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1. A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain

Author

Yao, Zizhen, van Velthoven, Cindy T. J., Kunst, Michael, Zhang, Meng, McMillen, Delissa, Lee, Changkyu, Jung, Won, Goldy, Jeff, Abdelhak, Aliya, Aitken, Matthew, Baker, Katherine, Baker, Pamela, Barkan, Eliza, Bertagnolli, Darren, Bhandiwad, Ashwin, Bielstein, Cameron, Bishwakarma, Prajal, Campos, Jazmin, Carey, Daniel, Casper, Tamara, Chakka, Anish Bhaswanth, Chakrabarty, Rushil, Chavan, Sakshi, Chen, Min, Clark, Michael, Close, Jennie, Crichton, Kirsten, Daniel, Scott, DiValentin, Peter, Dolbeare, Tim, Ellingwood, Lauren, Fiabane, Elysha, Fliss, Timothy, Gee, James, Gerstenberger, James, Glandon, Alexandra, Gloe, Jessica, Gould, Joshua, Gray, James, Guilford, Nathan, Guzman, Junitta, Hirschstein, Daniel, Ho, Windy, Hooper, Marcus, Huang, Mike, Hupp, Madie, Jin, Kelly, Kroll, Matthew, Lathia, Kanan, Leon, Arielle, Li, Su, Long, Brian, Madigan, Zach, Malloy, Jessica, Malone, Jocelin, Maltzer, Zoe, Martin, Naomi, McCue, Rachel, McGinty, Ryan, Mei, Nicholas, Melchor, Jose, Meyerdierks, Emma, Mollenkopf, Tyler, Moonsman, Skyler, Nguyen, Thuc Nghi, Otto, Sven, Pham, Trangthanh, Rimorin, Christine, Ruiz, Augustin, Sanchez, Raymond, Sawyer, Lane, Shapovalova, Nadiya, Shepard, Noah, Slaughterbeck, Cliff, Sulc, Josef, Tieu, Michael, Torkelson, Amy, Tung, Herman, Valera Cuevas, Nasmil, Vance, Shane, Wadhwani, Katherine, Ward, Katelyn, Levi, Boaz, Farrell, Colin, Young, Rob, Staats, Brian, Wang, Ming-Qiang Michael, Thompson, Carol L., Mufti, Shoaib, Pagan, Chelsea M., Kruse, Lauren, Dee, Nick, Sunkin, Susan M., Esposito, Luke, Hawrylycz, Michael J., Waters, Jack, Ng, Lydia, Smith, Kimberly, Tasic, Bosiljka, Zhuang, Xiaowei, and Zeng, Hongkui

Published
2023
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2. A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex

Author

Yao, Zizhen, Liu, Hanqing, Xie, Fangming, Fischer, Stephan, Adkins, Ricky S, Aldridge, Andrew I, Ament, Seth A, Bartlett, Anna, Behrens, M Margarita, Van den Berge, Koen, Bertagnolli, Darren, de Bézieux, Hector Roux, Biancalani, Tommaso, Booeshaghi, A Sina, Bravo, Héctor Corrada, Casper, Tamara, Colantuoni, Carlo, Crabtree, Jonathan, Creasy, Heather, Crichton, Kirsten, Crow, Megan, Dee, Nick, Dougherty, Elizabeth L, Doyle, Wayne I, Dudoit, Sandrine, Fang, Rongxin, Felix, Victor, Fong, Olivia, Giglio, Michelle, Goldy, Jeff, Hawrylycz, Mike, Herb, Brian R, Hertzano, Ronna, Hou, Xiaomeng, Hu, Qiwen, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, Li, Yang Eric, Lucero, Jacinta D, Luo, Chongyuan, Mahurkar, Anup, McMillen, Delissa, Nadaf, Naeem M, Nery, Joseph R, Nguyen, Thuc Nghi, Niu, Sheng-Yong, Ntranos, Vasilis, Orvis, Joshua, Osteen, Julia K, Pham, Thanh, Pinto-Duarte, Antonio, Poirion, Olivier, Preissl, Sebastian, Purdom, Elizabeth, Rimorin, Christine, Risso, Davide, Rivkin, Angeline C, Smith, Kimberly, Street, Kelly, Sulc, Josef, Svensson, Valentine, Tieu, Michael, Torkelson, Amy, Tung, Herman, Vaishnav, Eeshit Dhaval, Vanderburg, Charles R, van Velthoven, Cindy, Wang, Xinxin, White, Owen R, Huang, Z Josh, Kharchenko, Peter V, Pachter, Lior, Ngai, John, Regev, Aviv, Tasic, Bosiljka, Welch, Joshua D, Gillis, Jesse, Macosko, Evan Z, Ren, Bing, Ecker, Joseph R, Zeng, Hongkui, and Mukamel, Eran A

Subjects
Human Genome, Neurosciences, Genetics, Bioengineering, Biotechnology, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Animals, Atlases as Topic, Datasets as Topic, Epigenesis, Genetic, Epigenomics, Female, Gene Expression Profiling, Male, Mice, Motor Cortex, Neurons, Organ Specificity, Reproducibility of Results, Single-Cell Analysis, Transcriptome, General Science & Technology
Abstract

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain1-3. With the proliferation of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of cell-type organization. Here we generated transcriptomes and epigenomes from more than 500,000 individual cells in the mouse primary motor cortex, a structure that has an evolutionarily conserved role in locomotion. We developed computational and statistical methods to integrate multimodal data and quantitatively validate cell-type reproducibility. The resulting reference atlas-containing over 56 neuronal cell types that are highly replicable across analysis methods, sequencing technologies and modalities-is a comprehensive molecular and genomic account of the diverse neuronal and non-neuronal cell types in the mouse primary motor cortex. The atlas includes a population of excitatory neurons that resemble pyramidal cells in layer 4 in other cortical regions4. We further discovered thousands of concordant marker genes and gene regulatory elements for these cell types. Our results highlight the complex molecular regulation of cell types in the brain and will directly enable the design of reagents to target specific cell types in the mouse primary motor cortex for functional analysis.

Published
2021

3. Comparative cellular analysis of motor cortex in human, marmoset and mouse

Author

Bakken, Trygve E, Jorstad, Nikolas L, Hu, Qiwen, Lake, Blue B, Tian, Wei, Kalmbach, Brian E, Crow, Megan, Hodge, Rebecca D, Krienen, Fenna M, Sorensen, Staci A, Eggermont, Jeroen, Yao, Zizhen, Aevermann, Brian D, Aldridge, Andrew I, Bartlett, Anna, Bertagnolli, Darren, Casper, Tamara, Castanon, Rosa G, Crichton, Kirsten, Daigle, Tanya L, Dalley, Rachel, Dee, Nick, Dembrow, Nikolai, Diep, Dinh, Ding, Song-Lin, Dong, Weixiu, Fang, Rongxin, Fischer, Stephan, Goldman, Melissa, Goldy, Jeff, Graybuck, Lucas T, Herb, Brian R, Hou, Xiaomeng, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, van Lew, Baldur, Li, Yang Eric, Liu, Christine S, Liu, Hanqing, Lucero, Jacinta D, Mahurkar, Anup, McMillen, Delissa, Miller, Jeremy A, Moussa, Marmar, Nery, Joseph R, Nicovich, Philip R, Niu, Sheng-Yong, Orvis, Joshua, Osteen, Julia K, Owen, Scott, Palmer, Carter R, Pham, Thanh, Plongthongkum, Nongluk, Poirion, Olivier, Reed, Nora M, Rimorin, Christine, Rivkin, Angeline, Romanow, William J, Sedeño-Cortés, Adriana E, Siletti, Kimberly, Somasundaram, Saroja, Sulc, Josef, Tieu, Michael, Torkelson, Amy, Tung, Herman, Wang, Xinxin, Xie, Fangming, Yanny, Anna Marie, Zhang, Renee, Ament, Seth A, Behrens, M Margarita, Bravo, Hector Corrada, Chun, Jerold, Dobin, Alexander, Gillis, Jesse, Hertzano, Ronna, Hof, Patrick R, Höllt, Thomas, Horwitz, Gregory D, Keene, C Dirk, Kharchenko, Peter V, Ko, Andrew L, Lelieveldt, Boudewijn P, Luo, Chongyuan, Mukamel, Eran A, Pinto-Duarte, António, Preissl, Sebastian, Regev, Aviv, Ren, Bing, Scheuermann, Richard H, Smith, Kimberly, Spain, William J, White, Owen R, Koch, Christof, Hawrylycz, Michael, Tasic, Bosiljka, Macosko, Evan Z, McCarroll, Steven A, and Ting, Jonathan T

Subjects
Human Genome, Neurosciences, Genetics, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Animals, Atlases as Topic, Callithrix, Epigenesis, Genetic, Epigenomics, Female, GABAergic Neurons, Gene Expression Profiling, Glutamates, Humans, In Situ Hybridization, Fluorescence, Male, Mice, Middle Aged, Motor Cortex, Neurons, Organ Specificity, Phylogeny, Single-Cell Analysis, Species Specificity, Transcriptome, General Science & Technology
Abstract

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

Published
2021

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

Author

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, 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 TJ, Vanderburg, Charles R, Yanny, Anna Marie, Fang, Rongxin, Hou, Xiaomeng, Lucero, Jacinta D, Osteen, Julia K, Pinto-Duarte, Antonio, and Poirion, Olivier

Subjects
Genetics, Neurosciences, Human Genome, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Animals, Atlases as Topic, Callithrix, Epigenomics, Female, Gene Expression Profiling, Glutamates, Humans, In Situ Hybridization, Fluorescence, Male, Mice, Motor Cortex, Neurons, Organ Specificity, Phylogeny, Single-Cell Analysis, Species Specificity, Transcriptome, BRAIN Initiative Cell Census Network, General Science & Technology
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.

Published
2021

5. Human neocortical expansion involves glutamatergic neuron diversification

Author

Berg, Jim, Sorensen, Staci A., Ting, Jonathan T., Miller, Jeremy A., Chartrand, Thomas, Buchin, Anatoly, Bakken, Trygve E., Budzillo, Agata, Dee, Nick, Ding, Song-Lin, Gouwens, Nathan W., Hodge, Rebecca D., Kalmbach, Brian, Lee, Changkyu, Lee, Brian R., Alfiler, Lauren, Baker, Katherine, Barkan, Eliza, Beller, Allison, Berry, Kyla, Bertagnolli, Darren, Bickley, Kris, Bomben, Jasmine, Braun, Thomas, Brouner, Krissy, Casper, Tamara, Chong, Peter, Crichton, Kirsten, Dalley, Rachel, de Frates, Rebecca, Desta, Tsega, Lee, Samuel Dingman, D’Orazi, Florence, Dotson, Nadezhda, Egdorf, Tom, Enstrom, Rachel, Farrell, Colin, Feng, David, Fong, Olivia, Furdan, Szabina, Galakhova, Anna A., Gamlin, Clare, Gary, Amanda, Glandon, Alexandra, Goldy, Jeff, Gorham, Melissa, Goriounova, Natalia A., Gratiy, Sergey, Graybuck, Lucas, Gu, Hong, Hadley, Kristen, Hansen, Nathan, Heistek, Tim S., Henry, Alex M., Heyer, Djai B., Hill, DiJon, Hill, Chris, Hupp, Madie, Jarsky, Tim, Kebede, Sara, Keene, Lisa, Kim, Lisa, Kim, Mean-Hwan, Kroll, Matthew, Latimer, Caitlin, Levi, Boaz P., Link, Katherine E., Mallory, Matthew, Mann, Rusty, Marshall, Desiree, Maxwell, Michelle, McGraw, Medea, McMillen, Delissa, Melief, Erica, Mertens, Eline J., Mezei, Leona, Mihut, Norbert, Mok, Stephanie, Molnar, Gabor, Mukora, Alice, Ng, Lindsay, Ngo, Kiet, Nicovich, Philip R., Nyhus, Julie, Olah, Gaspar, Oldre, Aaron, Omstead, Victoria, Ozsvar, Attila, Park, Daniel, Peng, Hanchuan, Pham, Trangthanh, Pom, Christina A., Potekhina, Lydia, Rajanbabu, Ramkumar, Ransford, Shea, Reid, David, Rimorin, Christine, Ruiz, Augustin, Sandman, David, Sulc, Josef, Sunkin, Susan M., Szafer, Aaron, Szemenyei, Viktor, Thomsen, Elliot R., Tieu, Michael, Torkelson, Amy, Trinh, Jessica, Tung, Herman, Wakeman, Wayne, Waleboer, Femke, Ward, Katelyn, Wilbers, René, Williams, Grace, Yao, Zizhen, Yoon, Jae-Geun, Anastassiou, Costas, Arkhipov, Anton, Barzo, Pal, Bernard, Amy, Cobbs, Charles, de Witt Hamer, Philip C., Ellenbogen, Richard G., Esposito, Luke, Ferreira, Manuel, Gwinn, Ryder P., Hawrylycz, Michael J., Hof, Patrick R., Idema, Sander, Jones, Allan R., Keene, C. Dirk, Ko, Andrew L., Murphy, Gabe J., Ng, Lydia, Ojemann, Jeffrey G., Patel, Anoop P., Phillips, John W., Silbergeld, Daniel L., Smith, Kimberly, Tasic, Bosiljka, Yuste, Rafael, Segev, Idan, de Kock, Christiaan P. J., Mansvelder, Huibert D., Tamas, Gabor, Zeng, Hongkui, Koch, Christof, and Lein, Ed S.

