{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:31:15Z","timestamp":1789507875846,"version":"build-2803163510"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":77,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Aging accelerates central nervous system remyelination failure and neurodegeneration. Microglia promote remyelination by phagocytosing myelin debris, but this function is impaired by aging-related CD22 upregulation. However, the molecular mechanisms counteracting premature aging-related microglial dysfunction and remyelination impairment remain unclear. Here, we report that Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination by restraining progressive CD22 upregulation. We identified that microglia-enriched Bhlhe41 was negatively autoregulated and inhibited by\n                    <jats:italic>Aurka<\/jats:italic>\n                    loss.\n                    <jats:italic>Bhlhe41-<\/jats:italic>\n                    or\n                    <jats:italic>Aurka<\/jats:italic>\n                    -deficient young mice exhibited aging-like microglial morphology, phagocytic deficits, progressive CD22 upregulation, and remyelination impairment in cuprizone-induced demyelination model. Conversely, ectopic Bhlhe41 expression induced hypertrophic microglia, and counteracted phagocytic deficits and CD22 upregulation in\n                    <jats:italic>Aurka<\/jats:italic>\n                    -deficient microglia. CD22 blockade restored phagocytic function and remyelination in\n                    <jats:italic>Bhlhe41<\/jats:italic>\n                    -deficient mice. Notably, a conserved pattern of\n                    <jats:italic>CD22<\/jats:italic>\n                    upregulation was observed in human\n                    <jats:italic>PCDH9<\/jats:italic>\n                    <jats:sup>high<\/jats:sup>\n                    microglia subsets with\n                    <jats:italic>BHLHE41<\/jats:italic>\n                    downregulation. These findings offer insights into potential therapeutic strategies to combat aging-related neurodegeneration and central nervous system functional decline.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-71014-w","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:04:42Z","timestamp":1774609482000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1412-2223","authenticated-orcid":false,"given":"Weixing","family":"Yan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5826-6125","authenticated-orcid":false,"given":"Yelin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixue","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meizhen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzhu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbiao","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijia","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuxing","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2232-1000","authenticated-orcid":false,"given":"Jianhong","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0533-9890","authenticated-orcid":false,"given":"Jinghua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuiyang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2624-5028","authenticated-orcid":false,"given":"Jing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3610-2418","authenticated-orcid":false,"given":"Shuli","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8706-2217","authenticated-orcid":false,"given":"Hui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"71014_CR1","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","volume":"15","author":"Y Hou","year":"2019","unstructured":"Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565\u2013581 (2019).","journal-title":"Nat. Rev. Neurol."},{"key":"71014_CR2","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/s41577-023-00907-4","volume":"24","author":"SA Kent","year":"2024","unstructured":"Kent, S. A. & Miron, V. E. Microglia regulation of central nervous system myelin health and regeneration. Nat. Rev. Immunol. 24, 49\u201363 (2024).","journal-title":"Nat. Rev. Immunol."},{"key":"71014_CR3","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1016\/j.cell.2018.05.003","volume":"173","author":"A Deczkowska","year":"2018","unstructured":"Deczkowska, A. et al. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173, 1073\u20131081 (2018).","journal-title":"Cell"},{"key":"71014_CR4","doi-asserted-by":"publisher","first-page":"18150","DOI":"10.1073\/pnas.1210150109","volume":"109","author":"NH Varvel","year":"2012","unstructured":"Varvel, N. H. et al. Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc. Natl. Acad. Sci. USA 109, 18150\u201318155 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"71014_CR5","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.it.2008.01.010","volume":"29","author":"N Davoust","year":"2008","unstructured":"Davoust, N., Vuaillat, C., Androdias, G. & Nataf, S. From bone marrow to microglia: barriers and avenues. Trends Immunol. 29, 227\u2013234 (2008).","journal-title":"Trends Immunol."},{"key":"71014_CR6","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1126\/science.1194637","volume":"330","author":"F Ginhoux","year":"2010","unstructured":"Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841\u2013845 (2010).","journal-title":"Science"},{"key":"71014_CR7","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1038\/npp.2016.185","volume":"42","author":"A Niraula","year":"2017","unstructured":"Niraula, A., Sheridan, J. F. & Godbout, J. P. Microglia priming with aging and stress. Neuropsychopharmacology 42, 318\u2013333 (2017).","journal-title":"Neuropsychopharmacology"},{"key":"71014_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108835","volume":"34","author":"K Shen","year":"2021","unstructured":"Shen, K. et al. Multiple sclerosis risk gene Mertk is required for microglial activation and subsequent remyelination. Cell Rep. 34, 108835 (2021).","journal-title":"Cell Rep."},{"key":"71014_CR9","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1038\/nn1715","volume":"9","author":"AE Cardona","year":"2006","unstructured":"Cardona, A. E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917\u2013924 (2006).","journal-title":"Nat. Neurosci."},{"key":"71014_CR10","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1007\/s00401-020-02193-z","volume":"140","author":"F Cignarella","year":"2020","unstructured":"Cignarella, F. et al. TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis. Acta Neuropathol. 140, 513\u2013534 (2020).","journal-title":"Acta Neuropathol."},{"key":"71014_CR11","doi-asserted-by":"publisher","first-page":"2161","DOI":"10.1172\/JCI77983","volume":"125","author":"PL Poliani","year":"2015","unstructured":"Poliani, P. L. et al. TREM2 sustains microglial expansion during aging and response to demyelination. J. Clin. Invest. 125, 2161\u20132170 (2015).","journal-title":"J. Clin. Invest."},{"key":"71014_CR12","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1084\/jem.20141656","volume":"212","author":"A Lampron","year":"2015","unstructured":"Lampron, A. et al. Inefficient clearance of myelin debris by microglia impairs remyelinating processes. J. Exp. Med. 212, 481\u2013495 (2015).","journal-title":"J. Exp. Med."},{"key":"71014_CR13","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s40478-024-01855-3","volume":"12","author":"TJ McCray","year":"2024","unstructured":"McCray, T. J., Bedford, L. M., Bissel, S. J. & Lamb, B. T. Trem2-deficiency aggravates and accelerates age-related myelin degeneration. Acta Neuropathol. Commun. 12, 154 (2024).","journal-title":"Acta Neuropathol. Commun."},{"key":"71014_CR14","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1056\/NEJMoa1211851","volume":"368","author":"R Guerreiro","year":"2013","unstructured":"Guerreiro, R. et al. TREM2 variants in Alzheimer\u2019s disease. N. Engl. J. Med. 368, 117\u2013127 (2013).","journal-title":"N. Engl. J. Med."},{"key":"71014_CR15","doi-asserted-by":"publisher","first-page":"2368","DOI":"10.1093\/brain\/awae014","volume":"147","author":"K Kiianitsa","year":"2024","unstructured":"Kiianitsa, K. et al. TREM2 variants that cause early dementia and increase Alzheimer\u2019s disease risk affect gene splicing. Brain 147, 2368\u20132383 (2024).","journal-title":"Brain"},{"key":"71014_CR16","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/s41586-019-1088-4","volume":"568","author":"JV Pluvinage","year":"2019","unstructured":"Pluvinage, J. V. et al. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568, 187\u2013192 (2019).","journal-title":"Nature"},{"key":"71014_CR17","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1126\/science.1174443","volume":"325","author":"Y He","year":"2009","unstructured":"He, Y. et al. The transcriptional repressor DEC2 regulates sleep length in mammals. Science 325, 866\u2013870 (2009).","journal-title":"Science"},{"key":"71014_CR18","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1038\/nature01123","volume":"419","author":"S Honma","year":"2002","unstructured":"Honma, S. et al. Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 419, 841\u2013844 (2002).","journal-title":"Nature"},{"key":"71014_CR19","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1038\/ni.3694","volume":"18","author":"T Kreslavsky","year":"2017","unstructured":"Kreslavsky, T. et al. Essential role for the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells. Nat. Immunol. 18, 442\u2013455 (2017).","journal-title":"Nat. Immunol."},{"key":"71014_CR20","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2018101233","volume":"38","author":"R Rauschmeier","year":"2019","unstructured":"Rauschmeier, R. et al. Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self-renewal and identity. EMBO J. 38, e101233 (2019).","journal-title":"EMBO J."},{"key":"71014_CR21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.946202","volume":"13","author":"H Li","year":"2022","unstructured":"Li, H. et al. Identification of novel B-1 transitional progenitors by B-1 lymphocyte fate-mapping transgenic mouse model Bhlhe41 (dTomato-Cre). Front. Immunol. 13, 946202 (2022).","journal-title":"Front. Immunol."},{"key":"71014_CR22","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad8670","volume":"353","author":"O Matcovitch-Natan","year":"2016","unstructured":"Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).","journal-title":"Science"},{"key":"71014_CR23","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1002\/glia.10319","volume":"45","author":"WJ Streit","year":"2004","unstructured":"Streit, W. J., Sammons, N. W., Kuhns, A. J. & Sparks, D. L. Dystrophic microglia in the aging human brain. Glia 45, 208\u2013212 (2004).","journal-title":"Glia"},{"key":"71014_CR24","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s40478-014-0142-6","volume":"2","author":"WJ Streit","year":"2014","unstructured":"Streit, W. J., Xue, Q. S., Tischer, J. & Bechmann, I. Microglial pathology. Acta Neuropathol. Commun. 2, 142 (2014).","journal-title":"Acta Neuropathol. Commun."},{"key":"71014_CR25","doi-asserted-by":"crossref","unstructured":"Murinello, S. et al. Assessing retinal microglial phagocytic function in vivo using a flow cytometry-based assay. J. Vis. Exp. 54677 (2016).","DOI":"10.3791\/54677-v"},{"key":"71014_CR26","doi-asserted-by":"publisher","first-page":"4135","DOI":"10.1016\/j.cell.2022.09.030","volume":"185","author":"H Ennerfelt","year":"2022","unstructured":"Ennerfelt, H. et al. SYK coordinates neuroprotective microglial responses in neurodegenerative disease. Cell 185, 4135\u20134152.e4122 (2022).","journal-title":"Cell"},{"key":"71014_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10180","volume":"7","author":"F Zheng","year":"2016","unstructured":"Zheng, F. et al. Nuclear AURKA acquires kinase-independent transactivating function to enhance breast cancer stem cell phenotype. Nat. Commun. 7, 10180 (2016).","journal-title":"Nat. Commun."},{"key":"71014_CR28","doi-asserted-by":"publisher","first-page":"7844","DOI":"10.1093\/nar\/gkaa570","volume":"48","author":"E Guarino Almeida","year":"2020","unstructured":"Guarino Almeida, E., Renaudin, X. & Venkitaraman, A. R. A kinase-independent function for AURORA-A in replisome assembly during DNA replication initiation. Nucleic Acids Res. 48, 7844\u20137855 (2020).","journal-title":"Nucleic Acids Res."},{"key":"71014_CR29","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1158\/1541-7786.MCR-19-1226","volume":"18","author":"J Han","year":"2020","unstructured":"Han, J. et al. Inhibition of aurora-A promotes CD8(+) T-cell infiltration by mediating IL10 production in cancer cells. Mol. Cancer Res. 18, 1589\u20131602 (2020).","journal-title":"Mol. Cancer Res."},{"key":"71014_CR30","doi-asserted-by":"publisher","DOI":"10.1186\/s13008-018-0040-6","volume":"13","author":"E Willems","year":"2018","unstructured":"Willems, E. et al. The functional diversity of Aurora kinases: a comprehensive review. Cell Div. 13, 7 (2018).","journal-title":"Cell Div."},{"key":"71014_CR31","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/jid.2012.249","volume":"133","author":"EC Torchia","year":"2013","unstructured":"Torchia, E. C., Zhang, L., Huebner, A. J., Sen, S. & Roop, D. R. Aurora kinase-A deficiency during skin development impairs cell division and stratification. J. Invest. Dermatol. 133, 78\u201386 (2013).","journal-title":"J. Invest. Dermatol."},{"key":"71014_CR32","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.jneuroim.2014.11.018","volume":"278","author":"M Nikodemova","year":"2015","unstructured":"Nikodemova, M. et al. Microglial numbers attain adult levels after undergoing a rapid decrease in cell number in the third postnatal week. J. Neuroimmunol. 