Antoine Anfray, Samantha Schaeffer, Yorito Hattori, Monica M. Santisteban, Nicole Casey, Gang Wang, Michael Strickland, Ping Zhou, David M. Holtzman, Josef Anrather, Laibaik Park, Costantino Iadecola
{"title":"A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury","authors":"Antoine Anfray, Samantha Schaeffer, Yorito Hattori, Monica M. Santisteban, Nicole Casey, Gang Wang, Michael Strickland, Ping Zhou, David M. Holtzman, Josef Anrather, Laibaik Park, Costantino Iadecola","doi":"10.1038/s41593-024-01757-6","DOIUrl":"10.1038/s41593-024-01757-6","url":null,"abstract":"Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer’s disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs), myeloid cells closely apposed to neocortical microvessels, are both sources and effectors of ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAMs is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell-autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications. ApoE4 is a risk factor for Alzheimer’s disease and vascular dementia. We report that in ApoE4 mice perivascular macrophages are the sole source and effectors of the ApoE4 mediating the neurovascular dysfunction, enhanced white matter damage and cognitive impairment.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2138-2151"},"PeriodicalIF":21.2,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236283","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}
Jonathan Gallego-Rudolf, Alex I. Wiesman, Alexa Pichet Binette, Sylvia Villeneuve, Sylvain Baillet, PREVENT-AD Research Group
{"title":"Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults","authors":"Jonathan Gallego-Rudolf, Alex I. Wiesman, Alexa Pichet Binette, Sylvia Villeneuve, Sylvain Baillet, PREVENT-AD Research Group","doi":"10.1038/s41593-024-01763-8","DOIUrl":"10.1038/s41593-024-01763-8","url":null,"abstract":"Animal and computational models of Alzheimer’s disease (AD) indicate that early amyloid-β (Aβ) deposits drive neurons into a hyperactive regime, and that subsequent tau depositions manifest an opposite, suppressive effect as behavioral deficits emerge. Here we report analogous changes in macroscopic oscillatory neurophysiology in the human brain. We used positron emission tomography and task-free magnetoencephalography to test the effects of Aβ and tau deposition on cortical neurophysiology in 104 cognitively unimpaired older adults with a family history of sporadic AD. In these asymptomatic individuals, we found that Aβ depositions colocalize with accelerated neurophysiological activity. In those also presenting medial–temporal tau pathology, linear mixed effects of Aβ and tau depositions indicate a shift toward slower neurophysiological activity, which was also linked to cognitive decline. We conclude that early Aβ and tau depositions relate synergistically to human cortical neurophysiology and subsequent cognitive decline. Our findings provide insight into the multifaceted neurophysiological mechanisms engaged in the preclinical phases of AD. Gallego-Rudolf et al. report accelerated brain activity with initial amyloid-β deposition in asymptomatic individuals. In those where tau also starts accumulating, brain activity decelerates, correlating with subsequent cognitive decline.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2130-2137"},"PeriodicalIF":21.2,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01763-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236282","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}
W. Jeffrey Johnston, Justin M. Fine, Seng Bum Michael Yoo, R. Becket Ebitz, Benjamin Y. Hayden
{"title":"Semi-orthogonal subspaces for value mediate a binding and generalization trade-off","authors":"W. Jeffrey Johnston, Justin M. Fine, Seng Bum Michael Yoo, R. Becket Ebitz, Benjamin Y. Hayden","doi":"10.1038/s41593-024-01758-5","DOIUrl":"10.1038/s41593-024-01758-5","url":null,"abstract":"When choosing between options, we must associate their values with the actions needed to select them. We hypothesize that the brain solves this binding problem through neural population subspaces. Here, in macaques performing a choice task, we show that neural populations in five reward-sensitive regions encode the values of offers presented on the left and right in distinct subspaces. This encoding is sufficient to bind offer values to their locations while preserving abstract value information. After offer presentation, all areas encode the value of the first and second offers in orthogonal subspaces; this orthogonalization also affords binding. Our binding-by-subspace hypothesis makes two new predictions confirmed by the data. First, behavioral errors should correlate with spatial, but not temporal, neural misbinding. Second, behavioral errors should increase when offers have low or high values, compared to medium values, even when controlling for value difference. Together, these results support the idea that the brain uses semi-orthogonal subspaces to bind features. This study shows that the brain can link action to value through neural population subspaces, balancing reliable binding of action to value and generalization to novel stimuli.