Published
2021
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6. Molecular hallmarks of Alzheimer’s disease with a multimodal single cell atlas of the cortex

Author

Travaglini, Kyle J, primary, Gabitto, Mariano I, additional, Ariza, Jeanelle, additional, Ding, Yi, additional, Mahoney, Joseph T, additional, Casper, Tamara, additional, Chakrabarty, Rushil, additional, Clark, Michael, additional, Crane, Paul K, additional, Dee, Nick, additional, Ferrer, Rebecca, additional, Gatto, Nicole M, additional, Gloe, Jessica, additional, Goldy, Jeff, additional, Grabowski, Thomas J, additional, Guilford, Nathan, additional, Guzman, Junitta, additional, Hawrylycz, Michael J, additional, Hodge, Rebecca D, additional, Jayadev, Suman, additional, Kaplan, Eitan S, additional, Keene, C Dirk, additional, Larson, Eric B, additional, Latimer, Caitlin S, additional, Levi, Boaz P, additional, Melief, Erica J, additional, Meyerdierks, Emma, additional, Mukherjee, Shubhabrata, additional, Pham, Thanh, additional, Rachleff, Victoria M, additional, Smith, Kimberly, additional, Torkelson, Amy, additional, Lein, Ed S, additional, and Miller, Jeremy A, additional

Published
2023
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7. Multimodal and multiregional atlas of Alzheimer’s disease changes

Author

Gabitto, Mariano I, primary, Travaglini, Kyle J, additional, Ariza, Jeanelle, additional, Close, Jennie, additional, Ding, Yi, additional, Long, Brian, additional, Rachleff, Victoria M, additional, Chakrabarty, Rushil, additional, Crane, Paul K, additional, Ferrer, Rebecca, additional, Gatto, Nicole M, additional, Goldy, Jeff, additional, Grabowski, Thomas J, additional, Guilford, Nathan, additional, Guzman, Junitta, additional, Hawrylycz, Michael J, additional, Hodge, Rebecca D, additional, Jayadev, Suman, additional, Kaplan, Eitan S, additional, Keene, C Dirk, additional, Larson, Eric B, additional, Latimer, Caitlin S, additional, Levi, Boaz P, additional, Mahoney, Joseph T, additional, Melief, Erica J, additional, Miller, Jeremy A, additional, Mukherjee, Shubhabrata, additional, Pham, Thanh, additional, Smith, Kimberly, additional, Torkelson, Amy, additional, Chakka, Anish Bhaswanth, additional, and Lein, Ed S, additional

Published
2023
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8. Transcriptomic cytoarchitecture reveals principles of human neocortex organization

Author

Jorstad, Nikolas L., primary, Close, Jennie, additional, Johansen, Nelson, additional, Yanny, Anna Marie, additional, Barkan, Eliza R., additional, Travaglini, Kyle J., additional, Bertagnolli, Darren, additional, Campos, Jazmin, additional, Casper, Tamara, additional, Crichton, Kirsten, additional, Dee, Nick, additional, Ding, Song-Lin, additional, Gelfand, Emily, additional, Goldy, Jeff, additional, Hirschstein, Daniel, additional, Kiick, Katelyn, additional, Kroll, Matthew, additional, Kunst, Michael, additional, Lathia, Kanan, additional, Long, Brian, additional, Martin, Naomi, additional, McMillen, Delissa, additional, Pham, Trangthanh, additional, Rimorin, Christine, additional, Ruiz, Augustin, additional, Shapovalova, Nadiya, additional, Shehata, Soraya, additional, Siletti, Kimberly, additional, Somasundaram, Saroja, additional, Sulc, Josef, additional, Tieu, Michael, additional, Torkelson, Amy, additional, Tung, Herman, additional, Callaway, Edward M., additional, Hof, Patrick R., additional, Keene, C. Dirk, additional, Levi, Boaz P., additional, Linnarsson, Sten, additional, Mitra, Partha P., additional, Smith, Kimberly, additional, Hodge, Rebecca D., additional, Bakken, Trygve E., additional, and Lein, Ed S, additional

Published
2023
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9. Author Correction: Comparative cellular analysis of motor cortex in human, marmoset and mouse

Author

Bakken, Trygve E., Jorstad, Nikolas L., Hu, Qiwen, Lake, Blue B., Tian, Wei, Kalmbach, Brian E., Crow, Megan, Hodge, Rebecca D., Krienen, Fenna M., Sorensen, Staci A., Eggermont, Jeroen, Yao, Zizhen, Aevermann, Brian D., Aldridge, Andrew I., Bartlett, Anna, Bertagnolli, Darren, Casper, Tamara, Castanon, Rosa G., Crichton, Kirsten, Daigle, Tanya L., Dalley, Rachel, Dee, Nick, Dembrow, Nikolai, Diep, Dinh, Ding, Song-Lin, Dong, Weixiu, Fang, Rongxin, Fischer, Stephan, Goldman, Melissa, Goldy, Jeff, Graybuck, Lucas T., Herb, Brian R., Hou, Xiaomeng, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, van Lew, Baldur, Li, Yang Eric, Liu, Christine S., Liu, Hanqing, Lucero, Jacinta D., Mahurkar, Anup, McMillen, Delissa, Miller, Jeremy A., Moussa, Marmar, Nery, Joseph R., Nicovich, Philip R., Niu, Sheng-Yong, Orvis, Joshua, Osteen, Julia K., Owen, Scott, Palmer, Carter R., Pham, Thanh, Plongthongkum, Nongluk, Poirion, Olivier, Reed, Nora M., Rimorin, Christine, Rivkin, Angeline, Romanow, William J., Sedeño-Cortés, Adriana E., Siletti, Kimberly, Somasundaram, Saroja, Sulc, Josef, Tieu, Michael, Torkelson, Amy, Tung, Herman, Wang, Xinxin, Xie, Fangming, Yanny, Anna Marie, Zhang, Renee, Ament, Seth A., Behrens, M. Margarita, Bravo, Hector Corrada, Chun, Jerold, Dobin, Alexander, Gillis, Jesse, Hertzano, Ronna, Hof, Patrick R., Höllt, Thomas, Horwitz, Gregory D., Keene, C. Dirk, Kharchenko, Peter V., Ko, Andrew L., Lelieveldt, Boudewijn P., Luo, Chongyuan, Mukamel, Eran A., Pinto-Duarte, António, Preiss, Sebastian, Regev, Aviv, Ren, Bing, Scheuermann, Richard H., Smith, Kimberly, Spain, William J., White, Owen R., Koch, Christof, Hawrylycz, Michael, Tasic, Bosiljka, Macosko, Evan Z., McCarroll, Steven A., Ting, Jonathan T., Zeng, Hongkui, Zhang, Kun, Feng, Guoping, Ecker, Joseph R., Linnarsson, Sten, and Lein, Ed S.

Published
2022
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10. Author Correction: Human neocortical expansion involves glutamatergic neuron diversification

Author

Berg, Jim, Sorensen, Staci A., Ting, Jonathan T., Miller, Jeremy A., Chartrand, Thomas, Buchin, Anatoly, Bakken, Trygve E., Budzillo, Agata, Dee, Nick, Ding, Song-Lin, Gouwens, Nathan W., Hodge, Rebecca D., Kalmbach, Brian, Lee, Changkyu, Lee, Brian R., Alfiler, Lauren, Baker, Katherine, Barkan, Eliza, Beller, Allison, Berry, Kyla, Bertagnolli, Darren, Bickley, Kris, Bomben, Jasmine, Braun, Thomas, Brouner, Krissy, Casper, Tamara, Chong, Peter, Crichton, Kirsten, Dalley, Rachel, de Frates, Rebecca, Desta, Tsega, Lee, Samuel Dingman, D’Orazi, Florence, Dotson, Nadezhda, Egdorf, Tom, Enstrom, Rachel, Farrell, Colin, Feng, David, Fong, Olivia, Furdan, Szabina, Galakhova, Anna A., Gamlin, Clare, Gary, Amanda, Glandon, Alexandra, Goldy, Jeff, Gorham, Melissa, Goriounova, Natalia A., Gratiy, Sergey, Graybuck, Lucas, Gu, Hong, Hadley, Kristen, Hansen, Nathan, Heistek, Tim S., Henry, Alex M., Heyer, Djai B., Hill, DiJon, Hill, Chris, Hupp, Madie, Jarsky, Tim, Kebede, Sara, Keene, Lisa, Kim, Lisa, Kim, Mean-Hwan, Kroll, Matthew, Latimer, Caitlin, Levi, Boaz P., Link, Katherine E., Mallory, Matthew, Mann, Rusty, Marshall, Desiree, Maxwell, Michelle, McGraw, Medea, McMillen, Delissa, Melief, Erica, Mertens, Eline J., Mezei, Leona, Mihut, Norbert, Mok, Stephanie, Molnar, Gabor, Mukora, Alice, Ng, Lindsay, Ngo, Kiet, Nicovich, Philip R., Nyhus, Julie, Olah, Gaspar, Oldre, Aaron, Omstead, Victoria, Ozsvar, Attila, Park, Daniel, Peng, Hanchuan, Pham, Trangthanh, Pom, Christina A., Potekhina, Lydia, Rajanbabu, Ramkumar, Ransford, Shea, Reid, David, Rimorin, Christine, Ruiz, Augustin, Sandman, David, Sulc, Josef, Sunkin, Susan M., Szafer, Aaron, Szemenyei, Viktor, Thomsen, Elliot R., Tieu, Michael, Torkelson, Amy, Trinh, Jessica, Tung, Herman, Wakeman, Wayne, Waleboer, Femke, Ward, Katelyn, Wilbers, René, Williams, Grace, Yao, Zizhen, Yoon, Jae-Geun, Anastassiou, Costas, Arkhipov, Anton, Barzo, Pal, Bernard, Amy, Cobbs, Charles, de Witt Hamer, Philip C., Ellenbogen, Richard G., Esposito, Luke, Ferreira, Manuel, Gwinn, Ryder P., Hawrylycz, Michael J., Hof, Patrick R., Idema, Sander, Jones, Allan R., Keene, C. Dirk, Ko, Andrew L., Murphy, Gabe J., Ng, Lydia, Ojemann, Jeffrey G., Patel, Anoop P., Phillips, John W., Silbergeld, Daniel L., Smith, Kimberly, Tasic, Bosiljka, Yuste, Rafael, Segev, Idan, de Kock, Christiaan P. J., Mansvelder, Huibert D., Tamas, Gabor, Zeng, Hongkui, Koch, Christof, and Lein, Ed S.

