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1. Connecting single-cell transcriptomes to projectomes in mouse visual cortex

Author

Sorensen, Staci A., primary, Gouwens, Nathan W., additional, Wang, Yun, additional, Mallory, Matt, additional, Budzillo, Agata, additional, Dalley, Rachel, additional, Lee, Brian, additional, Gliko, Olga, additional, Kuo, Hsien-chi, additional, Kuang, Xiuli, additional, Mann, Rusty, additional, Ahmadinia, Leila, additional, Alfiler, Lauren, additional, Baftizadeh, Fahimeh, additional, Baker, Katherine, additional, Bannick, Sarah, additional, Bertagnolli, Darren, additional, Bickley, Kris, additional, Bohn, Phil, additional, Brown, Dillan, additional, Bomben, Jasmine, additional, Brouner, Krissy, additional, Chen, Chao, additional, Chen, Kai, additional, Chvilicek, Maggie, additional, Collman, Forrest, additional, Daigle, Tanya, additional, Dawes, Tim, additional, de Frates, Rebecca, additional, Dee, Nick, additional, DePartee, Maxwell, additional, Egdorf, Tom, additional, El-Hifnawi, Laila, additional, Enstrom, Rachel, additional, Esposito, Luke, additional, Farrell, Colin, additional, Gala, Rohan, additional, Glomb, Andrew, additional, Gamlin, Clare, additional, Gary, Amanda, additional, Goldy, Jeff, additional, Gu, Hong, additional, Hadley, Kristen, additional, Hawrylycz, Mike, additional, Henry, Alex, additional, Hill, Dijon, additional, Hirokawa, Karla E., additional, Huang, Zili, additional, Johnson, Katelyn, additional, Juneau, Zoe, additional, Kebede, Sara, additional, Kim, Lisa, additional, Lee, Changkyu, additional, Lesnar, Phil, additional, Li, Anan, additional, Li, Yaoyao, additional, Liang, Elizabeth, additional, Link, Katie, additional, Maxwell, Michelle, additional, McGraw, Medea, additional, McMillen, Delissa A., additional, Mukora, Alice, additional, Ng, Lindsay, additional, Ochoa, Thomas, additional, Oldre, Aaron, additional, Park, Daniel, additional, Pom, Christina Alice, additional, Popovich, Zoran, additional, Potekhina, Lydia, additional, Rajanbabu, Ram, additional, Ransford, Shea, additional, Reding, Melissa, additional, Ruiz, Augustin, additional, Sandman, David, additional, Siverts, La’Akea, additional, Smith, Kimberly A., additional, Stoecklin, Michelle, additional, Sulc, Josef, additional, Tieu, Michael, additional, Ting, Jonathan, additional, Trinh, Jessica, additional, Vargas, Sara, additional, Vumbaco, Dave, additional, Walker, Miranda, additional, Wang, Micheal, additional, Wanner, Adrian, additional, Waters, Jack, additional, Williams, Grace, additional, Wilson, Julia, additional, Xiong, Wei, additional, Lein, Ed, additional, Berg, Jim, additional, Kalmbach, Brian, additional, Yao, Shenqin, additional, Gong, Hui, additional, Luo, Qingming, additional, Ng, Lydia, additional, Sümbül, Uygar, additional, Jarsky, Tim, additional, Yao, Zizhen, additional, Tasic, Bosiljka, additional, and Zeng, Hongkui, additional

Published
2023
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2. 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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3. 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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4. Local connectivity and synaptic dynamics in mouse and human neocortex

