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1. Human neocortical expansion involves glutamatergic neuron diversification

Author

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

Subjects
Cell type, Multidisciplinary, Neocortex, Neurofilament, Molecular neuroscience, Biology, Article, Cellular neuroscience, chemistry.chemical_compound, Glutamatergic, medicine.anatomical_structure, chemistry, Biocytin, medicine, Neuron, Neuroscience
Abstract

The neocortex is disproportionately expanded in human compared with mouse1,2, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth3. Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer’s disease4,5. Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease., Combined patch clamp recording, biocytin staining and single-cell RNA-sequencing of human neurocortical neurons shows an expansion of glutamatergic neuron types relative to mouse that characterizes the greater complexity of the human neocortex.

Published
2021
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2. Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in spinocerebellar ataxia type 1

Author

H. Brent Clark, Vanessa C. Wheeler, Jean Paul Vonsattel, Marissa A Andrew, Sarah Maria von Hein, Pedram Razghandi, Kevin Correia, Larissa Arning, Suman Jayadaev, Ricardo Mouro Pinto, Diane Lucente, Carsten Saft, Huu Phuc Nguyen, C. Dirk Keene, Constanze R. Parwez, Eckart Förster, Debora M. Grote Urtubey, Thomas D. Bird, James Victor Giordano, Harry T. Orr, Jayalakshmi S. Mysore, Elisabeth Petrasch-Parwez, Tammy Gillis, and Allison Beller

Subjects
Adult, Central Nervous System, Male, AcademicSubjects/SCI01140, Spinocerebellar Ataxia Type 1, Cerebellum, Cell type, congenital, hereditary, and neonatal diseases and abnormalities, Somatic cell, Central nervous system, Disease, Biology, 03 medical and health sciences, 0302 clinical medicine, Huntington's disease, Trinucleotide Repeats, mental disorders, Genetics, medicine, Humans, Spinocerebellar Ataxias, Child, Molecular Biology, Genetics (clinical), 030304 developmental biology, Aged, 0303 health sciences, Huntingtin Protein, General Medicine, Middle Aged, medicine.disease, Neostriatum, medicine.anatomical_structure, Huntington Disease, Female, Autopsy, General Article, Trinucleotide repeat expansion, Trinucleotide Repeat Expansion, Neuroscience, 030217 neurology & neurosurgery
Abstract

The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.

Published
2020

3. Human cortical expansion involves diversification and specialization of supragranular intratelencephalic-projecting neurons

Author

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

Subjects
0303 health sciences, Cell type, Neocortex, Neurofilament, Biology, Transcriptome, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, medicine.anatomical_structure, Cortex (anatomy), Specialization (functional), medicine, Neuroscience, 030217 neurology & neurosurgery, Function (biology), 030304 developmental biology
Abstract

The neocortex is disproportionately expanded in human compared to mouse, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers that selectively make connections within the cortex and other telencephalic structures. Single-cell transcriptomic analyses of human and mouse cortex show an increased diversity of glutamatergic neuron types in supragranular cortex in human and pronounced gradients as a function of cortical depth. To probe the functional and anatomical correlates of this transcriptomic diversity, we describe a robust Patch-seq platform using neurosurgically-resected human tissues. We characterize the morphological and physiological properties of five transcriptomically defined human glutamatergic supragranular neuron types. Three of these types have properties that are specialized compared to the more homogeneous properties of transcriptomically defined homologous mouse neuron types. The two remaining supragranular neuron types, located exclusively in deep layer 3, do not have clear mouse homologues in supragranular cortex but are transcriptionally most similar to deep layer mouse intratelencephalic-projecting neuron types. Furthermore, we reveal the transcriptomic types in deep layer 3 that express high levels of non-phosphorylated heavy chain neurofilament protein that label long-range neurons known to be selectively depleted in Alzheimer’s disease. Together, these results demonstrate the power of transcriptomic cell type classification, provide a mechanistic underpinning for increased complexity of cortical function in human cortical evolution, and implicate discrete transcriptomic cell types as selectively vulnerable in disease.