Published
2022
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11. Cell-type specific molecular signatures of aging revealed in a brain-wide transcriptomic cell-type atlas

Author

Jin, Kelly, primary, Yao, Zizhen, additional, van Velthoven, Cindy T. J., additional, Kaplan, Eitan S., additional, Glattfelder, Katie, additional, Barlow, Samuel T., additional, Boyer, Gabriella, additional, Carey, Daniel, additional, Casper, Tamara, additional, Chakka, Anish Bhaswanth, additional, Chakrabarty, Rushil, additional, Clark, Michael, additional, Departee, Max, additional, Desierto, Marie, additional, Gary, Amanda, additional, Gloe, Jessica, additional, Goldy, Jeff, additional, Guilford, Nathan, additional, Guzman, Junitta, additional, Hirschstein, Daniel, additional, Lee, Changkyu, additional, Liang, Elizabeth, additional, Pham, Trangthanh, additional, Reding, Melissa, additional, Ronellenfitch, Kara, additional, Ruiz, Augustin, additional, Sevigny, Josh, additional, Shapovalova, Nadiya, additional, Shulga, Lyudmila, additional, Sulc, Josef, additional, Torkelson, Amy, additional, Tung, Herman, additional, Levi, Boaz, additional, Sunkin, Susan M., additional, Dee, Nick, additional, Esposito, Luke, additional, Smith, Kimberly, additional, Tasic, Bosiljka, additional, and Zeng, Hongkui, additional

Published
2023
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12. Integrated multimodal cell atlas of Alzheimer’s disease

Author

Gabitto, Mariano, primary, Travaglini, Kyle, additional, Ariza, Jeannelle, additional, Kaplan, Eitan, additional, Long, Brian, additional, Rachleff, Victoria, additional, Ding, Yi, additional, Mahoney, Joseph, additional, Dee, Nick, additional, Goldy, Jeff, additional, Melief, Erica, additional, Brouner, Krissy, additional, Compos, Jazmin, additional, Campos, John, additional, Carr, Ambrose, additional, Casper, Tamara, additional, Chakrabarty, Rushil, additional, Clark, Michael, additional, Cool, Jonah, additional, Dalley, Rachel, additional, Darvas, Martin, additional, Dolbeare, Tim, additional, Ding, Song-Lin, additional, Egdorf, Tom, additional, Esposito, Luke, additional, Ferrer, Rebecca, additional, Gala, Rohan, additional, Gary, Amanda, additional, Gloe, Jessica, additional, Guilford, Nathan, additional, Guzman, Junitta, additional, Ho, Windy, additional, Jarsky, Tim, additional, Johansen, Nelson, additional, Kalmbach, Brian, additional, Keene, Lisa, additional, Khawand, Sarah, additional, Kilgore, Mitchell, additional, Kirkland, Amanda, additional, Kunst, Michael, additional, Lee, Brian, additional, Donald, Christine Mac, additional, Malone, Jocelin, additional, Maltzer, Zoe, additional, Martin, Naomi, additional, McCue, Rachel, additional, McMillen, Delissa, additional, Meyerdierks, Emma, additional, Meyers, Kelly, additional, Mollenkopf, Tyler, additional, Montine, Mark, additional, Nolan, Amber, additional, Nyhus, Julie, additional, Olsen, Paul, additional, Pacleb, Maiya, additional, Pham, Trangthanh, additional, Pom, Christina, additional, Postupna, Nadia, additional, Ruiz, Augustin, additional, Schantz, Aimee, additional, Sorensen, Staci, additional, Staats, Brian, additional, Sullivan, Matt, additional, Sunkin, Susan, additional, Thompson, Carol, additional, Tieu, Michael, additional, Ting, Jonathan, additional, Torkelson, Amy, additional, Tran, Tracy, additional, Cuevas, Nasmil Valera, additional, Wang, Ming-Qiang, additional, Waters, Jack, additional, Wilson, Angela, additional, Haynor, David, additional, Gatto, Nicole, additional, Jayadev, Suman, additional, Mufti, Shoaib, additional, Ng, Lydia, additional, Mukherjee, Shubhabrata, additional, Crane, Paul, additional, Latimer, Caitlin, additional, Levi, Boaz, additional, Smith, Kimberly, additional, Close, Jennie, additional, Miller, Jeremy, additional, Hodge, Rebecca, additional, Larson, Eric, additional, Grabowski, Thomas, additional, Hawrylycz, Michael, additional, Keene, C., additional, and Lein, Ed, additional

Published
2023
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13. Integrated multimodal cell atlas of Alzheimer’s disease

Author

Gabitto, Mariano I., primary, Travaglini, Kyle J., additional, Rachleff, Victoria M., additional, Kaplan, Eitan S., additional, Long, Brian, additional, Ariza, Jeanelle, additional, Ding, Yi, additional, Mahoney, Joseph T., additional, Dee, Nick, additional, Goldy, Jeff, additional, Melief, Erica J., additional, Brouner, Krissy, additional, Campos, Jazmin, additional, Campos, John, additional, Carr, Ambrose J., additional, Casper, Tamara, additional, Chakrabarty, Rushil, additional, Clark, Michael, additional, Cool, Jonah, additional, Valera Cuevas, Nasmil J., additional, Dalley, Rachel, additional, Darvas, Martin, additional, Ding, Song-Lin, additional, Dolbeare, Tim, additional, Mac Donald, Christine L., additional, Egdorf, Tom, additional, Esposito, Luke, additional, Ferrer, Rebecca, additional, Gala, Rohan, additional, Gary, Amanda, additional, Gloe, Jessica, additional, Guilford, Nathan, additional, Guzman, Junitta, additional, Hirschstein, Daniel, additional, Ho, Windy, additional, Jarksy, Tim, additional, Johansen, Nelson, additional, Kalmbach, Brian E., additional, Keene, Lisa M., additional, Khawand, Sarah, additional, Kilgore, Mitch, additional, Kirkland, Amanda, additional, Kunst, Michael, additional, Lee, Brian R., additional, Malone, Jocelin, additional, Maltzer, Zoe, additional, Martin, Naomi, additional, McCue, Rachel, additional, McMillen, Delissa, additional, Meyerdierks, Emma, additional, Meyers, Kelly P., additional, Mollenkopf, Tyler, additional, Montine, Mark, additional, Nolan, Amber L., additional, Nyhus, Julie, additional, Olsen, Paul A., additional, Pacleb, Maiya, additional, Peña, Nicholas, additional, Pham, Thanh, additional, Pom, Christina Alice, additional, Postupna, Nadia, additional, Ruiz, Augustin, additional, Schantz, Aimee M., additional, Shapovalova, Nadiya V., additional, Sorensen, Staci A., additional, Staats, Brian, additional, Sullivan, Matt, additional, Sunkin, Susan M., additional, Thompson, Carol, additional, Tieu, Michael, additional, Ting, Jonathan, additional, Torkelson, Amy, additional, Tran, Tracy, additional, Wang, Ming-Qiang, additional, Waters, Jack, additional, Wilson, Angela M., additional, Haynor, David, additional, Gatto, Nicole, additional, Jayadev, Suman, additional, Mufti, Shoaib, additional, Ng, Lydia, additional, Mukherjee, Shubhabrata, additional, Crane, Paul K., additional, Latimer, Caitlin S., additional, Levi, Boaz P., additional, Smith, Kimberly, additional, Close, Jennie L., additional, Miller, Jeremy A., additional, Hodge, Rebecca D., additional, Larson, Eric B., additional, Grabowski, Thomas J., additional, Hawrylycz, Michael, additional, Dirk Keene, C., additional, and Lein, Ed S., additional

Published
2023
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14. Integrated multimodal cell atlas of Alzheimer’s disease

Author

Gabitto, Mariano I., Travaglini, Kyle J., Rachleff, Victoria M., Kaplan, Eitan S., Long, Brian, Ariza, Jeanelle, Ding, Yi, Mahoney, Joseph T., Dee, Nick, Goldy, Jeff, Melief, Erica J., Agrawal, Anamika, Kana, Omar, Zhen, Xingjian, Barlow, Samuel T., Brouner, Krissy, Campos, Jazmin, Campos, John, Carr, Ambrose J., Casper, Tamara, Chakrabarty, Rushil, Clark, Michael, Cool, Jonah, Dalley, Rachel, Darvas, Martin, Ding, Song-Lin, Dolbeare, Tim, Egdorf, Tom, Esposito, Luke, Ferrer, Rebecca, Fleckenstein, Lynn E., Gala, Rohan, Gary, Amanda, Gelfand, Emily, Gloe, Jessica, Guilford, Nathan, Guzman, Junitta, Hirschstein, Daniel, Ho, Windy, Hupp, Madison, Jarsky, Tim, Johansen, Nelson, Kalmbach, Brian E., Keene, Lisa M., Khawand, Sarah, Kilgore, Mitchell D., Kirkland, Amanda, Kunst, Michael, Lee, Brian R., Leytze, Mckaila, Mac Donald, Christine L., Malone, Jocelin, Maltzer, Zoe, Martin, Naomi, McCue, Rachel, McMillen, Delissa, Mena, Gonzalo, Meyerdierks, Emma, Meyers, Kelly P., Mollenkopf, Tyler, Montine, Mark, Nolan, Amber L., Nyhus, Julie K., Olsen, Paul A., Pacleb, Maiya, Pagan, Chelsea M., Peña, Nicholas, Pham, Trangthanh, Pom, Christina Alice, Postupna, Nadia, Rimorin, Christine, Ruiz, Augustin, Saldi, Giuseppe A., Schantz, Aimee M., Shapovalova, Nadiya V., Sorensen, Staci A., Staats, Brian, Sullivan, Matt, Sunkin, Susan M., Thompson, Carol, Tieu, Michael, Ting, Jonathan T., Torkelson, Amy, Tran, Tracy, Valera Cuevas, Nasmil J., Walling-Bell, Sarah, Wang, Ming-Qiang, Waters, Jack, Wilson, Angela M., Xiao, Ming, Haynor, David, Gatto, Nicole M., Jayadev, Suman, Mufti, Shoaib, Ng, Lydia, Mukherjee, Shubhabrata, Crane, Paul K., Latimer, Caitlin S., Levi, Boaz P., Smith, Kimberly A., Close, Jennie L., Miller, Jeremy A., Hodge, Rebecca D., Larson, Eric B., Grabowski, Thomas J., Hawrylycz, Michael, Keene, C. Dirk, and Lein, Ed S.

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies. This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years. We used quantitative neuropathology to place donors along a disease pseudoprogression score. Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin+inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells; and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb+and Vip+inhibitory neuron subtypes. These findings were replicated in other major AD studies.

Published
2024
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15. A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain

Author

Yao, Zizhen, primary, van Velthoven, Cindy T. J., additional, Kunst, Michael, additional, Zhang, Meng, additional, McMillen, Delissa, additional, Lee, Changkyu, additional, Jung, Won, additional, Goldy, Jeff, additional, Abdelhak, Aliya, additional, Baker, Pamela, additional, Barkan, Eliza, additional, Bertagnolli, Darren, additional, Campos, Jazmin, additional, Carey, Daniel, additional, Casper, Tamara, additional, Chakka, Anish Bhaswanth, additional, Chakrabarty, Rushil, additional, Chavan, Sakshi, additional, Chen, Min, additional, Clark, Michael, additional, Close, Jennie, additional, Crichton, Kirsten, additional, Daniel, Scott, additional, Dolbeare, Tim, additional, Ellingwood, Lauren, additional, Gee, James, additional, Glandon, Alexandra, additional, Gloe, Jessica, additional, Gould, Joshua, additional, Gray, James, additional, Guilford, Nathan, additional, Guzman, Junitta, additional, Hirschstein, Daniel, additional, Ho, Windy, additional, Jin, Kelly, additional, Kroll, Matthew, additional, Lathia, Kanan, additional, Leon, Arielle, additional, Long, Brian, additional, Maltzer, Zoe, additional, Martin, Naomi, additional, McCue, Rachel, additional, Meyerdierks, Emma, additional, Nguyen, Thuc Nghi, additional, Pham, Trangthanh, additional, Rimorin, Christine, additional, Ruiz, Augustin, additional, Shapovalova, Nadiya, additional, Slaughterbeck, Cliff, additional, Sulc, Josef, additional, Tieu, Michael, additional, Torkelson, Amy, additional, Tung, Herman, additional, Cuevas, Nasmil Valera, additional, Wadhwani, Katherine, additional, Ward, Katelyn, additional, Levi, Boaz, additional, Farrell, Colin, additional, Thompson, Carol L., additional, Mufti, Shoaib, additional, Pagan, Chelsea M., additional, Kruse, Lauren, additional, Dee, Nick, additional, Sunkin, Susan M., additional, Esposito, Luke, additional, Hawrylycz, Michael J., additional, Waters, Jack, additional, Ng, Lydia, additional, Smith, Kimberly A., additional, Tasic, Bosiljka, additional, Zhuang, Xiaowei, additional, and Zeng, Hongkui, additional