Author

Campagnola, Luke, primary, Seeman, Stephanie C., additional, Chartrand, Thomas, additional, Kim, Lisa, additional, Hoggarth, Alex, additional, Gamlin, Clare, additional, Ito, Shinya, additional, Trinh, Jessica, additional, Davoudian, Pasha, additional, Radaelli, Cristina, additional, Kim, Mean-Hwan, additional, Hage, Travis, additional, Braun, Thomas, additional, Alfiler, Lauren, additional, Andrade, Julia, additional, Bohn, Phillip, additional, Dalley, Rachel, additional, Henry, Alex, additional, Kebede, Sara, additional, Alice, Mukora, additional, Sandman, David, additional, Williams, Grace, additional, Larsen, Rachael, additional, Teeter, Corinne, additional, Daigle, Tanya L., additional, Berry, Kyla, additional, Dotson, Nadia, additional, Enstrom, Rachel, additional, Gorham, Melissa, additional, Hupp, Madie, additional, Dingman Lee, Samuel, additional, Ngo, Kiet, additional, Nicovich, Philip R., additional, Potekhina, Lydia, additional, Ransford, Shea, additional, Gary, Amanda, additional, Goldy, Jeff, additional, McMillen, Delissa, additional, Pham, Trangthanh, additional, Tieu, Michael, additional, Siverts, La’Akea, additional, Walker, Miranda, additional, Farrell, Colin, additional, Schroedter, Martin, additional, Slaughterbeck, Cliff, additional, Cobb, Charles, additional, Ellenbogen, Richard, additional, Gwinn, Ryder P., additional, Keene, C. Dirk, additional, Ko, Andrew L., additional, Ojemann, Jeffrey G., additional, Silbergeld, Daniel L., additional, Carey, Daniel, additional, Casper, Tamara, additional, Crichton, Kirsten, additional, Clark, Michael, additional, Dee, Nick, additional, Ellingwood, Lauren, additional, Gloe, Jessica, additional, Kroll, Matthew, additional, Sulc, Josef, additional, Tung, Herman, additional, Wadhwani, Katherine, additional, Brouner, Krissy, additional, Egdorf, Tom, additional, Maxwell, Michelle, additional, McGraw, Medea, additional, Pom, Christina Alice, additional, Ruiz, Augustin, additional, Bomben, Jasmine, additional, Feng, David, additional, Hejazinia, Nika, additional, Shi, Shu, additional, Szafer, Aaron, additional, Wakeman, Wayne, additional, Phillips, John, additional, Bernard, Amy, additional, Esposito, Luke, additional, D’Orazi, Florence D., additional, Sunkin, Susan, additional, Smith, Kimberly, additional, Tasic, Bosiljka, additional, Arkhipov, Anton, additional, Sorensen, Staci, additional, Lein, Ed, additional, Koch, Christof, additional, Murphy, Gabe, additional, Zeng, Hongkui, additional, and Jarsky, Tim, additional

Published
2022
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5. Local Connectivity and Synaptic Dynamics in Mouse and Human Neocortex

Author

Campagnola, Luke, primary, Seeman, Stephanie C, additional, Chartrand, Thomas, additional, Kim, Lisa, additional, Hoggarth, Alex, additional, Gamlin, Clare, additional, Ito, Shinya, additional, Trinh, Jessica, additional, Davoudian, Pasha, additional, Radaelli, Cristina, additional, Kim, Mean-Hwan, additional, Hage, Travis, additional, Braun, Thomas, additional, Alfiler, Lauren, additional, Andrade, Juia, additional, Bohn, Phillip, additional, Dalley, Rachel, additional, Henry, Alex, additional, Kebede, Sara, additional, Mukora, Alice, additional, Sandman, David, additional, Williams, Grace, additional, Larsen, Rachael, additional, Teeter, Corinne, additional, Daigle, Tanya L., additional, Berry, Kyla, additional, Dotson, Nadia, additional, Enstrom, Rachel, additional, Gorham, Melissa, additional, Hupp, Madie, additional, Lee, Samuel Dingman, additional, Ngo, Kiet, additional, Nicovich, Rusty, additional, Potekhina, Lydia, additional, Ransford, Shea, additional, Gary, Amanda, additional, Goldy, Jeff, additional, McMillen, Delissa, additional, Pham, Trangthanh, additional, Tieu, Michael, additional, Siverts, La’Akea, additional, Walker, Miranda, additional, Farrell, Colin, additional, Schroedter, Martin, additional, Slaughterbeck, Cliff, additional, Cobb, Charles, additional, Ellenbogen, Richard, additional, Gwinn, Ryder P, additional, Keene, C. Dirk, additional, Ko, Andrew L, additional, Ojemann, Jeffrey G, additional, Silbergeld, Daniel L, additional, Carey, Daniel, additional, Casper, Tamara, additional, Crichton, Kirsten, additional, Clark, Michael, additional, Dee, Nick, additional, Ellingwood, Lauren, additional, Gloe, Jessica, additional, Kroll, Matthew, additional, Sulc, Josef, additional, Tung, Herman, additional, Wadhwani, Katherine, additional, Brouner, Krissy, additional, Egdorf, Tom, additional, Maxwell, Michelle, additional, McGraw, Medea, additional, Pom, Christina Alice, additional, Ruiz, Augustin, additional, Bomben, Jasmine, additional, Feng, David, additional, Hejazinia, Nika, additional, Shi, Shu, additional, Szafer, Aaron, additional, Wakeman, Wayne, additional, Phillips, John, additional, Bernard, Amy, additional, Esposito, Luke, additional, D’Orazi, Florence D, additional, Sunkin, Susan, additional, Smith, Kimberly, additional, Tasic, Bosiljka, additional, Arkhipov, Anton, additional, Sorensen, Staci, additional, Lein, Ed, additional, Koch, Christof, additional, Murphy, Gabe, additional, Zeng, Hongkui, additional, and Jarsky, Tim, additional

