, Carolina Cardoso Gonçalves, Martina Schifferer, Georg Kislinger, Isabel Weisheit, Barbara Lindner, Dennis Crusius, Joseph Kroeger, Mila Borri, Ali Erturk, Mark Nelson, Thomas Misgeld, Stefan F. Lichtenthaler, Martin Dichgans, Dominik Paquet","doi":"10.1038/s41593-025-02123-w","DOIUrl":"https://doi.org/10.1038/s41593-025-02123-w","url":null,"abstract":"Blood–brain barrier (BBB) integrity is critical for brain homeostasis, with malfunctions contributing to neurovascular and neurodegenerative disorders. Mechanistic studies on BBB function have been mostly conducted in rodent and in vitro models, which recapitulate some disease features, but have limited translatability to humans and pose challenges for drug discovery. Here we report on a fully human induced pluripotent stem (iPS)-cell-derived, microfluidic three-dimensional (3D) BBB model consisting of endothelial cells (ECs), mural cells and astrocytes. Our model expresses typical fate markers, forms a barrier in vessel-like tubes and enables perfusion, including with human blood. Deletion of FOXF2 in ECs, a major risk gene for cerebral small vessel disease, induced key features of BBB dysfunction, including compromised cell junction integrity and enhanced caveolae formation. Proteomic analysis revealed dysregulated endocytosis and cell junction pathways. Disease features phenocopied those seen in mice with EC-specific Foxf2 deficiency. Moreover, lipid-nanoparticle-based treatment with Foxf2 mRNA rescued BBB deficits, demonstrating the potential for drug development.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"2 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759746","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 : 2025-12-15DOI: 10.1038/s41593-025-02136-5
Katalin Todorov-Völgyi, Judit González-Gallego, Stephan A. Müller, Mihail Ivilinov Todorov, Fatma Burcu Seker, Simon Frerich, Filippo M. Cernilogar, Luise Schröger, Rainer Malik, Jiayu Cao, Gemma Llovera, Stefan Roth, Ulrike Schillinger, Martina Schifferer, Azadeh Reyahi, Dennis Crusius, Liliana D. Pedro, Mikael Simons, Peter Carlsson, Ali Ertürk, Arthur Liesz, Gunnar Schotta, Nikolaus Plesnila, Stefan F. Lichtenthaler, Dominik Paquet, Martin Dichgans
Cerebral small vessel disease (SVD) is a common chronic cerebrovascular disorder with poorly understood pathomechanisms. Genetic studies have identified FOXF2 as a major risk gene for both SVD and stroke. FOXF2 encodes a transcription factor primarily expressed in brain pericytes and endothelial cells (ECs); however, its mechanistic role in cerebrovascular disease remains unknown. Here we show that Foxf2 maintains EC function through Tie2 signaling. RNA and chromatin sequencing identified FOXF2 as a transcriptional activator of Tie2 and other endothelial lineage-specific genes. The deletion of EC-specific Foxf2 in adult mice resulted in blood–brain barrier leakage, which worsened after experimental stroke. Proteomic analyses of Foxf2-deficient mouse brain-derived and human-induced pluripotent stem cell-derived ECs that lack FOXF2 revealed a downregulation of multiple proteins involved in Tie2 signaling. Endothelial Foxf2 deficiency impaired functional hyperemia, reduced NO production and increased infarct size through disrupted Tie2 signaling, effects that were rescued by pharmacological activation of Tie2 with AKB-9778. Collectively, our results highlight the critical role of Foxf2-regulated Tie2 signaling in SVD and stroke, suggesting new avenues for therapeutic interventions.