278, 280\u2013288 (2015).","journal-title":"J. Neuroimmunol."},{"key":"71014_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46315-7","volume":"15","author":"A Podlesny-Drabiniok","year":"2024","unstructured":"Podlesny-Drabiniok, A. et al. BHLHE40\/41 regulate microglia and peripheral macrophage responses associated with Alzheimer\u2019s disease and other disorders of lipid-rich tissues. Nat. Commun. 15, 2058 (2024).","journal-title":"Nat. Commun."},{"key":"71014_CR34","doi-asserted-by":"publisher","first-page":"1896","DOI":"10.1038\/nn.3554","volume":"16","author":"SE Hickman","year":"2013","unstructured":"Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896\u20131905 (2013).","journal-title":"Nat. Neurosci."},{"key":"71014_CR35","doi-asserted-by":"crossref","unstructured":"Jin, K. et al. Brain-wide cell-type-specific transcriptomic signatures of healthy ageing in mice. Nature, 638, 182\u2013196 (2025).","DOI":"10.1038\/s41586-024-08350-8"},{"key":"71014_CR36","doi-asserted-by":"publisher","DOI":"10.1186\/s13550-020-00673-7","volume":"10","author":"VM Baart","year":"2020","unstructured":"Baart, V. M. et al. Molecular imaging of the urokinase plasminogen activator receptor: opportunities beyond cancer. EJNMMI Res. 10, 87 (2020).","journal-title":"EJNMMI Res."},{"key":"71014_CR37","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.104962","volume":"143","author":"T Schwabe","year":"2020","unstructured":"Schwabe, T., Srinivasan, K. & Rhinn, H. Shifting paradigms: the central role of microglia in Alzheimer\u2019s disease. Neurobiol. Dis. 143, 104962 (2020).","journal-title":"Neurobiol. Dis."},{"key":"71014_CR38","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.jneuroim.2006.01.005","volume":"173","author":"RM Cowell","year":"2006","unstructured":"Cowell, R. M., Xu, H., Parent, J. M. & Silverstein, F. S. Microglial expression of chemokine receptor CCR5 during rat forebrain development and after perinatal hypoxia-ischemia. J. Neuroimmunol. 173, 155\u2013165 (2006).","journal-title":"J. Neuroimmunol."},{"key":"71014_CR39","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.nbd.2015.08.025","volume":"83","author":"YR Choi","year":"2015","unstructured":"Choi, Y. R. et al. FcgammaRIIB mediates the inhibitory effect of aggregated alpha-synuclein on microglial phagocytosis. Neurobiol. Dis. 83, 90\u201399 (2015).","journal-title":"Neurobiol. Dis."},{"key":"71014_CR40","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1286-2","volume":"15","author":"GP Williams","year":"2018","unstructured":"Williams, G. P. et al. Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson\u2019s disease. J. Neuroinflamm. 15, 244 (2018).","journal-title":"J. Neuroinflamm."},{"key":"71014_CR41","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s40478-015-0209-z","volume":"3","author":"AD Bachstetter","year":"2015","unstructured":"Bachstetter, A. D. et al. Disease-related microglia heterogeneity in the hippocampus of Alzheimer\u2019s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol. Commun. 3, 32 (2015).","journal-title":"Acta Neuropathol. Commun."},{"key":"71014_CR42","volume":"12","author":"AC Martini","year":"2020","unstructured":"Martini, A. C. et al. Distribution of microglial phenotypes as a function of age and Alzheimer\u2019s disease neuropathology in the brains of people with Down syndrome. Alzheimers Dement. 12, e12113 (2020).","journal-title":"Alzheimers Dement."},{"key":"71014_CR43","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/s40478-023-01568-z","volume":"11","author":"LA Seeker","year":"2023","unstructured":"Seeker, L. A. et al. Brain matters: unveiling the distinct contributions of region, age, and sex to glia diversity and CNS function. Acta Neuropathol. Commun. 11, 84 (2023).","journal-title":"Acta Neuropathol. Commun."},{"key":"71014_CR44","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41586-021-03910-8","volume":"598","author":"A Bhaduri","year":"2021","unstructured":"Bhaduri, A. et al. An atlas of cortical arealization identifies dynamic molecular signatures. Nature 598, 200\u2013204 (2021).","journal-title":"Nature"},{"key":"71014_CR45","doi-asserted-by":"crossref","unstructured":"Cao J. et al. A human cell atlas of fetal gene expression. Science 370, eaba7721 (2020).","DOI":"10.1126\/science.aba7721"},{"key":"71014_CR46","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.1038\/s41593-024-01774-5","volume":"27","author":"MI Gabitto","year":"2024","unstructured":"Gabitto, M. I. et al. Integrated multimodal cell atlas of Alzheimer\u2019s disease. Nat. Neurosci. 27, 2366\u20132383 (2024).","journal-title":"Nat. Neurosci."