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8 results on '"Graybuck, Lucas T."'

1. Trimodal single-cell profiling reveals a novel pediatric CD8αα+T cell subset and broad age-related molecular reprogramming across the T cell compartment

Author

Thomson, Zachary, He, Ziyuan, Swanson, Elliott, Henderson, Katherine, Phalen, Cole, Zaim, Samir Rachid, Pebworth, Mark-Phillip, Okada, Lauren Y., Heubeck, Alexander T., Roll, Charles R., Hernandez, Veronica, Weiss, Morgan, Genge, Palak C., Reading, Julian, Giles, Josephine R., Manne, Sasikanth, Dougherty, Jeanette, Jasen, C. J., Greenplate, Allison R., Becker, Lynne A., Graybuck, Lucas T., Vasaikar, Suhas V., Szeto, Gregory L., Savage, Adam K., Speake, Cate, Buckner, Jane H., Li, Xiao-jun, Bumol, Thomas F., Wherry, E.John, Torgerson, Troy R., Vella, Laura A., Henrickson, Sarah E., Skene, Peter J., and Gustafson, Claire E.

Abstract

Age-associated changes in the T cell compartment are well described. However, limitations of current single-modal or bimodal single-cell assays, including flow cytometry, RNA-seq (RNA sequencing) and CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), have restricted our ability to deconvolve more complex cellular and molecular changes. Here, we profile >300,000 single T cells from healthy children (aged 11–13 years) and older adults (aged 55–65 years) by using the trimodal assay TEA-seq (single-cell analysis of mRNA transcripts, surface protein epitopes and chromatin accessibility), which revealed that molecular programming of T cell subsets shifts toward a more activated basal state with age. Naive CD4+T cells, considered relatively resistant to aging, exhibited pronounced transcriptional and epigenetic reprogramming. Moreover, we discovered a novel CD8αα+T cell subset lost with age that is epigenetically poised for rapid effector responses and has distinct inhibitory, costimulatory and tissue-homing properties. Together, these data reveal new insights into age-associated changes in the T cell compartment that may contribute to differential immune responses.

Published
2023
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2. 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, and Lein, Ed S.

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
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3. Author Correction: Trimodal single-cell profiling reveals a novel pediatric CD8αα+T cell subset and broad age-related molecular reprogramming across the T cell compartment

Author

Thomson, Zachary, He, Ziyuan, Swanson, Elliott, Henderson, Katherine, Phalen, Cole, Zaim, Samir Rachid, Pebworth, Mark-Phillip, Okada, Lauren Y., Heubeck, Alexander T., Roll, Charles R., Hernandez, Veronica, Weiss, Morgan, Genge, Palak C., Reading, Julian, Giles, Josephine R., Manne, Sasikanth, Dougherty, Jeanette, Jasen, C. J., Greenplate, Allison R., Becker, Lynne A., Graybuck, Lucas T., Vasaikar, Suhas V., Szeto, Gregory L., Savage, Adam K., Speake, Cate, Buckner, Jane H., Li, Xiao-jun, Bumol, Thomas F., Wherry, E.John, Torgerson, Troy R., Vella, Laura A., Henrickson, Sarah E., Skene, Peter J., and Gustafson, Claire E.

Published
2024
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4. Shared and distinct transcriptomic cell types across neocortical areas

Author

Tasic, Bosiljka, Yao, Zizhen, Graybuck, Lucas T., Smith, Kimberly A., Nguyen, Thuc Nghi, Bertagnolli, Darren, Goldy, Jeff, Garren, Emma, Economo, Michael N., Viswanathan, Sarada, Penn, Osnat, Bakken, Trygve, Menon, Vilas, Miller, Jeremy, Fong, Olivia, Hirokawa, Karla E., Lathia, Kanan, Rimorin, Christine, Tieu, Michael, Larsen, Rachael, Casper, Tamara, Barkan, Eliza, Kroll, Matthew, Parry, Sheana, Shapovalova, Nadiya V., Hirschstein, Daniel, Pendergraft, Julie, Sullivan, Heather A., Kim, Tae Kyung, Szafer, Aaron, Dee, Nick, Groblewski, Peter, Wickersham, Ian, Cetin, Ali, Harris, Julie A., Levi, Boaz P., Sunkin, Susan M., Madisen, Linda, Daigle, Tanya L., Looger, Loren, Bernard, Amy, Phillips, John, Lein, Ed, Hawrylycz, Michael, Svoboda, Karel, Jones, Allan R., Koch, Christof, and Zeng, Hongkui

Abstract

The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here we analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. We define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, we match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Our study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.