{"title":"The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling","authors":"Katalin Todorov-Völgyi, Judit González-Gallego, Stephan A. Müller, Mihail Ivilinov Todorov, Fatma Burcu Seker, Simon Frerich, Filippo M. Cernilogar, Luise Schröger, Rainer Malik, Jiayu Cao, Gemma Llovera, Stefan Roth, Ulrike Schillinger, Martina Schifferer, Azadeh Reyahi, Dennis Crusius, Liliana D. Pedro, Mikael Simons, Peter Carlsson, Ali Ertürk, Arthur Liesz, Gunnar Schotta, Nikolaus Plesnila, Stefan F. Lichtenthaler, Dominik Paquet, Martin Dichgans","doi":"10.1038/s41593-025-02136-5","DOIUrl":"https://doi.org/10.1038/s41593-025-02136-5","url":null,"abstract":"Cerebral small vessel disease (SVD) is a common chronic cerebrovascular disorder with poorly understood pathomechanisms. Genetic studies have identified FOXF2 as a major risk gene for both SVD and stroke. FOXF2 encodes a transcription factor primarily expressed in brain pericytes and endothelial cells (ECs); however, its mechanistic role in cerebrovascular disease remains unknown. Here we show that Foxf2 maintains EC function through Tie2 signaling. RNA and chromatin sequencing identified FOXF2 as a transcriptional activator of Tie2 and other endothelial lineage-specific genes. The deletion of EC-specific Foxf2 in adult mice resulted in blood–brain barrier leakage, which worsened after experimental stroke. Proteomic analyses of Foxf2-deficient mouse brain-derived and human-induced pluripotent stem cell-derived ECs that lack FOXF2 revealed a downregulation of multiple proteins involved in Tie2 signaling. Endothelial Foxf2 deficiency impaired functional hyperemia, reduced NO production and increased infarct size through disrupted Tie2 signaling, effects that were rescued by pharmacological activation of Tie2 with AKB-9778. Collectively, our results highlight the critical role of Foxf2-regulated Tie2 signaling in SVD and stroke, suggesting new avenues for therapeutic interventions.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"16 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759779","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 : 2025-12-12DOI: 10.1038/s41593-025-02168-x
Alex James Major,Ahmed Abdaltawab,Jessica M Phillips,Tian Wang,Eric Kenji Lee,Maxwell J Lichtenfeld,Chandramouli Chandrasekaran,Yuri B Saalmann,Alexander Maier,Robert Desimone,Earl K Miller,André M Bastos,Diego Mendoza-Halliday
{"title":"A. J. Major et al. reply.","authors":"Alex James Major,Ahmed Abdaltawab,Jessica M Phillips,Tian Wang,Eric Kenji Lee,Maxwell J Lichtenfeld,Chandramouli Chandrasekaran,Yuri B Saalmann,Alexander Maier,Robert Desimone,Earl K Miller,André M Bastos,Diego Mendoza-Halliday","doi":"10.1038/s41593-025-02168-x","DOIUrl":"https://doi.org/10.1038/s41593-025-02168-x","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"100 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732584","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}
Environmental light regulates nonimage-forming functions like feeding, and bright light therapy shows anti-obesity potential, yet its neural basis remains unclear. Here we show that bright light treatment effectively reduces food intake and mitigates weight gain in mice through a visual circuit involving the lateral hypothalamic area (LHA). Specifically, a subset of SMI-32-expressing ON-type retinal ganglion cells innervate GABAergic neurons in the ventral lateral geniculate nucleus (vLGN), which in turn inhibits GABAergic neurons in the LHA. Activation of both vLGN-projecting retinal ganglion cells and the vLGN-to-LHA projection is sufficient to suppress food consumption and attenuate weight gain. Notably, we provide direct evidence that the suppressive effects of bright light treatment on food consumption and weight gain rely on the activation of the retina-vLGN-LHA pathway. Together, our results delineate an LHA-related visual circuit underlying the food consumption-suppressing and weight gain-attenuating effects of bright light treatment.