},{"key":"71014_CR47","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/s41593-022-01061-1","volume":"25","author":"T Kamath","year":"2022","unstructured":"Kamath, T. et al. Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson\u2019s disease. Nat. Neurosci. 25, 588\u2013595 (2022).","journal-title":"Nat. Neurosci."},{"key":"71014_CR48","doi-asserted-by":"publisher","first-page":"2091","DOI":"10.1016\/j.neuron.2021.05.003","volume":"109","author":"F Ayhan","year":"2021","unstructured":"Ayhan, F. et al. Resolving cellular and molecular diversity along the hippocampal anterior-to-posterior axis in humans. Neuron 109, 2091\u20132105.e2096 (2021).","journal-title":"Neuron"},{"key":"71014_CR49","doi-asserted-by":"publisher","first-page":"E1738","DOI":"10.1073\/pnas.1525528113","volume":"113","author":"ML Bennett","year":"2016","unstructured":"Bennett, M. L. et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl. Acad. Sci. USA 113, E1738\u2013E1746 (2016).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"71014_CR50","doi-asserted-by":"publisher","first-page":"2832","DOI":"10.1016\/j.molcel.2022.05.024","volume":"82","author":"G Unlu","year":"2022","unstructured":"Unlu, G. et al. Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability. Mol. Cell 82, 2832\u20132843.e2837 (2022).","journal-title":"Mol. Cell"},{"key":"71014_CR51","doi-asserted-by":"publisher","first-page":"13421","DOI":"10.1074\/jbc.RA119.007645","volume":"294","author":"K Namekata","year":"2019","unstructured":"Namekata, K. et al. DOCK8 is expressed in microglia, and it regulates microglial activity during neurodegeneration in murine disease models. J. Biol. Chem. 294, 13421\u201313433 (2019).","journal-title":"J. Biol. Chem."},{"key":"71014_CR52","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1002\/glia.23097","volume":"65","author":"A Mildner","year":"2017","unstructured":"Mildner, A., Huang, H., Radke, J., Stenzel, W. & Priller, J. P2Y(12) receptor is expressed on human microglia under physiological conditions throughout development and is sensitive to neuroinflammatory diseases. Glia 65, 375\u2013387 (2017).","journal-title":"Glia"},{"key":"71014_CR53","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abg2919","volume":"13","author":"JV Pluvinage","year":"2021","unstructured":"Pluvinage, J. V. et al. The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C. Sci. Transl. Med. 13, eabg2919 (2021).","journal-title":"Sci. Transl. Med."},{"key":"71014_CR54","doi-asserted-by":"publisher","first-page":"2679","DOI":"10.1038\/s41591-024-03150-z","volume":"30","author":"X Chen","year":"2024","unstructured":"Chen, X. et al. A brain cell atlas integrating single-cell transcriptomes across human brain regions. Nat. Med 30, 2679\u20132691 (2024).","journal-title":"Nat. Med"},{"key":"71014_CR55","doi-asserted-by":"publisher","first-page":"3434","DOI":"10.1073\/pnas.1801693115","volume":"115","author":"A Hirano","year":"2018","unstructured":"Hirano, A. et al. DEC2 modulates orexin expression and regulates sleep. Proc. Natl. Acad. Sci. USA 115, 3434\u20133439 (2018).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"71014_CR56","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.5665\/sleep.3924","volume":"37","author":"R Pellegrino","year":"2014","unstructured":"Pellegrino, R. et al. A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans. Sleep 37, 1327\u20131336 (2014).","journal-title":"Sleep"},{"key":"71014_CR57","doi-asserted-by":"crossref","unstructured":"Vaidyanathan T. V., Collard M., Yokoyama S., Reitman M. E., Poskanzer K. E. Cortical astrocytes independently regulate sleep depth and duration via separate GPCR pathways. eLife 10, e63329 (2021).","DOI":"10.7554\/eLife.63329"},{"key":"71014_CR58","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.conb.2017.02.008","volume":"44","author":"PG Haydon","year":"2017","unstructured":"Haydon, P. G. Astrocytes and the modulation of sleep. Curr. Opin. Neurobiol. 44, 28\u201333 (2017).","journal-title":"Curr. Opin. Neurobiol."},{"key":"71014_CR59","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1016\/j.neuron.2017.01.014","volume":"93","author":"TE Scammell","year":"2017","unstructured":"Scammell, T. E., Arrigoni, E. & Lipton, J. O. Neural circuitry of wakefulness and sleep. Neuron 93, 747\u2013765 (2017).","journal-title":"Neuron"},{"key":"71014_CR60","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1002\/glia.23698","volume":"68","author":"ME Choudhury","year":"2020","unstructured":"Choudhury, M. E. et al. Phagocytic elimination of synapses by microglia during sleep. Glia 68, 44\u201359 (2020).","journal-title":"Glia"},{"key":"71014_CR61","doi-asserted-by":"crossref","unstructured":"Gu X. et al. Imaging microglia surveillance during sleep-wake cycles in freely behaving mice. eLife 12, RP86749 (2023).","DOI":"10.7554\/eLife.86749.3"},{"key":"71014_CR62","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/s41593-023-01548-5","volume":"27","author":"C Ma","year":"2024","unstructured":"Ma, C. et al. Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission. Nat. Neurosci. 27, 249\u2013258 (2024).","journal-title":"Nat. Neurosci."},{"key":"71014_CR63","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1002\/glia.24090","volume":"70","author":"G Corsi","year":"2022","unstructured":"Corsi, G. et al. Microglia modulate hippocampal synaptic transmission and sleep duration along the light\/dark cycle. Glia 70, 89\u2013105 (2022).","journal-title":"Glia"},{"key":"71014_CR64","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24915-x","volume":"12","author":"H Liu","year":"2021","unstructured":"Liu, H. et al. Microglia modulate stable wakefulness via the thalamic reticular nucleus in mice. Nat. Commun. 12, 4646 (2021).","journal-title":"Nat. Commun."},{"key":"71014_CR65","doi-asserted-by":"crossref","unstructured":"Hall S., Deurveilher S., Robertson G. S., Semba K. Homeostatic state of microglia in a rat model of chronic sleep restriction. Sleep 43, zsaa108 (2020).","DOI":"10.1093\/sleep\/zsaa108"},{"key":"71014_CR66","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1038\/ncb1919","volume":"11","author":"D Mori","year":"2009","unstructured":"Mori, D. et al. An essential role of the aPKC-Aurora A-NDEL1 pathway in neurite elongation by modulation of microtubule dynamics. Nat. Cell Biol. 11, 1057\u20131068 (2009).","journal-title":"Nat. Cell Biol."},{"key":"71014_CR67","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1016\/j.cell.2007.04.035","volume":"129","author":"EN Pugacheva","year":"2007","unstructured":"Pugacheva, E. N., Jablonski, S. A., Hartman, T. R., Henske, E. P. & Golemis, E. A. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129, 1351\u20131363 (2007).","journal-title":"Cell"},{"key":"71014_CR68","doi-asserted-by":"crossref","unstructured":"Rolfe, A. J., Bosco, D. B., Broussard, E. N. & Ren, Y. In vitro phagocytosis of myelin debris by bone marrow-derived macrophages. J. Vis. Exp. 56322 (2017).","DOI":"10.3791\/56322-v"},{"key":"71014_CR69","first-page":"Unit3 25","volume":"Chapter 3","author":"JN Larocca","year":"2007","unstructured":"Larocca, J. N. & Norton, W. T. Isolation of myelin. Curr. Protoc. Cell Biol. Chapter 3, Unit3 25 (2007).","journal-title":"Curr. Protoc. Cell Biol."},{"key":"71014_CR70","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1093\/brain\/aws262","volume":"136","author":"T Skripuletz","year":"2013","unstructured":"Skripuletz, T. et al. Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain 136, 147\u2013167 (2013).","journal-title":"Brain"},{"key":"71014_CR71","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/j.jaci.2013.05.033","volume":"132","author":"H Zhang","year":"2013","unstructured":"Zhang, H. et al. Profiling of human CD4+ T-cell subsets identifies the TH2-specific noncoding RNA GATA3-AS1. J. Allergy Clin. Immunol. 132, 1005\u20131008 (2013).","journal-title":"J. Allergy Clin. Immunol."},{"key":"71014_CR72","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gkae1142","volume":"53","author":"CCS Program","year":"2024","unstructured":"Program, C. C. S. et al. CZ CELLxGENE Discover: a single-cell data platform for scalable exploration, analysis and modeling of aggregated data. Nucleic Acids Res. 53, D886\u2013D900 (2024).","journal-title":"Nucleic Acids Res."},{"key":"71014_CR73","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0","volume":"19","author":"FA Wolf","year":"2018","unstructured":"Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).","journal-title":"Genome Biol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-71014-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-71014-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-71014-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:02:55Z","timestamp":1781222575000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-71014-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":73,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["71014"],"URL":"https:\/\/doi.org\/10.1038\/s41467-026-71014-w","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]},"assertion":[{"value":"13 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5238"}}