Published
2018
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5. Distinct descending motor cortex pathways and their roles in movement

Author

Economo, Michael N., Viswanathan, Sarada, Tasic, Bosiljka, Bas, Erhan, Winnubst, Johan, Menon, Vilas, Graybuck, Lucas T., Nguyen, Thuc Nghi, Smith, Kimberly A., Yao, Zizhen, Wang, Lihua, Gerfen, Charles R., Chandrashekar, Jayaram, Zeng, Hongkui, Looger, Loren L., and Svoboda, Karel

Abstract

Activity in the motor cortex predicts movements, seconds before they are initiated. This preparatory activity has been observed across cortical layers, including in descending pyramidal tract neurons in layer 5. A key question is how preparatory activity is maintained without causing movement, and is ultimately converted to a motor command to trigger appropriate movements. Here, using single-cell transcriptional profiling and axonal reconstructions, we identify two types of pyramidal tract neuron. Both types project to several targets in the basal ganglia and brainstem. One type projects to thalamic regions that connect back to motor cortex; populations of these neurons produced early preparatory activity that persisted until the movement was initiated. The second type projects to motor centres in the medulla and mainly produced late preparatory activity and motor commands. These results indicate that two types of motor cortex output neurons have specialized roles in motor control.

Published
2018
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6. 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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7. Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex

Author

Mich, John K., Graybuck, Lucas T., Hess, Erik E., Mahoney, Joseph T., Kojima, Yoshiko, Ding, Yi, Somasundaram, Saroja, Miller, Jeremy A., Kalmbach, Brian E., Radaelli, Cristina, Gore, Bryan B., Weed, Natalie, Omstead, Victoria, Bishaw, Yemeserach, Shapovalova, Nadiya V., Martinez, Refugio A., Fong, Olivia, Yao, Shenqin, Mortrud, Marty, Chong, Peter, Loftus, Luke, Bertagnolli, Darren, Goldy, Jeff, Casper, Tamara, Dee, Nick, Opitz-Araya, Ximena, Cetin, Ali, Smith, Kimberly A., Gwinn, Ryder P., Cobbs, Charles, Ko, Andrew L., Ojemann, Jeffrey G., Keene, C. Dirk, Silbergeld, Daniel L., Sunkin, Susan M., Gradinaru, Viviana, Horwitz, Gregory D., Zeng, Hongkui, Tasic, Bosiljka, Lein, Ed S., Ting, Jonathan T., and Levi, Boaz P.

Abstract

Viral genetic tools that target specific brain cell types could transform basic neuroscience and targeted gene therapy. Here, we use comparative open chromatin analysis to identify thousands of human-neocortical-subclass-specific putative enhancers from across the genome to control gene expression in adeno-associated virus (AAV) vectors. The cellular specificity of reporter expression from enhancer-AAVs is established by molecular profiling after systemic AAV delivery in mouse. Over 30% of enhancer-AAVs produce specific expression in the targeted subclass, including both excitatory and inhibitory subclasses. We present a collection of Parvalbumin (PVALB) enhancer-AAVs that show highly enriched expression not only in cortical PVALB cells but also in some subcortical PVALB populations. Five vectors maintain PVALB-enriched expression in primate neocortex. These results demonstrate how genome-wide open chromatin data mining and cross-species AAV validation can be used to create the next generation of non-species-restricted viral genetic tools.

Published
2021
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8. Distinct Transcriptomic Cell Types and Neural Circuits of the Subiculum and Prosubiculum along the Dorsal-Ventral Axis

Author

Ding, Song-Lin, Yao, Zizhen, Hirokawa, Karla E., Nguyen, Thuc Nghi, Graybuck, Lucas T., Fong, Olivia, Bohn, Phillip, Ngo, Kiet, Smith, Kimberly A., Koch, Christof, Phillips, John W., Lein, Ed S., Harris, Julie A., Tasic, Bosiljka, and Zeng, Hongkui

Abstract

Subicular regions play important roles in spatial processing and many cognitive functions, and these are mainly attributed to the subiculum (Sub) rather than the prosubiculum (PS). Using single-cell RNA sequencing, we identify 27 transcriptomic cell types residing in sub-domains of the Sub and PS. Based on in situexpression of reliable transcriptomic markers, the precise boundaries of the Sub and PS are consistently defined along the dorsoventral axis. Using these borders to evaluate Cre-line specificity and tracer injections, we find bona fide Sub projections topographically to structures important for spatial processing and navigation. In contrast, the PS sends its outputs to widespread brain regions crucial for motivation, emotion, reward, stress, anxiety, and fear. The Sub and PS, respectively, dominate dorsal and ventral subicular regions and receive different afferents. These results reveal two molecularly and anatomically distinct circuits centered in the Sub and PS, respectively, providing a consistent explanation for historical data and a clearer foundation for future studies.

Published
2020
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