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2218-2230"},"PeriodicalIF":21.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235132","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}
Ebrahim Asadollahi, Andrea Trevisiol, Aiman S. Saab, Zoe J. Looser, Payam Dibaj, Reyhane Ebrahimi, Kathrin Kusch, Torben Ruhwedel, Wiebke Möbius, Olaf Jahn, Jun Yup Lee, Anthony S. Don, Michelle-Amirah Khalil, Karsten Hiller, Myriam Baes, Bruno Weber, E. Dale Abel, Andrea Ballabio, Brian Popko, Celia M. Kassmann, Hannelore Ehrenreich, Johannes Hirrlinger, Klaus-Armin Nave
{"title":"Author Correction: Oligodendroglial fatty acid metabolism as a central nervous system energy reserve","authors":"Ebrahim Asadollahi, Andrea Trevisiol, Aiman S. Saab, Zoe J. Looser, Payam Dibaj, Reyhane Ebrahimi, Kathrin Kusch, Torben Ruhwedel, Wiebke Möbius, Olaf Jahn, Jun Yup Lee, Anthony S. Don, Michelle-Amirah Khalil, Karsten Hiller, Myriam Baes, Bruno Weber, E. Dale Abel, Andrea Ballabio, Brian Popko, Celia M. Kassmann, Hannelore Ehrenreich, Johannes Hirrlinger, Klaus-Armin Nave","doi":"10.1038/s41593-024-01776-3","DOIUrl":"10.1038/s41593-024-01776-3","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"2046-2046"},"PeriodicalIF":21.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01776-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292073","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}
Christina Grimm, Sian N. Duss, Mattia Privitera, Brandon R. Munn, Nikolaos Karalis, Stefan Frässle, Maria Wilhelm, Tommaso Patriarchi, Daniel Razansky, Nicole Wenderoth, James M. Shine, Johannes Bohacek, Valerio Zerbi
{"title":"Tonic and burst-like locus coeruleus stimulation distinctly shift network activity across the cortical hierarchy","authors":"Christina Grimm, Sian N. Duss, Mattia Privitera, Brandon R. Munn, Nikolaos Karalis, Stefan Frässle, Maria Wilhelm, Tommaso Patriarchi, Daniel Razansky, Nicole Wenderoth, James M. Shine, Johannes Bohacek, Valerio Zerbi","doi":"10.1038/s41593-024-01755-8","DOIUrl":"10.1038/s41593-024-01755-8","url":null,"abstract":"Noradrenaline (NA) release from the locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, modulating multiple behavioral states. NA release is mediated by both tonic and burst-like LC activity. However, it is unknown whether the functional changes in target areas depend on these firing patterns. Using optogenetics, photometry, electrophysiology and functional magnetic resonance imaging in mice, we show that tonic and burst-like LC firing patterns elicit brain responses that hinge on their distinct NA release dynamics. During moderate tonic LC activation, NA release engages regions associated with associative processing, while burst-like stimulation biases the brain toward sensory processing. These activation patterns locally couple with increased astrocytic and inhibitory activity and change the brain’s topological configuration in line with the hierarchical organization of the cerebral cortex. Together, these findings reveal how the LC–NA system achieves a nuanced regulation of global circuit operations. Tonic and burst-like locus coeruleus firing distinctly tune brain topology toward associative and sensory regions, recruiting both astrocytic and neuronal inhibitory activity.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2167-2177"},"PeriodicalIF":21.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01755-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234451","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}
Laura Pritschet, Caitlin M. Taylor, Daniela Cossio, Joshua Faskowitz, Tyler Santander, Daniel A. Handwerker, Hannah Grotzinger, Evan Layher, Elizabeth R. Chrastil, Emily G. Jacobs