Published
2021
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6. Connecting single-cell transcriptomes to projectomes in mouse visual cortex.

Author

Sorensen SA, Gouwens NW, Wang Y, Mallory M, Budzillo A, Dalley R, Lee B, Gliko O, Kuo HC, Kuang X, Mann R, Ahmadinia L, Alfiler L, Baftizadeh F, Baker K, Bannick S, Bertagnolli D, Bickley K, Bohn P, Brown D, Bomben J, Brouner K, Chen C, Chen K, Chvilicek M, Collman F, Daigle T, Dawes T, de Frates R, Dee N, DePartee M, Egdorf T, El-Hifnawi L, Enstrom R, Esposito L, Farrell C, Gala R, Glomb A, Gamlin C, Gary A, Goldy J, Gu H, Hadley K, Hawrylycz M, Henry A, Hill D, Hirokawa KE, Huang Z, Johnson K, Juneau Z, Kebede S, Kim L, Lee C, Lesnar P, Li A, Glomb A, Li Y, Liang E, Link K, Maxwell M, McGraw M, McMillen DA, Mukora A, Ng L, Ochoa T, Oldre A, Park D, Pom CA, Popovich Z, Potekhina L, Rajanbabu R, Ransford S, Reding M, Ruiz A, Sandman D, Siverts L, Smith KA, Stoecklin M, Sulc J, Tieu M, Ting J, Trinh J, Vargas S, Vumbaco D, Walker M, Wang M, Wanner A, Waters J, Williams G, Wilson J, Xiong W, Lein E, Berg J, Kalmbach B, Yao S, Gong H, Luo Q, Ng L, Sümbül U, Jarsky T, Yao Z, Tasic B, and Zeng H

Abstract

The mammalian brain is composed of diverse neuron types that play different functional roles. Recent single-cell RNA sequencing approaches have led to a whole brain taxonomy of transcriptomically-defined cell types, yet cell type definitions that include multiple cellular properties can offer additional insights into a neuron's role in brain circuits. While the Patch-seq method can investigate how transcriptomic properties relate to the local morphological and electrophysiological properties of cell types, linking transcriptomic identities to long-range projections is a major unresolved challenge. To address this, we collected coordinated Patch-seq and whole brain morphology data sets of excitatory neurons in mouse visual cortex. From the Patch-seq data, we defined 16 integrated morpho-electric-transcriptomic (MET)-types; in parallel, we reconstructed the complete morphologies of 300 neurons. We unified the two data sets with a multi-step classifier, to integrate cell type assignments and interrogate cross-modality relationships. We find that transcriptomic variations within and across MET-types correspond with morphological and electrophysiological phenotypes. In addition, this variation, along with the anatomical location of the cell, can be used to predict the projection targets of individual neurons. We also shed new light on infragranular cell types and circuits, including cell-type-specific, interhemispheric projections. With this approach, we establish a comprehensive, integrated taxonomy of excitatory neuron types in mouse visual cortex and create a system for integrated, high-dimensional cell type classification that can be extended to the whole brain and potentially across species.

Published
2023
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7. 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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