Published
2023
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16. A multimodal atlas of the molecular and cellular changes to cortex driven by Alzheimer’s disease

Author

Travaglini, Kyle J, primary, Gabitto, Mariano, additional, Ding, Yi, additional, Ariza, Jeanelle, additional, Chakrabarty, Rushil, additional, Crane, Paul K., additional, Ferrer, Rebecca, additional, Goldy, Jeff, additional, Grabowski, Thomas J, additional, Guilford, Nathan, additional, Guzman, Junitta, additional, Hawrylycz, Michael J, additional, Hodge, Rebecca D, additional, Jayadev, Suman, additional, Kaplan, Eitan S, additional, Keene, C Dirk, additional, Larson, Eric B, additional, Latimer, Caitlin S, additional, Levi, Boaz, additional, Mahoney, Joseph, additional, Melief, Erica J, additional, Mukherjee, Shubhabrata, additional, Pham, Thanh, additional, Rachleff, Victoria M, additional, Smith, Kimberly A, additional, Torkelson, Amy, additional, Lein, Ed S, additional, and Miller, Jeremy A, additional

Published
2022
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17. Transcriptomic cytoarchitecture reveals principles of human neocortex organization

Author

Jorstad, Nikolas L., primary, Close, Jennie, additional, Johansen, Nelson, additional, Yanny, Anna Marie, additional, Barkan, Eliza R., additional, Travaglini, Kyle J., additional, Bertagnolli, Darren, additional, Campos, Jazmin, additional, Casper, Tamara, additional, Crichton, Kirsten, additional, Dee, Nick, additional, Ding, Song-Lin, additional, Gelfand, Emily, additional, Goldy, Jeff, additional, Hirschstein, Daniel, additional, Kroll, Matthew, additional, Kunst, Michael, additional, Lathia, Kanan, additional, Long, Brian, additional, Martin, Naomi, additional, McMillen, Delissa, additional, Pham, Trangthanh, additional, Rimorin, Christine, additional, Ruiz, Augustin, additional, Shapovalova, Nadiya, additional, Shehata, Soraya, additional, Siletti, Kimberly, additional, Somasundaram, Saroja, additional, Sulc, Josef, additional, Tieu, Michael, additional, Torkelson, Amy, additional, Tung, Herman, additional, Ward, Katelyn, additional, Callaway, Edward M., additional, Hof, Patrick R., additional, Keene, C. Dirk, additional, Levi, Boaz P., additional, Linnarsson, Sten, additional, Mitra, Partha P., additional, Smith, Kimberly, additional, Hodge, Rebecca D., additional, Bakken, Trygve E., additional, and Lein, Ed S., additional

Published
2022
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18. Inter-individual variation in human cortical cell type abundance and expression

Author

Johansen, Nelson, primary, Somasundaram, Saroja, additional, Travaglini, Kyle J., additional, Yanny, Anna Marie, additional, Shumyatcher, Maya, additional, Casper, Tamara, additional, Cobbs, Charles, additional, Dee, Nick, additional, Ellenbogen, Richard, additional, Ferreira, Manuel, additional, Goldy, Jeff, additional, Guzman, Junitta, additional, Gwinn, Ryder, additional, Hirschstein, Daniel, additional, Jorstad, Nikolas L., additional, Keene, C. Dirk, additional, Ko, Andrew, additional, Levi, Boaz P., additional, Ojemann, Jeffrey G., additional, Pham, Thanh, additional, Shapovalova, Nadiya, additional, Silbergeld, Daniel, additional, Sulc, Josef, additional, Torkelson, Amy, additional, Tung, Herman, additional, Smith, Kimberly, additional, Lein, Ed S., additional, Bakken, Trygve E., additional, Hodge, Rebecca D., additional, and Miller, Jeremy A., additional

Published
2022
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19. Comparative transcriptomics reveals human-specific cortical features

Author

Jorstad, Nikolas L., primary, Song, Janet H.T., additional, Exposito-Alonso, David, additional, Suresh, Hamsini, additional, Castro, Nathan, additional, Krienen, Fenna M., additional, Yanny, Anna Marie, additional, Close, Jennie, additional, Gelfand, Emily, additional, Travaglini, Kyle J., additional, Basu, Soumyadeep, additional, Beaudin, Marc, additional, Bertagnolli, Darren, additional, Crow, Megan, additional, Ding, Song-Lin, additional, Eggermont, Jeroen, additional, Glandon, Alexandra, additional, Goldy, Jeff, additional, Kroes, Thomas, additional, Long, Brian, additional, McMillen, Delissa, additional, Pham, Trangthanh, additional, Rimorin, Christine, additional, Siletti, Kimberly, additional, Somasundaram, Saroja, additional, Tieu, Michael, additional, Torkelson, Amy, additional, Ward, Katelyn, additional, Feng, Guoping, additional, Hopkins, William D., additional, Höllt, Thomas, additional, Keene, C. Dirk, additional, Linnarsson, Sten, additional, McCarroll, Steven A., additional, Lelieveldt, Boudewijn P., additional, Sherwood, Chet C., additional, Smith, Kimberly, additional, Walsh, Christopher A., additional, Dobin, Alexander, additional, Gillis, Jesse, additional, Lein, Ed S., additional, Hodge, Rebecca D., additional, and Bakken, Trygve E., additional

Published
2022
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20. Comparative cellular analysis of motor cortex in human, marmoset and mouse

Author

Bakken, Trygve E., Jorstad, Nikolas L., Hu, Qiwen, Lake, Blue B., Tian, Wei, Kalmbach, Brian E., Crow, Megan, Hodge, Rebecca D., Krienen, Fenna M., Sorensen, Staci A., Eggermont, Jeroen, Yao, Zizhen, Aevermann, Brian D., Aldridge, Andrew I., Bartlett, Anna, Bertagnolli, Darren, Casper, Tamara, Castanon, Rosa G., Crichton, Kirsten, Daigle, Tanya L., Dalley, Rachel, Dee, Nick, Dembrow, Nikolai, Diep, Dinh, Ding, Song-Lin, Dong, Weixiu, Fang, Rongxin, Fischer, Stephan, Goldman, Melissa, Goldy, Jeff, Graybuck, Lucas T., Herb, Brian R., Hou, Xiaomeng, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, van Lew, Baldur, Li, Yang Eric, Liu, Christine S., Liu, Hanqing, Lucero, Jacinta D., Mahurkar, Anup, McMillen, Delissa, Miller, Jeremy A., Moussa, Marmar, Nery, Joseph R., Nicovich, Philip R., Niu, Sheng-Yong, Orvis, Joshua, Osteen, Julia K., Owen, Scott, Palmer, Carter R., Pham, Thanh, Plongthongkum, Nongluk, Poirion, Olivier, Reed, Nora M., Rimorin, Christine, Rivkin, Angeline, Romanow, William J., Sedeño-Cortés, Adriana E., Siletti, Kimberly, Somasundaram, Saroja, Sulc, Josef, Tieu, Michael, Torkelson, Amy, Tung, Herman, Wang, Xinxin, Xie, Fangming, Yanny, Anna Marie, Zhang, Renee, Ament, Seth A., Behrens, M. Margarita, Bravo, Hector Corrada, Chun, Jerold, Dobin, Alexander, Gillis, Jesse, Hertzano, Ronna, Hof, Patrick R., Höllt, Thomas, Horwitz, Gregory D., Keene, C. Dirk, Kharchenko, Peter V., Ko, Andrew L., Lelieveldt, Boudewijn P., Luo, Chongyuan, Mukamel, Eran A., Pinto-Duarte, António, Preissl, Sebastian, Regev, Aviv, Ren, Bing, Scheuermann, Richard H., Smith, Kimberly, Spain, William J., White, Owen R., Koch, Christof, Hawrylycz, Michael, Tasic, Bosiljka, Macosko, Evan Z., McCarroll, Steven A., Ting, Jonathan T., Zeng, Hongkui, Zhang, Kun, Feng, Guoping, Ecker, Joseph R., Linnarsson, Sten, Lein, Ed S., Bakken, Trygve E., Jorstad, Nikolas L., Hu, Qiwen, Lake, Blue B., Tian, Wei, Kalmbach, Brian E., Crow, Megan, Hodge, Rebecca D., Krienen, Fenna M., Sorensen, Staci A., Eggermont, Jeroen, Yao, Zizhen, Aevermann, Brian D., Aldridge, Andrew I., Bartlett, Anna, Bertagnolli, Darren, Casper, Tamara, Castanon, Rosa G., Crichton, Kirsten, Daigle, Tanya L., Dalley, Rachel, Dee, Nick, Dembrow, Nikolai, Diep, Dinh, Ding, Song-Lin, Dong, Weixiu, Fang, Rongxin, Fischer, Stephan, Goldman, Melissa, Goldy, Jeff, Graybuck, Lucas T., Herb, Brian R., Hou, Xiaomeng, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, van Lew, Baldur, Li, Yang Eric, Liu, Christine S., Liu, Hanqing, Lucero, Jacinta D., Mahurkar, Anup, McMillen, Delissa, Miller, Jeremy A., Moussa, Marmar, Nery, Joseph R., Nicovich, Philip R., Niu, Sheng-Yong, Orvis, Joshua, Osteen, Julia K., Owen, Scott, Palmer, Carter R., Pham, Thanh, Plongthongkum, Nongluk, Poirion, Olivier, Reed, Nora M., Rimorin, Christine, Rivkin, Angeline, Romanow, William J., Sedeño-Cortés, Adriana E., Siletti, Kimberly, Somasundaram, Saroja, Sulc, Josef, Tieu, Michael, Torkelson, Amy, Tung, Herman, Wang, Xinxin, Xie, Fangming, Yanny, Anna Marie, Zhang, Renee, Ament, Seth A., Behrens, M. Margarita, Bravo, Hector Corrada, Chun, Jerold, Dobin, Alexander, Gillis, Jesse, Hertzano, Ronna, Hof, Patrick R., Höllt, Thomas, Horwitz, Gregory D., Keene, C. Dirk, Kharchenko, Peter V., Ko, Andrew L., Lelieveldt, Boudewijn P., Luo, Chongyuan, Mukamel, Eran A., Pinto-Duarte, António, Preissl, Sebastian, Regev, Aviv, Ren, Bing, Scheuermann, Richard H., Smith, Kimberly, Spain, William J., White, Owen R., Koch, Christof, Hawrylycz, Michael, Tasic, Bosiljka, Macosko, Evan Z., McCarroll, Steven A., Ting, Jonathan T., Zeng, Hongkui, Zhang, Kun, Feng, Guoping, Ecker, Joseph R., Linnarsson, Sten, and Lein, Ed S.

