Transcriptional Landscape of the Prenatal Human Brain

Summary The anatomical and functional architecture of the human brain is largely determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and postmitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and human-expanded outer subventricular zones. Both germinal and postmitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in frontal lobe. Finally, many neurodevelopmental disorder and human evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development

Morphological diversity of single neurons in molecularly defined cell types.

Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types1,2, yet our knowledge of its diversity remains limited. Here, to systematically examine complete single-neuron morphologies on a brain-wide scale, we established a pipeline encompassing sparse labelling, whole-brain imaging, reconstruction, registration and analysis. We fully reconstructed 1,741 neurons from cortex, claustrum, thalamus, striatum and other brain regions in mice. We identified 11 major projection neuron types with distinct morphological features and corresponding transcriptomic identities. Extensive projectional diversity was found within each of these major types, on the basis of which some types were clustered into more refined subtypes. This diversity follows a set of generalizable principles that govern long-range axonal projections at different levels, including molecular correspondence, divergent or convergent projection, axon termination pattern, regional specificity, topography, and individual cell variability. Although clear concordance with transcriptomic profiles is evident at the level of major projection type, fine-grained morphological diversity often does not readily correlate with transcriptomic subtypes derived from unsupervised clustering, highlighting the need for single-cell cross-modality studies. Overall, our study demonstrates the crucial need for quantitative description of complete single-cell anatomy in cell-type classification, as single-cell morphological diversity reveals a plethora of ways in which different cell types and their individual members may contribute to the configuration and function of their respective circuits

A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACT We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) 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. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties

Comprehensive cellular‐resolution atlas of the adult human brain

ABSTRACT Detailed anatomical understanding of the human brain is essential for unraveling its functional architecture, yet current reference atlases have major limitations such as lack of whole‐brain coverage, relatively low image resolution, and sparse structural annotation. We present the first digital human brain atlas to incorporate neuroimaging, high‐resolution histology, and chemoarchitecture across a complete adult female brain, consisting of magnetic resonance imaging (MRI), diffusion‐weighted imaging (DWI), and 1,356 large‐format cellular resolution (1 µm/pixel) Nissl and immunohistochemistry anatomical plates. The atlas is comprehensively annotated for 862 structures, including 117 white matter tracts and several novel cyto‐ and chemoarchitecturally defined structures, and these annotations were transferred onto the matching MRI dataset. Neocortical delineations were done for sulci, gyri, and modified Brodmann areas to link macroscopic anatomical and microscopic cytoarchitectural parcellations. Correlated neuroimaging and histological structural delineation allowed fine feature identification in MRI data and subsequent structural identification in MRI data from other brains. This interactive online digital atlas is integrated with existing Allen Institute for Brain Science gene expression atlases and is publicly accessible as a resource for the neuroscience community. J. Comp. Neurol. 524:3127–3481, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc

Transcriptional landscape of the prenatal human brain.

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development

Transcriptional landscape of the prenatal human brain

The anatomical and functional architecture of the human brain is largely determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and postmitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and human-expanded outer subventricular zones. Both germinal and postmitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in frontal lobe. Finally, many neurodevelopmental disorder and human evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development

A multimodal cell census and atlas of the mammalian primary motor cortex

none258Here 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.openCallaway, 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; 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; 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; Armand, Ethan; Yao, Zizhen; 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; Fang, Rongxin; Hou, Xiaomeng; Lucero, Jacinta D.; Osteen, Julia K.; Pinto-Duarte, Antonio; Poirion, Olivier; Preissl, Sebastian; Wang, Xinxin; 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; 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; 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.; 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.; 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; Narasimhan, Arun; Palaniswamy, Ramesh; 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; Eichhorn, Stephen W.; 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; Allen, Shona; Hockemeyer, Dirk; Lee, Angus Y.; Veldman, Matthew B.; 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; Hood, Greg; Dichter, Benjamin; Grauer, Michael; Helba, Brian; Bandrowski, Anita; Barkas, Nikolaos; Carlin, Benjamin; D’Orazi, Florence D.; Degatano, Kylee; Gillespie, Thomas H.; Khajouei, Farzaneh; Konwar, Kishori; Thompson, Carol; Kelly, Kathleen; Mok, Stephanie; Sunkin, SusanCallaway, 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; 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; 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; Armand, Ethan; Yao, Zizhen; 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; Fang, Rongxin; Hou, Xiaomeng; Lucero, Jacinta D.; Osteen, Julia K.; Pinto-Duarte, Antonio; Poirion, Olivier; Preissl, Sebastian; Wang, Xinxin; 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; 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; 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.; 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.; 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; Narasimhan, Arun; Palaniswamy, Ramesh; 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; Eichhorn, Stephen W.; 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; Allen, Shona; Hockemeyer, Dirk; Lee, Angus Y.; Veldman, Matthew B.; 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; Hood, Greg; Dichter, Benjamin; Grauer, Michael; Helba, Brian; Bandrowski, Anita; Barkas, Nikolaos; Carlin, Benjamin; D’Orazi, Florence D.; Degatano, Kylee; Gillespie, Thomas H.; Khajouei, Farzaneh; Konwar, Kishori; Thompson, Carol; Kelly, Kathleen; Mok, Stephanie; Sunkin, Susa