@article{a155169a43974d338f232d2047d9ad59,
title = "A multimodal cell census and atlas of the mammalian primary motor cortex",
abstract = "Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1-5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.",
author = "{BRAIN Initiative Cell Census Network (BICCN)} and Callaway, {Edward M.} and Dong, {Hong Wei} and Ecker, {Joseph R.} and Hawrylycz, {Michael J.} and Huang, {Z. Josh} and Lein, {Ed S.} and John Ngai and Pavel Osten and Bing Ren and Tolias, {Andreas Savas} and Owen White and Hongkui Zeng and Xiaowei Zhuang and Ascoli, {Giorgio A.} and Behrens, {M. Margarita} and Jerold Chun and Guoping Feng and Gee, {James C.} and Ghosh, {Satrajit S.} and Ronna Hertzano and Lim, {Byung Kook} and Martone, {Maryann E.} and Lior Pachter and Ropelewski, {Alexander J.} and Tickle, {Timothy L.} and Yang, {X. William} and Bakken, {Trygve E.} and Philipp Berens and Daigle, {Tanya L.} and Jorstad, {Nikolas L.} and Kalmbach, {Brian E.} and Matho, {Katherine S.} and Mukamel, {Eran A.} and Maitham Naeemi and Federico Scala and Ting, {Jonathan T.} and Meng Zhang and Zhuzhu Zhang and Brian Zingg and Harris, {Julie A.} and Ethan Armand and Pengcheng Tan and Fangming Xie and Jingtian Zhou and Darren Bertagnolli and Tamara Casper and Kirsten Crichton and Nick Dee and Dinh Diep and Krienen, {Fenna M.}",
note = "Funding Information: Acknowledgements We thank additional members of our laboratories and institutions who contributed to the experimental and analytical components of this project. This work was supported by grants from the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) under: U24MH114827, U19MH114821, U19MH114830, U19MH114831, U01MH117072, U01MH114829, U01MH121282, U01MH117023, U01MH114825, U01MH114819, U01MH114812, U01MH121260, U01MH114824, U01MH117079, U01MH116990, U01MH114828, R24MH117295, R24MH114793, R24MH114788, R24MH114815. We thank NIH BICCN program officers, in particular Yong Yao, for their guidance and support throughout this study. Additional support: NIH grants R01NS39600 and R01NS86082 to G.A.A. H.S.B. is a Chan Zuckerberg Biohub Investigator. Deutsche Forschungsgemeinschaft through a Heisenberg Professorship (BE5601/4-1), the Cluster of Excellence Machine Learning—New Perspectives for Science (EXC 2064, project number 390727645) and the Collaborative Research Center 1233 Robust Vision (project number 276693517), the German Federal Ministry of Education and Research (FKZ 01GQ1601 and 01IS18039A) to P.B. This work was supported in part by the Flow Cytometry Core Facility of the Salk Institute with funding from NIH-NCI CCSG: P30 014195 and Shared Instrumentation Grant S10-OD023689. NIH grant R01MH094360 to H.-W.D. We thank M. Becerra, T. Boesen, C. Cao, M. Fayzullina, K. Cotter, L. Gao, L. Gacia, L. Korobkova, D. Lo, C. Mun, S. Yamashita and M Zhu for their technical and informatics support. Hearing Health Foundation Hearing Restoration Project grant to R.H. NIH grant OD010425 to G.D.H. NIH grant RF1MH114126 to E.S.L. and J.T.T. National Natural Science Foundation of China (NNSFC) grant 61890953 to H.G. NNSFC grant 81827901 to Q.L. This project was supported in part by NIH grants P51OD010425 from the Office of Research Infrastructure Programs (ORIP) and UL1TR000423 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH, ORIP, NCATS or the Institute of Translational Health Sciences at the Washington National Primate Research Center. NNSFC grant 61871411 and the University Synergy Innovation Program of Anhui Province GXXT-2019-008 to L.Q. Howard Hughes Medical Institute and the Klarman Cell Observatory for A.R. Howard Hughes Medical Institute for J.R.E. and X. Zhuang. NNSFC Grant 32071367 and NSF Shanghai Grant 20ZR1420100 to Yimin Wang. NIH grants R01EY023173 and U01MH105982 to H.Z. Researchers from Allen Institute for Brain Science wish to thank the Allen Institute founder, P. G. Allen, for his vision, encouragement and support. Publisher Copyright: {\textcopyright} The Author(s) 2021.",
year = "2021",
doi = "10.1038/s41586-021-03950-0",
language = "English (US)",
volume = "598",
pages = "86--102",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
}