Abstract

AbstractThe primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch–seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

Published
2022

21. Author Correction:Human neocortical expansion involves glutamatergic neuron diversification (Nature, (2021), 598, 7879, (151-158), 10.1038/s41586-021-03813-8)

Author

Berg, Jim, Sorensen, Staci A., Ting, Jonathan T., Miller, Jeremy A., Chartrand, Thomas, Buchin, Anatoly, Bakken, Trygve E., Budzillo, Agata, Dee, Nick, Ding, Song-Lin, Gouwens, Nathan W., Hodge, Rebecca D., Kalmbach, Brian, Lee, Changkyu, Lee, Brian R., Alfiler, Lauren, Baker, Katherine, Barkan, Eliza, Beller, Allison, Berry, Kyla, Bertagnolli, Darren, Bickley, Kris, Bomben, Jasmine, Braun, Thomas, Brouner, Krissy, Casper, Tamara, Chong, Peter, Crichton, Kirsten, Dalley, Rachel, de Frates, Rebecca, Desta, Tsega, Lee, Samuel Dingman, D’Orazi, Florence, Dotson, Nadezhda, Egdorf, Tom, Enstrom, Rachel, Farrell, Colin, Feng, David, Fong, Olivia, Furdan, Szabina, Galakhova, Anna A., Gamlin, Clare, Gary, Amanda, Glandon, Alexandra, Goldy, Jeff, Gorham, Melissa, Goriounova, Natalia A., Gratiy, Sergey, Graybuck, Lucas, Gu, Hong, Hadley, Kristen, Hansen, Nathan, Heistek, Tim S., Henry, Alex M., Heyer, Djai B., Hill, DiJon, Hill, Chris, Hupp, Madie, Jarsky, Tim, Kebede, Sara, Keene, Lisa, Kim, Lisa, Kim, Mean-Hwan, Kroll, Matthew, Latimer, Caitlin, Levi, Boaz P., Link, Katherine E., Mallory, Matthew, Mann, Rusty, Marshall, Desiree, Maxwell, Michelle, McGraw, Medea, McMillen, Delissa, Melief, Erica, Mertens, Eline J., Mezei, Leona, Mihut, Norbert, Mok, Stephanie, Molnar, Gabor, Mukora, Alice, Ng, Lindsay, Ngo, Kiet, Nicovich, Philip R., Nyhus, Julie, Olah, Gaspar, Oldre, Aaron, Omstead, Victoria, Ozsvar, Attila, Park, Daniel, Peng, Hanchuan, Pham, Trangthanh, Pom, Christina A., Potekhina, Lydia, Rajanbabu, Ramkumar, Ransford, Shea, Reid, David, Rimorin, Christine, Ruiz, Augustin, Sandman, David, Sulc, Josef, Sunkin, Susan M., Szafer, Aaron, Szemenyei, Viktor, Thomsen, Elliot R., Tieu, Michael, Torkelson, Amy, Trinh, Jessica, Tung, Herman, Wakeman, Wayne, Waleboer, Femke, Ward, Katelyn, Wilbers, René, Williams, Grace, Yao, Zizhen, Yoon, Jae-Geun, Anastassiou, Costas, Arkhipov, Anton, Barzo, Pal, Bernard, Amy, Cobbs, Charles, de Witt Hamer, Philip C., Ellenbogen, Richard G., Esposito, Luke, Ferreira, Manuel, Gwinn, Ryder P., Hawrylycz, Michael J., Hof, Patrick R., Idema, Sander, Jones, Allan R., Keene, C. Dirk, Ko, Andrew L., Murphy, Gabe J., Ng, Lydia, Ojemann, Jeffrey G., Patel, Anoop P., Phillips, John W., Silbergeld, Daniel L., Smith, Kimberly, Tasic, Bosiljka, Yuste, Rafael, Segev, Idan, de Kock, Christiaan P. J., Mansvelder, Huibert D., Tamas, Gabor, Zeng, Hongkui, Koch, Christof, and Lein, Ed S.

Abstract

In the version of this Article initially published, the Acknowledgements statement contained an error. Originally appearing with thanks for support given in part as follows, “R01EY023173 from The National Eye Institute, U01MH105982 from the National Institute of Mental Health and Eunice Kennedy Shriver National Institute of Child Health and Human Development, and R011EY023173 from The National Institute of Allergy and Infectious Disease,” the last number (R011EY023173) was mistakenly added and is not in fact a grant or one provided by the NIAID. The mention has been removed. The changes have been made to the online version of the Article.

Published
2022
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22. A multimodal cell census and atlas of the mammalian primary motor cortex

Author

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, 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, Susan, BRAIN Initiative Cell Census Network (BICCN) Corresponding authors, [missing], BICCN contributing principal investigators, [missing], Principal manuscript editors, [missing], Manuscript writing and figure generation, [missing], Analysis coordination, [missing], Integrated data analysis, [missing], scRNA-seq and snRNA-seq data generation and processing, [missing], ATAC-seq data generation and processing, [missing], Methylcytosine data production and analysis, [missing], Epi-retro-seq data generation and processing, [missing], ‘Omics data analysis, [missing], Tracing and connectivity data generation, [missing], Morphology data generation and reconstruction, [missing], OLST/STPT and other data generation, [missing], Morphology, connectivity and imaging analysis, [missing], Spatially resolved single-cell transcriptomics (MERFISH), [missing], Multimodal profiling (Patch-seq), [missing], Transgenic tools, [missing], NeMO archive and analytics, [missing], Brain Image Library (BIL) archive, [missing], DANDI archive, [missing], Brain Cell Data Center (BCDC), [missing], Project management, [missing], and BRAIN Initiative Cell Census Network (BICCN), [missing]

Subjects
Epigenomics, Male, INTERNEURONS, ORGANIZATION, MOUSE, Molecular neuroscience, Neural circuits, CLASSIFICATION, Article, Mice, Atlases as Topic, Glutamates, Species Specificity, Animals, Humans, TRANSCRIPTOMICS, SPECIFICATION, NEURONS, In Situ Hybridization, Fluorescence, Phylogeny, Neurons, Multidisciplinary, Gene Expression Profiling, Biology and Life Sciences, PATHWAYS, Brain, Callithrix, Censuses, Cellular neuroscience, Mathematics and Statistics, SINGLE, Organ Specificity, MORPHOLOGY, Motor cortex, Female, Single-Cell Analysis, Transcriptome
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., The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Published
2021

23. INTER-INDIVIDUAL VARIATION IN HUMAN CORTICAL CELL TYPE ABUNDANCE AND EXPRESSION

Author

Johansen, Nelson, Somasundaram, Saroja, Travaglini, Kyle, Yanny, Anna Marie, Shumyatcher, Maya, Casper, Tamara, Cobbs, Charles, Dee, Nick, Ellenbogen, Richard, Ferreira, Manuel, Goldy, Jeff, Guzman, Junitta, Gwinn, Ryder, Hirschstein, Daniel, Jorstad, Nikolas, Keene, C. Dirk, Ko, Andrew, Levi, Boaz, Ojemann, Jeffrey, Pham, Thanh, Shapovalova, Nadiya, Silbergeld, Daniel, Sulc, Josef, Torkelson, Amy, Tung, Herman, Smith, Kimberly, Lein, Ed, Bakken, Trygve, Hodge, Rebecca, and Miller, Jeremy

Published
2023
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24. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation

Author

Yao, Zizhen, primary, van Velthoven, Cindy T.J., additional, Nguyen, Thuc Nghi, additional, Goldy, Jeff, additional, Sedeno-Cortes, Adriana E., additional, Baftizadeh, Fahimeh, additional, Bertagnolli, Darren, additional, Casper, Tamara, additional, Chiang, Megan, additional, Crichton, Kirsten, additional, Ding, Song-Lin, additional, Fong, Olivia, additional, Garren, Emma, additional, Glandon, Alexandra, additional, Gouwens, Nathan W., additional, Gray, James, additional, Graybuck, Lucas T., additional, Hawrylycz, Michael J., additional, Hirschstein, Daniel, additional, Kroll, Matthew, additional, Lathia, Kanan, additional, Lee, Changkyu, additional, Levi, Boaz, additional, McMillen, Delissa, additional, Mok, Stephanie, additional, Pham, Thanh, additional, Ren, Qingzhong, additional, Rimorin, Christine, additional, Shapovalova, Nadiya, additional, Sulc, Josef, additional, Sunkin, Susan M., additional, Tieu, Michael, additional, Torkelson, Amy, additional, Tung, Herman, additional, Ward, Katelyn, additional, Dee, Nick, additional, Smith, Kimberly A., additional, Tasic, Bosiljka, additional, and Zeng, Hongkui, additional

Published
2021
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25. An integrated transcriptomic and epigenomic atlas of mouse primary motor cortex cell types

Author

Yao, Zizhen, Liu, Hanqing, Xie, Fangming, Fischer, Stephan, Adkins, Ricky S., Aldrige, Andrew I., Ament, Seth A., Bartlett, Ann, Behrens, M. Margarita, Van den Berge, Koen, Bertagnolli, Darren, Biancalani, Tommaso, Booeshaghi, A. Sina, Corrada Bravo, Hector, Casper, Tamara, Colantuoni, Carlo, Crabtree, Jonathan, Creasy, Heather, Crichton, Kirsten, Crow, Megan, Dee, Nick, Dougherty, Elizabeth L., Doyle, Wayne I., Dudoit, Sandrine, Fang, Rongxin, Felix, Victor, Fong, Olivia, Giglio, Michelle, Goldy, Jeff, Hawrylycz, Michael, Roux de Bezieux, Hector, Herb, Brian R., Hertzano, Ronna, Hou, Xiaomeng, Hu, Qiwen, Huang, Z. Josh, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, Li, Yang Eric, Lucero, Jacinta D., Luo, Chongyuan, Mahurkar, Anup, McMillen, Delissa, Nadaf, Naeem M., Nery, Joseph R., Nguyen, Thuc Nghi, Niu, Sheng-Yong, Ntranos, Vasilis, Orvis, Joshua, Osteen, Julia K., Pham, Thanh, Pinto-Duarte, Antonio, Poirion, Olivier, Preissl, Sebastian, Purdom, Elizabeth, Rimorin, Christine, Risso, Davide, Rivkin, Angeline C., Smith, Kimberly, Street, Kelly, Sulc, Josef, Svensson, Valentine, Tieu, Michael, Torkelson, Amy, Tung, Herman, Vaishnav, Eeshit Dhaval, Vanderburg, Charles R., van Velthoven, Cindy, Wang, Xinxin, White, Owen, Gillis, Jesse, Kharchenko, Peter V., Ngai, John, Pachter, Lior, Regev, Aviv, Tasic, Bosiljka, Welch, Joshua D., Ecker, Joseph R., Macosko, Evan, Ren, Bing, Zeng, Hongkui, Mukamel, Eran A., Yao, Zizhen, Liu, Hanqing, Xie, Fangming, Fischer, Stephan, Adkins, Ricky S., Aldrige, Andrew I., Ament, Seth A., Bartlett, Ann, Behrens, M. Margarita, Van den Berge, Koen, Bertagnolli, Darren, Biancalani, Tommaso, Booeshaghi, A. Sina, Corrada Bravo, Hector, Casper, Tamara, Colantuoni, Carlo, Crabtree, Jonathan, Creasy, Heather, Crichton, Kirsten, Crow, Megan, Dee, Nick, Dougherty, Elizabeth L., Doyle, Wayne I., Dudoit, Sandrine, Fang, Rongxin, Felix, Victor, Fong, Olivia, Giglio, Michelle, Goldy, Jeff, Hawrylycz, Michael, Roux de Bezieux, Hector, Herb, Brian R., Hertzano, Ronna, Hou, Xiaomeng, Hu, Qiwen, Huang, Z. Josh, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, Li, Yang Eric, Lucero, Jacinta D., Luo, Chongyuan, Mahurkar, Anup, McMillen, Delissa, Nadaf, Naeem M., Nery, Joseph R., Nguyen, Thuc Nghi, Niu, Sheng-Yong, Ntranos, Vasilis, Orvis, Joshua, Osteen, Julia K., Pham, Thanh, Pinto-Duarte, Antonio, Poirion, Olivier, Preissl, Sebastian, Purdom, Elizabeth, Rimorin, Christine, Risso, Davide, Rivkin, Angeline C., Smith, Kimberly, Street, Kelly, Sulc, Josef, Svensson, Valentine, Tieu, Michael, Torkelson, Amy, Tung, Herman, Vaishnav, Eeshit Dhaval, Vanderburg, Charles R., van Velthoven, Cindy, Wang, Xinxin, White, Owen, Gillis, Jesse, Kharchenko, Peter V., Ngai, John, Pachter, Lior, Regev, Aviv, Tasic, Bosiljka, Welch, Joshua D., Ecker, Joseph R., Macosko, Evan, Ren, Bing, Zeng, Hongkui, and Mukamel, Eran A.

Abstract

Single cell transcriptomics has transformed the characterization of brain cell identity by providing quantitative molecular signatures for large, unbiased samples of brain cell populations. With the proliferation of taxonomies based on individual datasets, a major challenge is to integrate and validate results toward defining biologically meaningful cell types. We used a battery of single-cell transcriptome and epigenome measurements generated by the BRAIN Initiative Cell Census Network (BICCN) to comprehensively assess the molecular signatures of cell types in the mouse primary motor cortex (MOp). We further developed computational and statistical methods to integrate these multimodal data and quantitatively validate the reproducibility of the cell types. The reference atlas, based on more than 600,000 high quality single-cell or -nucleus samples assayed by six molecular modalities, is a comprehensive molecular account of the diverse neuronal and non-neuronal cell types in MOp. Collectively, our study indicates that the mouse primary motor cortex contains over 55 neuronal cell types that are highly replicable across analysis methods, sequencing technologies, and modalities. We find many concordant multimodal markers for each cell type, as well as thousands of genes and gene regulatory elements with discrepant transcriptomic and epigenomic signatures. These data highlight the complex molecular regulation of brain cell types and will directly enable design of reagents to target specific MOp cell types for functional analysis.