{"title":"Bright light exposure suppresses feeding and weight gain via a visual circuit linked to the lateral hypothalamus.","authors":"Wen Li,Xiaodan Huang,Xiaohuai Xu,Qingguo Lv,Jijin Wu,Zhengfang Hu,Ran Li,Yan Yang,Lijie Yu,Bingjie Liu,Li Song,Yue Xi,Kwok-Fai So,Song Lin,Qian Tao,Chaoran Ren,Lu Huang","doi":"10.1038/s41593-025-02156-1","DOIUrl":"https://doi.org/10.1038/s41593-025-02156-1","url":null,"abstract":"Environmental light regulates nonimage-forming functions like feeding, and bright light therapy shows anti-obesity potential, yet its neural basis remains unclear. Here we show that bright light treatment effectively reduces food intake and mitigates weight gain in mice through a visual circuit involving the lateral hypothalamic area (LHA). Specifically, a subset of SMI-32-expressing ON-type retinal ganglion cells innervate GABAergic neurons in the ventral lateral geniculate nucleus (vLGN), which in turn inhibits GABAergic neurons in the LHA. Activation of both vLGN-projecting retinal ganglion cells and the vLGN-to-LHA projection is sufficient to suppress food consumption and attenuate weight gain. Notably, we provide direct evidence that the suppressive effects of bright light treatment on food consumption and weight gain rely on the activation of the retina-vLGN-LHA pathway. Together, our results delineate an LHA-related visual circuit underlying the food consumption-suppressing and weight gain-attenuating effects of bright light treatment.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"372 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732583","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 : 2025-12-12DOI: 10.1038/s41593-025-02167-y
Chase A Mackey, Katharina Duecker, Samuel Neymotin, Salvador Dura-Bernal, Saskia Haegens, Annamaria Barczak, Monica N O'Connell, Stephanie R Jones, Mingzhou Ding, Avniel S Ghuman, Charles E Schroeder
{"title":"Is there a ubiquitous spectrolaminar motif of local field potential power across primate neocortex?","authors":"Chase A Mackey, Katharina Duecker, Samuel Neymotin, Salvador Dura-Bernal, Saskia Haegens, Annamaria Barczak, Monica N O'Connell, Stephanie R Jones, Mingzhou Ding, Avniel S Ghuman, Charles E Schroeder","doi":"10.1038/s41593-025-02167-y","DOIUrl":"10.1038/s41593-025-02167-y","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":" ","pages":""},"PeriodicalIF":20.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743568","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}
Unraveling the cellular and molecular characteristics of human prefrontal cortex (PFC) development is crucial for understanding human cognitive abilities and vulnerability to neurological and neuropsychiatric disorders. Here, in this study, we created a comparative repository for gene expression, chromatin accessibility and spatial transcriptomics of human and macaque postnatal PFC development at single-cell resolution. Integrative analyses outlined species-specific dynamic trajectories of different cell types, highlighting key windows and gene regulatory networks for processes such as synaptogenesis, synaptic pruning and gliogenesis. We identified regulatory correlates of the prolonged development of human PFC relative to macaques. Glial progenitors showed higher proliferation capability in humans compared to macaques, associated with distinct gene expression profiles. Furthermore, we uncovered cell types and lineages most susceptible to neurodevelopmental and neuropsychiatric disorders, focusing on transcription factors with human-specific expression features. In summary, our discoveries shed light on human-specific regulatory programs extending postnatal cortical maturation through coordinated neuronal and glial development, with implications for cognition and neurodevelopmental disorders.
