A multimodal cell census and atlas of the mammalian primary motor cortex
Authors:   BRAIN Initiative Cell Census Network (BICCN),   BRAIN Initiative Cell Census Network (BICCN) Corresponding authors, Callaway Edward M. , Dong Hong-Wei , Ecker Joseph R. , Hawrylycz Michael J. , Huang Z. Josh , Lein Ed S. , Ngai John , Osten Pavel , Ren Bing , Tolias Andreas Savas , White Owen , Zeng Hongkui , Zhuang Xiaowei ,   BICCN contributing principal investigators, Ascoli Giorgio A. , Behrens M. Margarita , Chun Jerold , Feng Guoping , Gee James C. , Ghosh Satrajit S. , Halchenko Yaroslav O. , Hertzano Ronna , Lim Byung Kook , Martone Maryann E. , Ng Lydia , Pachter Lior , Ropelewski Alexander J. , Tickle Timothy L. , Yang X. William , Zhang Kun ,   Principal manuscript editors,   Manuscript writing and figure generation, Bakken Trygve E. , Berens Philipp , Daigle Tanya L. , Harris Julie A. , Jorstad Nikolas L. , Kalmbach Brian E. , Kobak Dmitry , Li Yang Eric , Liu Hanqing , Matho Katherine S. , Mukamel Eran A. , Naeemi Maitham , Scala Federico , Tan Pengcheng , Ting Jonathan T. , Xie Fangming , Zhang Meng , Zhang Zhuzhu , Zhou Jingtian , Zingg Brian ,   Analysis coordination,   Integrated data analysis, Armand Ethan , Yao Zizhen ,   scRNA-seq and snRNA-seq data generation and processing, Bertagnolli Darren , Casper Tamara , Crichton Kirsten , Dee Nick , Diep Dinh , Ding Song-Lin , Dong Weixiu , Dougherty Elizabeth L. , Fong Olivia , Goldman Melissa , Goldy Jeff , Hodge Rebecca D. , Hu Lijuan , Keene C. Dirk , Krienen Fenna M. , Kroll Matthew , Lake Blue B. , Lathia Kanan , Linnarsson Sten , Liu Christine S. , Macosko Evan Z. , McCarroll Steven A. , McMillen Delissa , Nadaf Naeem M. , Nguyen Thuc Nghi , Palmer Carter R. , Pham Thanh , Plongthongkum Nongluk , Reed Nora M. , Regev Aviv , Rimorin Christine , Romanow William J. , Savoia Steven , Siletti Kimberly , Smith Kimberly , Sulc Josef , Tasic Bosiljka , Tieu Michael , Torkelson Amy , Tung Herman , van Velthoven Cindy T. J. , Vanderburg Charles R. , Yanny Anna Marie ,   ATAC-seq data generation and processing, Fang Rongxin , Hou Xiaomeng , Lucero Jacinta D. , Osteen Julia K. , Pinto-Duarte Antonio , Poirion Olivier , Preissl Sebastian , Wang Xinxin ,   Methylcytosine data production and analysis, Aldridge Andrew I. , Bartlett Anna , Boggeman Lara , O’Connor Carolyn , Castanon Rosa G. , Chen Huaming , Fitzpatrick Conor , Luo Chongyuan , Nery Joseph R. , Nunn Michael , Rivkin Angeline C. , Tian Wei ,   Epi-retro-seq data generation and processing, Dominguez Bertha , Ito-Cole Tony , Jacobs Matthew , Jin Xin , Lee Cheng-Ta , Lee Kuo-Fen , Miyazaki Paula Assakura , Pang Yan , Rashid Mohammad , Smith Jared B. , Vu Minh , Williams Elora ,   ‘Omics data analysis, Biancalani Tommaso , Booeshaghi A. Sina , Crow Megan , Dudoit Sandrine , Fischer Stephan , Gillis Jesse , Hu Qiwen , Kharchenko Peter V. , Niu Sheng-Yong , Ntranos Vasilis , Purdom Elizabeth , Risso Davide , de Bézieux Hector Roux , Somasundaram Saroja , Street Kelly , Svensson Valentine , Vaishnav Eeshit Dhaval , Van den Berge Koen , Welch Joshua D. ,   Tracing and connectivity data generation, An Xu , Bateup Helen S. , Bowman Ian , Chance Rebecca K. , Foster Nicholas N. , Galbavy William , Gong Hui , Gou Lin , Hatfield Joshua T. , Hintiryan Houri , Hirokawa Karla E. , Kim Gukhan , Kramer Daniel J. , Li Anan , Li Xiangning , Luo Qingming , Muñoz-Castañeda Rodrigo , Stafford David A. ,   Morphology data generation and reconstruction, Feng Zhao , Jia Xueyan , Jiang Shengdian , Jiang Tao , Kuang Xiuli , Larsen Rachael , Lesnar Phil , Li Yaoyao , Li Yuanyuan , Liu Lijuan , Peng Hanchuan , Qu Lei , Ren Miao , Ruan Zongcai , Shen Elise , Song Yuanyuan , Wakeman Wayne , Wang Peng , Wang Yimin , Wang Yun , Yin Lulu , Yuan Jing , Zhao Sujun , Zhao Xuan ,   OLST/STPT and other data generation, Narasimhan Arun , Palaniswamy Ramesh ,   Morphology, connectivity and imaging analysis, Banerjee Samik , Ding Liya , Huilgol Dhananjay , Huo Bingxing , Kuo Hsien-Chi , Laturnus Sophie , Li Xu , Mitra Partha P. , Mizrachi Judith , Wang Quanxin , Xie Peng , Xiong Feng , Yu Yang ,   Spatially resolved single-cell transcriptomics (MERFISH), Eichhorn Stephen W. ,   Multimodal profiling (Patch-seq), Berg Jim , Bernabucci Matteo , Bernaerts Yves , Cadwell Cathryn René , Castro Jesus Ramon , Dalley Rachel , Hartmanis Leonard , Horwitz Gregory D. , Jiang Xiaolong , Ko Andrew L. , Miranda Elanine , Mulherkar Shalaka , Nicovich Philip R. , Owen Scott F. , Sandberg Rickard , Sorensen Staci A. , Tan Zheng Huan ,   Transgenic tools, Allen Shona , Hockemeyer Dirk , Lee Angus Y. , Veldman Matthew B. ,   NeMO archive and analytics, Adkins Ricky S. , Ament Seth A. , Bravo Héctor Corrada , Carter Robert , Chatterjee Apaala , Colantuoni Carlo , Crabtree Jonathan , Creasy Heather , Felix Victor , Giglio Michelle , Herb Brian R. , Kancherla Jayaram , Mahurkar Anup , McCracken Carrie , Nickel Lance , Olley Dustin , Orvis Joshua , Schor Michael ,   Brain Image Library (BIL) archive, Hood Greg ,   DANDI archive, Dichter Benjamin , Grauer Michael , Helba Brian ,   Brain Cell Data Center (BCDC), Bandrowski Anita , Barkas Nikolaos , Carlin Benjamin , D’Orazi Florence D. , Degatano Kylee , Gillespie Thomas H. , Khajouei Farzaneh , Konwar Kishori , Thompson Carol ,   Project management, Kelly Kathleen , Mok Stephanie , Sunkin Susan 
Published: October 2021

AbstractHere 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.