Published
2020

26. Integrated Morphoelectric and Transcriptomic Classification of Cortical GABAergic Cells

Author

Gouwens, Nathan W., primary, Sorensen, Staci A., additional, Baftizadeh, Fahimeh, additional, Budzillo, Agata, additional, Lee, Brian R., additional, Jarsky, Tim, additional, Alfiler, Lauren, additional, Baker, Katherine, additional, Barkan, Eliza, additional, Berry, Kyla, additional, Bertagnolli, Darren, additional, Bickley, Kris, additional, Bomben, Jasmine, additional, Braun, Thomas, additional, Brouner, Krissy, additional, Casper, Tamara, additional, Crichton, Kirsten, additional, Daigle, Tanya L., additional, Dalley, Rachel, additional, de Frates, Rebecca A., additional, Dee, Nick, additional, Desta, Tsega, additional, Lee, Samuel Dingman, additional, Dotson, Nadezhda, additional, Egdorf, Tom, additional, Ellingwood, Lauren, additional, Enstrom, Rachel, additional, Esposito, Luke, additional, Farrell, Colin, additional, Feng, David, additional, Fong, Olivia, additional, Gala, Rohan, additional, Gamlin, Clare, additional, Gary, Amanda, additional, Glandon, Alexandra, additional, Goldy, Jeff, additional, Gorham, Melissa, additional, Graybuck, Lucas, additional, Gu, Hong, additional, Hadley, Kristen, additional, Hawrylycz, Michael J., additional, Henry, Alex M., additional, Hill, DiJon, additional, Hupp, Madie, additional, Kebede, Sara, additional, Kim, Tae Kyung, additional, Kim, Lisa, additional, Kroll, Matthew, additional, Lee, Changkyu, additional, Link, Katherine E., additional, Mallory, Matthew, additional, Mann, Rusty, additional, Maxwell, Michelle, additional, McGraw, Medea, additional, McMillen, Delissa, additional, Mukora, Alice, additional, Ng, Lindsay, additional, Ng, Lydia, additional, Ngo, Kiet, additional, Nicovich, Philip R., additional, Oldre, Aaron, additional, Park, Daniel, additional, Peng, Hanchuan, additional, Penn, Osnat, additional, Pham, Thanh, additional, Pom, Alice, additional, Popović, Zoran, additional, Potekhina, Lydia, additional, Rajanbabu, Ramkumar, additional, Ransford, Shea, additional, Reid, David, additional, Rimorin, Christine, additional, Robertson, Miranda, additional, Ronellenfitch, Kara, additional, Ruiz, Augustin, additional, Sandman, David, additional, Smith, Kimberly, additional, Sulc, Josef, additional, Sunkin, Susan M., additional, Szafer, Aaron, additional, Tieu, Michael, additional, Torkelson, Amy, additional, Trinh, Jessica, additional, Tung, Herman, additional, Wakeman, Wayne, additional, Ward, Katelyn, additional, Williams, Grace, additional, Zhou, Zhi, additional, Ting, Jonathan T., additional, Arkhipov, Anton, additional, Sümbül, Uygar, additional, Lein, Ed S., additional, Koch, Christof, additional, Yao, Zizhen, additional, Tasic, Bosiljka, additional, Berg, Jim, additional, Murphy, Gabe J., additional, and Zeng, Hongkui, additional

Published
2020
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27. Human cortical expansion involves diversification and specialization of supragranular intratelencephalic-projecting neurons

Author

Berg, Jim, primary, Sorensen, Staci A., additional, Ting, Jonathan T., additional, Miller, Jeremy A., additional, Chartrand, Thomas, additional, Buchin, Anatoly, additional, Bakken, Trygve E., additional, Budzillo, Agata, additional, Dee, Nick, additional, Ding, Song-Lin, additional, Gouwens, Nathan W., additional, Hodge, Rebecca D., additional, Kalmbach, Brian, additional, Lee, Changkyu, additional, Lee, Brian R., additional, Alfiler, Lauren, additional, Baker, Katherine, additional, Barkan, Eliza, additional, Beller, Allison, additional, Berry, Kyla, additional, Bertagnolli, Darren, additional, Bickley, Kris, additional, Bomben, Jasmine, additional, Braun, Thomas, additional, Brouner, Krissy, additional, Casper, Tamara, additional, Chong, Peter, additional, Crichton, Kirsten, additional, Dalley, Rachel, additional, de Frates, Rebecca, additional, Desta, Tsega, additional, Dingman Lee, Samuel, additional, D’Orazi, Florence, additional, Dotson, Nadezhda, additional, Egdorf, Tom, additional, Enstrom, Rachel, additional, Farrell, Colin, additional, Feng, David, additional, Fong, Olivia, additional, Furdan, Szabina, additional, Galakhova, Anna A., additional, Gamlin, Clare, additional, Gary, Amanda, additional, Glandon, Alexandra, additional, Goldy, Jeff, additional, Gorham, Melissa, additional, Goriounova, Natalia A., additional, Gratiy, Sergey, additional, Graybuck, Lucas, additional, Gu, Hong, additional, Hadley, Kristen, additional, Hansen, Nathan, additional, Heistek, Tim S., additional, Henry, Alex M., additional, Heyer, Djai B., additional, Hill, DiJon, additional, Hill, Chris, additional, Hupp, Madie, additional, Jarsky, Tim, additional, Kebede, Sara, additional, Keene, Lisa, additional, Kim, Lisa, additional, Kim, Mean-Hwan, additional, Kroll, Matthew, additional, Latimer, Caitlin, additional, Levi, Boaz P., additional, Link, Katherine E., additional, Mallory, Matthew, additional, Mann, Rusty, additional, Marshall, Desiree, additional, Maxwell, Michelle, additional, McGraw, Medea, additional, McMillen, Delissa, additional, Melief, Erica, additional, Mertens, Eline J., additional, Mezei, Leona, additional, Mihut, Norbert, additional, Mok, Stephanie, additional, Molnar, Gabor, additional, Mukora, Alice, additional, Ng, Lindsay, additional, Ngo, Kiet, additional, Nicovich, Philip R., additional, Nyhus, Julie, additional, Olah, Gaspar, additional, Oldre, Aaron, additional, Omstead, Victoria, additional, Ozsvar, Attila, additional, Park, Daniel, additional, Peng, Hanchuan, additional, Pham, Trangthanh, additional, Pom, Christina A., additional, Potekhina, Lydia, additional, Rajanbabu, Ramkumar, additional, Ransford, Shea, additional, Reid, David, additional, Rimorin, Christine, additional, Ruiz, Augustin, additional, Sandman, David, additional, Sulc, Josef, additional, Sunkin, Susan M., additional, Szafer, Aaron, additional, Szemenyei, Viktor, additional, Thomsen, Elliot R., additional, Tieu, Michael, additional, Torkelson, Amy, additional, Trinh, Jessica, additional, Tung, Herman, additional, Wakeman, Wayne, additional, Ward, Katelyn, additional, Wilbers, René, additional, Williams, Grace, additional, Yao, Zizhen, additional, Yoon, Jae-Geun, additional, Anastassiou, Costas, additional, Arkhipov, Anton, additional, Barzo, Pal, additional, Bernard, Amy, additional, Cobbs, Charles, additional, de Witt Hamer, Philip C., additional, Ellenbogen, Richard G., additional, Esposito, Luke, additional, Ferreira, Manuel, additional, Gwinn, Ryder P., additional, Hawrylycz, Michael J., additional, Hof, Patrick R., additional, Idema, Sander, additional, Jones, Allan R., additional, Keene, C.Dirk, additional, Ko, Andrew L., additional, Murphy, Gabe J., additional, Ng, Lydia, additional, Ojemann, Jeffrey G., additional, Patel, Anoop P., additional, Phillips, John W., additional, Silbergeld, Daniel L., additional, Smith, Kimberly, additional, Tasic, Bosiljka, additional, Yuste, Rafael, additional, Segev, Idan, additional, de Kock, Christiaan P.J., additional, Mansvelder, Huibert D., additional, Tamas, Gabor, additional, Zeng, Hongkui, additional, Koch, Christof, additional, and Lein, Ed S., additional

Published
2020
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28. Evolution of cellular diversity in primary motor cortex of human, marmoset monkey, and mouse

Author

Bakken, Trygve E., primary, Jorstad, Nikolas L., additional, Hu, Qiwen, additional, Lake, Blue B., additional, Tian, Wei, additional, Kalmbach, Brian E., additional, Crow, Megan, additional, Hodge, Rebecca D., additional, Krienen, Fenna M., additional, Sorensen, Staci A., additional, Eggermont, Jeroen, additional, Yao, Zizhen, additional, Aevermann, Brian D., additional, Aldridge, Andrew I., additional, Bartlett, Anna, additional, Bertagnolli, Darren, additional, Casper, Tamara, additional, Castanon, Rosa G., additional, Crichton, Kirsten, additional, Daigle, Tanya L., additional, Dalley, Rachel, additional, Dee, Nick, additional, Dembrow, Nikolai, additional, Diep, Dinh, additional, Ding, Song-Lin, additional, Dong, Weixiu, additional, Fang, Rongxin, additional, Fischer, Stephan, additional, Goldman, Melissa, additional, Goldy, Jeff, additional, Graybuck, Lucas T., additional, Herb, Brian R., additional, Hou, Xiaomeng, additional, Kancherla, Jayaram, additional, Kroll, Matthew, additional, Lathia, Kanan, additional, van Lew, Baldur, additional, Li, Yang Eric, additional, Liu, Christine S., additional, Liu, Hanqing, additional, Lucero, Jacinta D., additional, Mahurkar, Anup, additional, McMillen, Delissa, additional, Miller, Jeremy A., additional, Moussa, Marmar, additional, Nery, Joseph R., additional, Nicovich, Philip R., additional, Orvis, Joshua, additional, Osteen, Julia K., additional, Owen, Scott, additional, Palmer, Carter R., additional, Pham, Thanh, additional, Plongthongkum, Nongluk, additional, Poirion, Olivier, additional, Reed, Nora M., additional, Rimorin, Christine, additional, Rivkin, Angeline, additional, Romanow, William J., additional, Sedeño-Cortés, Adriana E., additional, Siletti, Kimberly, additional, Somasundaram, Saroja, additional, Sulc, Josef, additional, Tieu, Michael, additional, Torkelson, Amy, additional, Tung, Herman, additional, Wang, Xinxin, additional, Xie, Fangming, additional, Yanny, Anna Marie, additional, Zhang, Renee, additional, Ament, Seth A., additional, Behrens, M. Margarita, additional, Bravo, Hector Corrada, additional, Chun, Jerold, additional, Dobin, Alexander, additional, Gillis, Jesse, additional, Hertzano, Ronna, additional, Hof, Patrick R., additional, Höllt, Thomas, additional, Horwitz, Gregory D., additional, Keene, C. Dirk, additional, Kharchenko, Peter V., additional, Ko, Andrew L., additional, Lelieveldt, Boudewijn P., additional, Luo, Chongyuan, additional, Mukamel, Eran A., additional, Preissl, Sebastian, additional, Regev, Aviv, additional, Ren, Bing, additional, Scheuermann, Richard H., additional, Smith, Kimberly, additional, Spain, William J., additional, White, Owen R., additional, Koch, Christof, additional, Hawrylycz, Michael, additional, Tasic, Bosiljka, additional, Macosko, Evan Z., additional, McCarroll, Steven A., additional, Ting, Jonathan T., additional, Zeng, Hongkui, additional, Zhang, Kun, additional, Feng, Guoping, additional, Ecker, Joseph R., additional, Linnarsson, Sten, additional, and Lein, Ed S., additional

Published
2020
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29. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation

Author

Yao, Zizhen, primary, Nguyen, Thuc Nghi, additional, van Velthoven, Cindy T. J., additional, Goldy, Jeff, additional, Sedeno-Cortes, Adriana E., additional, Baftizadeh, Fahimeh, additional, Bertagnolli, Darren, additional, Casper, Tamara, additional, Crichton, Kirsten, additional, Ding, Song-Lin, additional, Fong, Olivia, additional, Garren, Emma, additional, Glandon, Alexandra, additional, Gray, James, additional, Graybuck, Lucas T., additional, Hirschstein, Daniel, additional, Kroll, Matthew, additional, Lathia, Kanan, additional, Levi, Boaz, additional, McMillen, Delissa, additional, Mok, Stephanie, additional, Pham, Thanh, additional, Ren, Qingzhong, additional, Rimorin, Christine, additional, Shapovalova, Nadiya, additional, Sulc, Josef, additional, Sunkin, Susan M., additional, Tieu, Michael, additional, Torkelson, Amy, additional, Tung, Herman, additional, Ward, Katelyn, additional, Dee, Nick, additional, Smith, Kimberly A., additional, Tasic, Bosiljka, additional, and Zeng, Hongkui, additional

Published
2020
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30. An integrated transcriptomic and epigenomic atlas of mouse primary motor cortex cell types

Author

Yao, Zizhen, primary, Liu, Hanqing, additional, Xie, Fangming, additional, Fischer, Stephan, additional, Booeshaghi, A. Sina, additional, Adkins, Ricky S, additional, Aldridge, Andrew I., additional, Ament, Seth A., additional, Pinto-Duarte, Antonio, additional, Bartlett, Anna, additional, Behrens, M. Margarita, additional, Van den Berge, Koen, additional, Bertagnolli, Darren, additional, Biancalani, Tommaso, additional, Bravo, Héctor Corrada, additional, Casper, Tamara, additional, Colantuoni, Carlo, additional, Creasy, Heather, additional, Crichton, Kirsten, additional, Crow, Megan, additional, Dee, Nick, additional, Dougherty, Elizabeth L, additional, Doyle, Wayne I., additional, Dudoit, Sandrine, additional, Fang, Rongxin, additional, Felix, Victor, additional, Fong, Olivia, additional, Giglio, Michelle, additional, Goldy, Jeff, additional, Hawrylycz, Mike, additional, de Bézieux, Hector Roux, additional, Herb, Brian R., additional, Hertzano, Ronna, additional, Hou, Xiaomeng, additional, Hu, Qiwen, additional, Crabtree, Jonathan, additional, Kancherla, Jayaram, additional, Kroll, Matthew, additional, Lathia, Kanan, additional, Li, Yang Eric, additional, Lucero, Jacinta D., additional, Luo, Chongyuan, additional, Mahurkar, Anup, additional, McMillen, Delissa, additional, Nadaf, Naeem, additional, Nery, Joseph R., additional, Niu, Sheng-Yong, additional, Orvis, Joshua, additional, Osteen, Julia K., additional, Pham, Thanh, additional, Poirion, Olivier, additional, Preissl, Sebastian, additional, Purdom, Elizabeth, additional, Rimorin, Christine, additional, Risso, Davide, additional, Rivkin, Angeline C., additional, Smith, Kimberly, additional, Street, Kelly, additional, Sulc, Josef, additional, Nguyen, Thuc Nghi, additional, Tieu, Michael, additional, Torkelson, Amy, additional, Tung, Herman, additional, Vaishnav, Eeshit Dhaval, additional, Svensson, Valentine, additional, Vanderburg, Charles R., additional, Ntranos, Vasilis, additional, van Velthoven, Cindy, additional, Wang, Xinxin, additional, White, Owen R., additional, Huang, Z. Josh, additional, Kharchenko, Peter V., additional, Pachter, Lior, additional, Ngai, John, additional, Regev, Aviv, additional, Tasic, Bosiljka, additional, Welch, Joshua D., additional, Gillis, Jesse, additional, Macosko, Evan Z., additional, Ren, Bing, additional, Ecker, Joseph R., additional, Zeng, Hongkui, additional, and Mukamel, Eran A., additional

Published
2020
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31. Toward an integrated classification of neuronal cell types: morphoelectric and transcriptomic characterization of individual GABAergic cortical neurons

Author

Gouwens, Nathan W., primary, Sorensen, Staci A., additional, Baftizadeh, Fahimeh, additional, Budzillo, Agata, additional, Lee, Brian R., additional, Jarsky, Tim, additional, Alfiler, Lauren, additional, Arkhipov, Anton, additional, Baker, Katherine, additional, Barkan, Eliza, additional, Berry, Kyla, additional, Bertagnolli, Darren, additional, Bickley, Kris, additional, Bomben, Jasmine, additional, Braun, Thomas, additional, Brouner, Krissy, additional, Casper, Tamara, additional, Crichton, Kirsten, additional, Daigle, Tanya L., additional, Dalley, Rachel, additional, de Frates, Rebecca, additional, Dee, Nick, additional, Desta, Tsega, additional, Lee, Samuel Dingman, additional, Dotson, Nadezhda, additional, Egdorf, Tom, additional, Ellingwood, Lauren, additional, Enstrom, Rachel, additional, Esposito, Luke, additional, Farrell, Colin, additional, Feng, David, additional, Fong, Olivia, additional, Gala, Rohan, additional, Gamlin, Clare, additional, Gary, Amanda, additional, Glandon, Alexandra, additional, Goldy, Jeff, additional, Gorham, Melissa, additional, Graybuck, Lucas, additional, Gu, Hong, additional, Hadley, Kristen, additional, Hawrylycz, Michael J., additional, Henry, Alex M., additional, Hill, DiJon, additional, Hupp, Madie, additional, Kebede, Sara, additional, Kim, Tae Kyung, additional, Kim, Lisa, additional, Kroll, Matthew, additional, Lee, Changkyu, additional, Link, Katherine E., additional, Mallory, Matthew, additional, Mann, Rusty, additional, Maxwell, Michelle, additional, McGraw, Medea, additional, McMillen, Delissa, additional, Mukora, Alice, additional, Ng, Lindsay, additional, Ng, Lydia, additional, Ngo, Kiet, additional, Nicovich, Philip R., additional, Oldre, Aaron, additional, Park, Daniel, additional, Peng, Hanchuan, additional, Penn, Osnat, additional, Pham, Thanh, additional, Pom, Alice, additional, Potekhina, Lydia, additional, Rajanbabu, Ramkumar, additional, Ransford, Shea, additional, Reid, David, additional, Rimorin, Christine, additional, Robertson, Miranda, additional, Ronellenfitch, Kara, additional, Ruiz, Augustin, additional, Sandman, David, additional, Smith, Kimberly, additional, Sulc, Josef, additional, Sunkin, Susan M., additional, Szafer, Aaron, additional, Tieu, Michael, additional, Torkelson, Amy, additional, Trinh, Jessica, additional, Tung, Herman, additional, Wakeman, Wayne, additional, Ward, Katelyn, additional, Williams, Grace, additional, Zhou, Zhi, additional, Ting, Jonathan, additional, Sumbul, Uygar, additional, Lein, Ed, additional, Koch, Christof, additional, Yao, Zizhen, additional, Tasic, Bosiljka, additional, Berg, Jim, additional, Murphy, Gabe J., additional, and Zeng, Hongkui, additional

Published
2020
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32. Toward an Integrated Classification of Cell Types: Morphoelectric and Transcriptomic Characterization of Individual GABAergic Cortical Neurons

Author

Gouwens, Nathan W., primary, Sorensen, Staci A., additional, Baftizadeh, Fahimeh, additional, Budzillo, Agata, additional, Lee, Brian R., additional, Jarsky, Tim, additional, Alfiler, Lauren, additional, Baker, Katherine, additional, Barkan, Eliza, additional, Berry, Kyla, additional, Bertagnolli, Darren, additional, Bickley, Kris, additional, Bomben, Jasmine, additional, Braun, Thomas, additional, Brouner, Kirssy, additional, Casper, Tamara, additional, Crichton, Kirsten, additional, Daigle, Tanya L., additional, Dalley, Rachel, additional, de Frates, Rebeeca, additional, Dee, Nick, additional, Desta, Tsega, additional, Dingman Lee, Samuel, additional, Dotson, Nadezhda, additional, Egdorf, Tom, additional, Ellingwood, Lauren, additional, Enstrom, Rachel, additional, Esposito, Luke, additional, Farrell, Colin, additional, Feng, David, additional, Fong, Olivia, additional, Gala, Rohan, additional, Gamlin, Clare, additional, Gary, Amanda, additional, Glandon, Alexandra, additional, Goldy, Jeff, additional, Gorham, Melissa, additional, Graybuck, Lucas, additional, Gu, Hong, additional, Hadley, Kirsten, additional, Hawrylycz, Michael J., additional, Henry, Alex M., additional, Hill, DiJon, additional, Happ, Madie, additional, Kebede, Sara, additional, Kyung Kim, Tae, additional, Kim, Lisa, additional, Kroll, Matthew, additional, Lee, Changkyu, additional, Link, Katherine E., additional, Mallory, Matthew, additional, Mann, Rusty, additional, Maxwell, Michelle, additional, McGraw, Medea, additional, McMillen, Delissa, additional, Mukora, Alice, additional, Ng, Lindsay, additional, Ng, Lydia, additional, Ngo, Kiet, additional, Nicovich, Philip R., additional, Oldre, Aaron, additional, Park, Daniel, additional, Peng, Hanchuan, additional, Penn, Osnat, additional, Pham, Thanh, additional, Pom, Alice, additional, Potekhina, Lyida, additional, Rajanbabu, Ramkumar, additional, Ransford, Shea, additional, Reid, David, additional, Rimorin, Christine, additional, Robertson, Miranda, additional, Ronellenfitch, Kara, additional, Ruiz, Augustin, additional, Sandman, David, additional, Smith, Kimberly, additional, Sulc, Josef, additional, Sunkin, Susan M., additional, Szafer, Aaron, additional, Tieu, Michael, additional, Torkelson, Amy, additional, Trinh, Jessica, additional, Tung, Herman, additional, Wakeman, Wayne, additional, Ward, Katelyn, additional, Williams, Grace, additional, Zhou, Zhi, additional, Ting, Jonathan, additional, Arkhipov, Anton, additional, Sumbul, Uygar, additional, Lein, Ed, additional, Koch, Christof, additional, Yao, Zizhen, additional, Tasic, Bosiljka, additional, Berg, Jim, additional, Murphy, Gabe J., additional, and Zeng, Hongkui, additional

Published
2020
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34. Enhancer AAVs for targeting spinal motor neurons and descending motor pathways in rodents and macaque.

Author

Kussick E, Johansen N, Taskin N, Wynalda B, Martinez R, Groce EL, Reding M, Liang E, Shulga L, Huang C, Casper T, Clark M, Ho W, Gao Y, van Velthoven CTJ, Sobieski C, Ferrer R, Berg MR, Curtis BC, English C, Day JC, Fortuna M, Donadio N, Newman D, Yao S, Chakka AB, Goldy J, Torkelson A, Guzman JB, Chakrabarty R, Nguy B, Guilford N, Pham TH, Wright V, Ronellenfitch K, Gudsnuk K, Thyagarajan B, Smith KA, Dee N, Zeng H, Yao Z, Tasic B, Levi BP, Hodge R, Bakken TE, Lein ES, Ting JT, and Daigle TL

Abstract

Experimental access to cell types within the mammalian spinal cord is severely limited by the availability of genetic tools. To enable access to lower motor neurons (LMNs) and LMN subtypes, which function to integrate information from the brain and control movement through direct innervation of effector muscles, we generated single cell multiome datasets from mouse and macaque spinal cords and discovered putative enhancers for each neuronal population. We cloned these enhancers into adeno-associated viral vectors (AAVs) driving a reporter fluorophore and functionally screened them in mouse. The most promising candidate enhancers were then extensively characterized using imaging and molecular techniques and further tested in rat and macaque to show conservation of LMN labeling. Additionally, we combined enhancer elements into a single vector to achieve simultaneous labeling of upper motor neurons (UMNs) and LMNs. This unprecedented LMN toolkit will enable future investigations of cell type function across species and potential therapeutic interventions for human neurodegenerative diseases., Competing Interests: Declaration of interests T.L.D., B.P.L, B.T., E.S.L, H.Z, J.T.T., N.J., Y.G., Z.Y., are inventors on one or more U.S. provisional patent applications related to this work. All authors declare no other competing interests.

Published
2024
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35. The transcriptomic and spatial organization of telencephalic GABAergic neuronal types.