{"title":"Neuroanatomical changes observed over the course of a human pregnancy","authors":"Laura Pritschet, Caitlin M. Taylor, Daniela Cossio, Joshua Faskowitz, Tyler Santander, Daniel A. Handwerker, Hannah Grotzinger, Evan Layher, Elizabeth R. Chrastil, Emily G. Jacobs","doi":"10.1038/s41593-024-01741-0","DOIUrl":"10.1038/s41593-024-01741-0","url":null,"abstract":"Pregnancy is a period of profound hormonal and physiological changes experienced by millions of women annually, yet the neural changes unfolding in the maternal brain throughout gestation are not well studied in humans. Leveraging precision imaging, we mapped neuroanatomical changes in an individual from preconception through 2 years postpartum. Pronounced decreases in gray matter volume and cortical thickness were evident across the brain, standing in contrast to increases in white matter microstructural integrity, ventricle volume and cerebrospinal fluid, with few regions untouched by the transition to motherhood. This dataset serves as a comprehensive map of the human brain across gestation, providing an open-access resource for the brain imaging community to further explore and understand the maternal brain. Neural changes in pregnancy are not well understood. Here Pritschet et al. present an open-access precision brain imaging resource, mapping neuroanatomical change in an individual from preconception through postpartum.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2253-2260"},"PeriodicalIF":21.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01741-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235133","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}
Kathleen A. Martin, Eleni S. Papadoyannis, Jennifer K. Schiavo, Saba Shokat Fadaei, Habon A. Issa, Soomin C. Song, Sofia Orrey Valencia, Nesibe Z. Temiz, Matthew J. McGinley, David A. McCormick, Robert C. Froemke
{"title":"Vagus nerve stimulation recruits the central cholinergic system to enhance perceptual learning","authors":"Kathleen A. Martin, Eleni S. Papadoyannis, Jennifer K. Schiavo, Saba Shokat Fadaei, Habon A. Issa, Soomin C. Song, Sofia Orrey Valencia, Nesibe Z. Temiz, Matthew J. McGinley, David A. McCormick, Robert C. Froemke","doi":"10.1038/s41593-024-01767-4","DOIUrl":"10.1038/s41593-024-01767-4","url":null,"abstract":"Perception can be refined by experience, up to certain limits. It is unclear whether perceptual limits are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest that peripheral nerve stimulation, specifically vagus nerve stimulation (VNS), can alter neural activity and augment experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS applied during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Two-photon imaging revealed VNS induced changes to auditory cortical responses and activated cortically projecting cholinergic axons. Anatomical and optogenetic experiments indicated that VNS can enhance task performance through activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS and may contribute to further refinement of VNS methodology for clinical conditions. Perceptual abilities can be improved by training, up to certain limits. Martin et al. show that vagus nerve stimulation in mice boosts performance on an auditory task via cholinergic modulation, beyond the level achieved by training alone.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2152-2166"},"PeriodicalIF":21.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234504","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}
Guojiao Huang, Zhidan Li, Xuezhao Liu, Menglong Guan, Songlin Zhou, Xiaowen Zhong, Tao Zheng, Dazhuan Xin, Xiaosong Gu, Dezhi Mu, Yingkun Guo, Lin Zhang, Liguo Zhang, Q. Richard Lu, Xuelian He
{"title":"DOR activation in mature oligodendrocytes regulates α-ketoglutarate metabolism leading to enhanced remyelination in aged mice","authors":"Guojiao Huang, Zhidan Li, Xuezhao Liu, Menglong Guan, Songlin Zhou, Xiaowen Zhong, Tao Zheng, Dazhuan Xin, Xiaosong Gu, Dezhi Mu, Yingkun Guo, Lin Zhang, Liguo Zhang, Q. Richard Lu, Xuelian He","doi":"10.1038/s41593-024-01754-9","DOIUrl":"10.1038/s41593-024-01754-9","url":null,"abstract":"The decreased ability of mature oligodendrocytes to produce myelin negatively affects remyelination in demyelinating diseases and aging, but the underlying mechanisms are incompletely understood. In the present study, we identify a mature oligodendrocyte-enriched transcriptional coregulator diabetes- and obesity-related gene (DOR)/tumor protein p53-inducible nuclear protein 2 (TP53INP2), downregulated in demyelinated lesions of donors with multiple sclerosis and in aged oligodendrocyte-lineage cells. Dor ablation in mice of both sexes