{"title":"Single-cell spatiotemporal transcriptomic and chromatin accessibility profiling in developing postnatal human and macaque prefrontal cortex","authors":"Jiyao Zhang, Mayuqing Li, Mengdi Wang, Yu Sun, Chonghai Yin, Shaotong Yang, Bosong Wang, Zeyuan Liu, Wei Wang, Min Liu, Yuqing Zhao, Xin Zhou, Lixin Cai, Suijuan Zhong, Xiaoqun Wang, Qian Wu","doi":"10.1038/s41593-025-02150-7","DOIUrl":"https://doi.org/10.1038/s41593-025-02150-7","url":null,"abstract":"Unraveling the cellular and molecular characteristics of human prefrontal cortex (PFC) development is crucial for understanding human cognitive abilities and vulnerability to neurological and neuropsychiatric disorders. Here, in this study, we created a comparative repository for gene expression, chromatin accessibility and spatial transcriptomics of human and macaque postnatal PFC development at single-cell resolution. Integrative analyses outlined species-specific dynamic trajectories of different cell types, highlighting key windows and gene regulatory networks for processes such as synaptogenesis, synaptic pruning and gliogenesis. We identified regulatory correlates of the prolonged development of human PFC relative to macaques. Glial progenitors showed higher proliferation capability in humans compared to macaques, associated with distinct gene expression profiles. Furthermore, we uncovered cell types and lineages most susceptible to neurodevelopmental and neuropsychiatric disorders, focusing on transcription factors with human-specific expression features. In summary, our discoveries shed light on human-specific regulatory programs extending postnatal cortical maturation through coordinated neuronal and glial development, with implications for cognition and neurodevelopmental disorders.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"6 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718491","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 : 2025-12-11DOI: 10.1038/s41593-025-02141-8
Graham Findlay, Matias Lorenzo Cavelli, Tom Bugnon, William Marshall, Giulio Tononi, Chiara Cirelli
Cortical slow waves reflect the need for sleep, and their presence indicates a state of disconnection and homeostatic regulation. However, little is known about the neural signatures of sleep need beyond the cortex. Here we performed chronic, continuous, 48-h Neuropixels recordings in male rats to capture hippocampal activity over sleep/wake cycles. We show that hippocampal sharp waves (SPWs) and, to some extent, ripples and dentate spikes (DSs) closely reflect sleep need. Hippocampal SPWs occurred during behavioral sleep and, unlike cortical slow waves, also during quiet wake. The expression of hippocampal SPW, ripple and DS during cortical wakefulness was negatively correlated with that during subsequent cortical sleep, suggesting that these events fulfill similar homeostatic functions. Moreover, the slow-to-fast gamma ratio was always high during SPW, consistent with a switch to a partially disconnected mode. We propose that SPWs define a partially disconnected, homeostatically regulated, unitary state of the hippocampus, which we refer to as ‘hippocampal sharp wave sleep’.
{"title":"A hippocampal ‘sharp-wave sleep’ state that is dissociable from cortical sleep","authors":"Graham Findlay, Matias Lorenzo Cavelli, Tom Bugnon, William Marshall, Giulio Tononi, Chiara Cirelli","doi":"10.1038/s41593-025-02141-8","DOIUrl":"https://doi.org/10.1038/s41593-025-02141-8","url":null,"abstract":"Cortical slow waves reflect the need for sleep, and their presence indicates a state of disconnection and homeostatic regulation. However, little is known about the neural signatures of sleep need beyond the cortex. Here we performed chronic, continuous, 48-h Neuropixels recordings in male rats to capture hippocampal activity over sleep/wake cycles. We show that hippocampal sharp waves (SPWs) and, to some extent, ripples and dentate spikes (DSs) closely reflect sleep need. Hippocampal SPWs occurred during behavioral sleep and, unlike cortical slow waves, also during quiet wake. The expression of hippocampal SPW, ripple and DS during cortical wakefulness was negatively correlated with that during subsequent cortical sleep, suggesting that these events fulfill similar homeostatic functions. Moreover, the slow-to-fast gamma ratio was always high during SPW, consistent with a switch to a partially disconnected mode. We propose that SPWs define a partially disconnected, homeostatically regulated, unitary state of the hippocampus, which we refer to as ‘hippocampal sharp wave sleep’.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"42 1","pages":""},"PeriodicalIF":25.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718495","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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