Author

van Velthoven CTJ, Gao Y, Kunst M, Lee C, McMillen D, Chakka AB, Casper T, Clark M, Chakrabarty R, Daniel S, Dolbeare T, Ferrer R, Gloe J, Goldy J, Guzman J, Halterman C, Ho W, Huang M, James K, Nguy B, Pham T, Ronellenfitch K, Thomas ED, Torkelson A, Pagan CM, Kruse L, Dee N, Ng L, Waters J, Smith KA, Tasic B, Yao Z, and Zeng H

Abstract

The telencephalon of the mammalian brain comprises multiple regions and circuit pathways that play adaptive and integrative roles in a variety of brain functions. There is a wide array of GABAergic neurons in the telencephalon; they play a multitude of circuit functions, and dysfunction of these neurons has been implicated in diverse brain disorders. In this study, we conducted a systematic and in-depth analysis of the transcriptomic and spatial organization of GABAergic neuronal types in all regions of the mouse telencephalon and their developmental origins. This was accomplished by utilizing 611,423 single-cell transcriptomes from the comprehensive and high-resolution transcriptomic and spatial cell type atlas for the adult whole mouse brain we have generated, supplemented with an additional single-cell RNA-sequencing dataset containing 99,438 high-quality single-cell transcriptomes collected from the pre- and postnatal developing mouse brain. We present a hierarchically organized adult telencephalic GABAergic neuronal cell type taxonomy of 7 classes, 52 subclasses, 284 supertypes, and 1,051 clusters, as well as a corresponding developmental taxonomy of 450 clusters across different ages. Detailed charting efforts reveal extraordinary complexity where relationships among cell types reflect both spatial locations and developmental origins. Transcriptomically and developmentally related cell types can often be found in distant and diverse brain regions indicating that long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons. Additionally, we find various spatial dimensions of both discrete and continuous variations among related cell types that are correlated with gene expression gradients. Lastly, we find that cortical, striatal and some pallidal GABAergic neurons undergo extensive postnatal diversification, whereas septal and most pallidal GABAergic neuronal types emerge simultaneously during the embryonic stage with limited postnatal diversification. Overall, the telencephalic GABAergic cell type taxonomy can serve as a foundational reference for molecular, structural and functional studies of cell types and circuits by the entire community., Competing Interests: Competing Interests H.Z. is on the scientific advisory board of MapLight Therapeutics, Inc. The other authors declare no competing interests.

Published
2024
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36. Interindividual variation in human cortical cell type abundance and expression.

Author

Johansen N, Somasundaram S, Travaglini KJ, Yanny AM, Shumyatcher M, Casper T, Cobbs C, Dee N, Ellenbogen R, Ferreira M, Goldy J, Guzman J, Gwinn R, Hirschstein D, Jorstad NL, Keene CD, Ko A, Levi BP, Ojemann JG, Pham T, Shapovalova N, Silbergeld D, Sulc J, Torkelson A, Tung H, Smith K, Lein ES, Bakken TE, Hodge RD, and Miller JA

Subjects
Adult, Humans, Epilepsy metabolism, Gene Expression Profiling, Neurons metabolism, Nervous System Diseases genetics, Mental Disorders genetics, Temporal Lobe cytology, Temporal Lobe metabolism, Transcriptome
Abstract

Single-cell transcriptomic studies have identified a conserved set of neocortical cell types from small postmortem cohorts. We extended these efforts by assessing cell type variation across 75 adult individuals undergoing epilepsy and tumor surgeries. Nearly all nuclei map to one of 125 robust cell types identified in the middle temporal gyrus. However, we found interindividual variance in abundances and gene expression signatures, particularly in deep-layer glutamatergic neurons and microglia. A minority of donor variance is explainable by age, sex, ancestry, disease state, and cell state. Genomic variation was associated with expression of 150 to 250 genes for most cell types. This characterization of cellular variation provides a baseline for cell typing in health and disease.

Published
2023
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37. Comparative transcriptomics reveals human-specific cortical features.

Author

Jorstad NL, Song JHT, Exposito-Alonso D, Suresh H, Castro-Pacheco N, Krienen FM, Yanny AM, Close J, Gelfand E, Long B, Seeman SC, Travaglini KJ, Basu S, Beaudin M, Bertagnolli D, Crow M, Ding SL, Eggermont J, Glandon A, Goldy J, Kiick K, Kroes T, McMillen D, Pham T, Rimorin C, Siletti K, Somasundaram S, Tieu M, Torkelson A, Feng G, Hopkins WD, Höllt T, Keene CD, Linnarsson S, McCarroll SA, Lelieveldt BP, Sherwood CC, Smith K, Walsh CA, Dobin A, Gillis J, Lein ES, Hodge RD, and Bakken TE

Subjects
Animals, Humans, Gene Expression Profiling, Gorilla gorilla genetics, Macaca mulatta genetics, Pan troglodytes genetics, Phylogeny, Transcriptome, Species Specificity, Hominidae genetics, Hominidae physiology, Neocortex physiology, Temporal Lobe physiology, Cognition
Abstract

The cognitive abilities of humans are distinctive among primates, but their molecular and cellular substrates are poorly understood. We used comparative single-nucleus transcriptomics to analyze samples of the middle temporal gyrus (MTG) from adult humans, chimpanzees, gorillas, rhesus macaques, and common marmosets to understand human-specific features of the neocortex. Human, chimpanzee, and gorilla MTG showed highly similar cell-type composition and laminar organization as well as a large shift in proportions of deep-layer intratelencephalic-projecting neurons compared with macaque and marmoset MTG. Microglia, astrocytes, and oligodendrocytes had more-divergent expression across species compared with neurons or oligodendrocyte precursor cells, and neuronal expression diverged more rapidly on the human lineage. Only a few hundred genes showed human-specific patterning, suggesting that relatively few cellular and molecular changes distinctively define adult human cortical structure.

Published
2023
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38. Cell-type specific molecular signatures of aging revealed in a brain-wide transcriptomic cell-type atlas.

Author

Jin K, Yao Z, van Velthoven CTJ, Kaplan ES, Glattfelder K, Barlow ST, Boyer G, Carey D, Casper T, Chakka AB, Chakrabarty R, Clark M, Departee M, Desierto M, Gary A, Gloe J, Goldy J, Guilford N, Guzman J, Hirschstein D, Lee C, Liang E, Pham T, Reding M, Ronellenfitch K, Ruiz A, Sevigny J, Shapovalova N, Shulga L, Sulc J, Torkelson A, Tung H, Levi B, Sunkin SM, Dee N, Esposito L, Smith K, Tasic B, and Zeng H

Abstract

Biological aging can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function. Aging is a complex and dynamic process which influences distinct cell types in a myriad of ways. The cellular architecture of the mammalian brain is heterogeneous and diverse, making it challenging to identify precise areas and cell types of the brain that are more susceptible to aging than others. Here, we present a high-resolution single-cell RNA sequencing dataset containing ~1.2 million high-quality single-cell transcriptomic profiles of brain cells from young adult and aged mice across both sexes, including areas spanning the forebrain, midbrain, and hindbrain. We find age-associated gene expression signatures across nearly all 130+ neuronal and non-neuronal cell subclasses we identified. We detect the greatest gene expression changes in non-neuronal cell types, suggesting that different cell types in the brain vary in their susceptibility to aging. We identify specific, age-enriched clusters within specific glial, vascular, and immune cell types from both cortical and subcortical regions of the brain, and specific gene expression changes associated with cell senescence, inflammation, decrease in new myelination, and decreased vasculature integrity. We also identify genes with expression changes across multiple cell subclasses, pointing to certain mechanisms of aging that may occur across wide regions or broad cell types of the brain. Finally, we discover the greatest gene expression changes in cell types localized to the third ventricle of the hypothalamus, including tanycytes, ependymal cells, and Tbx3 + neurons found in the arcuate nucleus that are part of the neuronal circuits regulating food intake and energy homeostasis. These findings suggest that the area surrounding the third ventricle in the hypothalamus may be a hub for aging in the mouse brain. Overall, we reveal a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal aging that will serve as a foundation for the investigation of functional changes in the aging process and the interaction of aging and diseases., Competing Interests: Competing Interests H.Z. is on the scientific advisory board of MapLight Therapeutics, Inc. The other authors declare no competing interests.

Published
2023
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39. Integrated multimodal cell atlas of Alzheimer's disease.

Author

Gabitto MI, Travaglini KJ, Rachleff VM, Kaplan ES, Long B, Ariza J, Ding Y, Mahoney JT, Dee N, Goldy J, Melief EJ, Brouner K, Campos J, Carr AJ, Casper T, Chakrabarty R, Clark M, Compos J, Cool J, Valera Cuevas NJ, Dalley R, Darvas M, Ding SL, Dolbeare T, Mac Donald CL, Egdorf T, Esposito L, Ferrer R, Gala R, Gary A, Gloe J, Guilford N, Guzman J, Ho W, Jarksy T, Johansen N, Kalmbach BE, Keene LM, Khawand S, Kilgore M, Kirkland A, Kunst M, Lee BR, Malone J, Maltzer Z, Martin N, McCue R, McMillen D, Meyerdierks E, Meyers KP, Mollenkopf T, Montine M, Nolan AL, Nyhus J, Olsen PA, Pacleb M, Pham T, Pom CA, Postupna N, Ruiz A, Schantz AM, Sorensen SA, Staats B, Sullivan M, Sunkin SM, Thompson C, Tieu M, Ting J, Torkelson A, Tran T, Wang MQ, Waters J, Wilson AM, Haynor D, Gatto N, Jayadev S, Mufti S, Ng L, Mukherjee S, Crane PK, Latimer CS, Levi BP, Smith K, Close JL, Miller JA, Hodge RD, Larson EB, Grabowski TJ, Hawrylycz M, Keene CD, and Lein ES

Abstract

Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org., Competing Interests: Additional Declarations: There is NO Competing Interest.

Published
2023
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40. A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain.

Author

Yao Z, van Velthoven CTJ, Kunst M, Zhang M, McMillen D, Lee C, Jung W, Goldy J, Abdelhak A, Baker P, Barkan E, Bertagnolli D, Campos J, Carey D, Casper T, Chakka AB, Chakrabarty R, Chavan S, Chen M, Clark M, Close J, Crichton K, Daniel S, Dolbeare T, Ellingwood L, Gee J, Glandon A, Gloe J, Gould J, Gray J, Guilford N, Guzman J, Hirschstein D, Ho W, Jin K, Kroll M, Lathia K, Leon A, Long B, Maltzer Z, Martin N, McCue R, Meyerdierks E, Nguyen TN, Pham T, Rimorin C, Ruiz A, Shapovalova N, Slaughterbeck C, Sulc J, Tieu M, Torkelson A, Tung H, Cuevas NV, Wadhwani K, Ward K, Levi B, Farrell C, Thompson CL, Mufti S, Pagan CM, Kruse L, Dee N, Sunkin SM, Esposito L, Hawrylycz MJ, Waters J, Ng L, Smith KA, Tasic B, Zhuang X, and Zeng H

Abstract

The mammalian brain is composed of millions to billions of cells that are organized into numerous cell types with specific spatial distribution patterns and structural and functional properties. An essential step towards understanding brain function is to obtain a parts list, i.e., a catalog of cell types, of the brain. Here, we report a comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain. The cell type atlas was created based on the combination of two single-cell-level, whole-brain-scale datasets: a single-cell RNA-sequencing (scRNA-seq) dataset of ~7 million cells profiled, and a spatially resolved transcriptomic dataset of ~4.3 million cells using MERFISH. The atlas is hierarchically organized into five nested levels of classification: 7 divisions, 32 classes, 306 subclasses, 1,045 supertypes and 5,200 clusters. We systematically analyzed the neuronal, non-neuronal, and immature neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain: the dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. We also systematically characterized cell-type specific expression of neurotransmitters, neuropeptides, and transcription factors. The study uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types across the brain, suggesting they mediate a myriad of modes of intercellular communications. Finally, we found that transcription factors are major determinants of cell type classification in the adult mouse brain and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole-mouse-brain transcriptomic and spatial cell type atlas establishes a benchmark reference atlas and a foundational resource for deep and integrative investigations of cell type and circuit function, development, and evolution of the mammalian brain., Competing Interests: Competing Interests X.Z. is a co-founder and consultant of Vizgen.

Published
2023
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