results in defective myelinogenesis and remyelination. Genomic occupancy in oligodendrocytes and transcriptome profiling of the optic nerves of wild-type and Dor conditional knockout mice reveal that DOR and SOX10 co-occupy enhancers of critical myelinogenesis-associated genes including Prr18, encoding an oligodendrocyte-enriched, proline-rich factor. We show that DOR targets regulatory elements of genes responsible for α-ketoglutarate biosynthesis in mature oligodendrocytes and is essential for α-ketoglutarate production and lipid biosynthesis. Supplementation with α-ketoglutarate restores oligodendrocyte-maturation defects in Dor-deficient adult mice and improves remyelination after lysolecithin-induced demyelination and cognitive function in 17-month-old wild-type mice. Our data suggest that activation of α-ketoglutarate metabolism in mature oligodendrocytes can promote myelin production during demyelination and aging. The mechanisms underlying the ability to remyelinate in aging and disease are unclear. Here, the authors show that DOR-mediated activation of α-ketoglutarate in mature oligodendrocytes can promote myelin production in mice during demyelination and aging.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2073-2085"},"PeriodicalIF":21.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170841","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":"Myelin lipid metabolism can provide energy for starved axons","authors":"","doi":"10.1038/s41593-024-01750-z","DOIUrl":"10.1038/s41593-024-01750-z","url":null,"abstract":"We reveal that lipid turnover in the myelin sheath generates a fatty acid pool in oligodendrocytes that can contribute to the energy balance of white matter tracts. We also demonstrate that when glucose levels are limiting, fatty acid metabolism can support glial cell survival and the basic functional integrity of myelinated axons.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"1862-1863"},"PeriodicalIF":21.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175023","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}
Sanjid Shahriar, Saptarshi Biswas, Kaitao Zhao, Uğur Akcan, Mary Claire Tuohy, Michael D. Glendinning, Ali Kurt, Charlotte R. Wayne, Grace Prochilo, Maxwell Z. Price, Heidi Stuhlmann, Rolf A. Brekken, Vilas Menon, Dritan Agalliu
{"title":"VEGF-A-mediated venous endothelial cell proliferation results in neoangiogenesis during neuroinflammation","authors":"Sanjid Shahriar, Saptarshi Biswas, Kaitao Zhao, Uğur Akcan, Mary Claire Tuohy, Michael D. Glendinning, Ali Kurt, Charlotte R. Wayne, Grace Prochilo, Maxwell Z. Price, Heidi Stuhlmann, Rolf A. Brekken, Vilas Menon, Dritan Agalliu","doi":"10.1038/s41593-024-01746-9","DOIUrl":"10.1038/s41593-024-01746-9","url":null,"abstract":"Newly formed leaky vessels and blood–brain barrier (BBB) damage are present in demyelinating acute and chronic lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, the endothelial cell subtypes and signaling pathways contributing to these leaky neovessels are unclear. Here, using single-cell transcriptional profiling and in vivo validation studies, we show that venous endothelial cells express neoangiogenesis gene signatures and show increased proliferation resulting in enlarged veins and higher venous coverage in acute and chronic EAE lesions in female adult mice. These changes correlate with the upregulation of vascular endothelial growth factor A (VEGF-A) signaling. We also confirmed increased expression of neoangiogenic markers in acute and chronic human MS lesions. Treatment with a VEGF-A blocking antibody diminishes the neoangiogenic transcriptomic signatures and vascular proliferation in female adult mice with EAE, but it does not restore BBB function or ameliorate EAE pathology. Our data demonstrate that venous endothelial cells contribute to neoangiogenesis in demyelinating neuroinflammatory conditions. Defective neoangiogenesis and blood–brain barrier leakiness are pathological hallmarks of neuroinflammation. Here the authors show that vascular endothelial growth factor A (VEGF-A) promotes venous endothelial cell proliferation, resulting in the formation of leaky vessels around demyelinating lesions in multiple sclerosis and experimental autoimmune encephalomyelitis.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"1904-1917"},"PeriodicalIF":21.2,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160457","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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