Published
2020
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4. Conserved cell types with divergent features in human versus mouse cortex

Author

Elliot R. Thomsen, Ahmed Mahfouz, Saroja Somasundaram, Aaron Oldre, Bosiljka Tasic, Songlin Ding, Richard H. Scheuermann, Daniel Hirschstein, Thomas Höllt, Christine Rimorin, Thuc Nghi Nguyen, Jennie L. Close, John W. Phillips, Lydia Ng, Jeff Goldy, Darren Bertagnolli, Amy Bernard, Zizhen Yao, Boaz P. Levi, Trygve E. Bakken, Soraya I. Shehata, Susan M. Sunkin, Osnat Penn, Michael Tieu, Allison Beller, Boudewijn P. F. Lelieveldt, Jeffrey G. Ojemann, Shannon Reynolds, Michael Hawrylycz, Jeroen Eggermont, Medea McGraw, Ryder P. Gwinn, Sheana Parry, Kimberly A. Smith, Brian Long, Olivia Fong, Zoe Maltzer, Rafael Yuste, David Feng, Julie Nyhus, Rebecca D. Hodge, Ed Lein, Jeremy A. Miller, Brian D. Aevermann, Gerald Quon, Emma Garren, Christof Koch, Aaron Szafer, Nick Dee, Nadiya V. Shapovalova, Rachel A. Dalley, Tamara Casper, Mohamed Keshk, Nelson Johansen, Krissy Brouner, Andrew L. Ko, Allan R. Jones, Eliza Barkan, Hongkui Zeng, Richard G. Ellenbogen, C. Dirk Keene, Kanan Lathia, Lucas T. Graybuck, and Charles Cobbs

Subjects
0301 basic medicine, Adult, Male, Cell type, Adolescent, General Science & Technology, Middle temporal gyrus, 1.1 Normal biological development and functioning, Biology, 03 medical and health sciences, Mice, Young Adult, 0302 clinical medicine, Single-cell analysis, Species Specificity, Underpinning research, Cortex (anatomy), medicine, Genetics, Animals, Humans, 2.1 Biological and endogenous factors, RNA-Seq, Aetiology, Aged, Cerebral Cortex, Neurons, Principal Component Analysis, Multidisciplinary, Cellular architecture, Neurosciences, Neural Inhibition, Human brain, Middle Aged, Biological Evolution, 030104 developmental biology, medicine.anatomical_structure, Cerebral cortex, Astrocytes, Neurological, Excitatory postsynaptic potential, Female, Single-Cell Analysis, Transcriptome, Neuroscience, 030217 neurology & neurosurgery
Abstract

Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to similar mouse cortex single-cell RNA-sequencing datasets revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of properties of human cell types. Despite this general conservation, we also found extensive differences between homologous human and mouse cell types, including marked alterations in proportions, laminar distributions, gene expression and morphology. These species-specific features emphasize the importance of directly studying human brain.

Published
2019
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5. Conserved cell types with divergent features between human and mouse cortex

Author

Jeff Goldy, Sheana Parry, Jeremy A. Miller, Brian Long, Susan M. Sunkin, Saroja Somasundaram, Rebecca D. Hodge, Hongkui Zeng, Aaron Oldre, Kimberly A. Smith, Zoe Maltzer, Brian D. Aevermann, Mohamed Keshk, Jeroen Eggermont, Ed Lein, Daniel Hirschstein, Darren Bertagnolli, Jennie L. Close, Osnat Penn, John W. Phillips, Rachel A. Dalley, Allan R. Jones, Ahmed Mahfouz, Olivia Fong, Allison Beller, Soraya I. Shehata, Thuc Nghi Nguyen, Jeffrey G. Ojemann, Shannon Reynolds, Eliza Barkan, Michael Tieu, Christof Koch, Michael Hawrylycz, Songlin Ding, Richard H. Scheuermann, Ryder P. Gwinn, Elliot R. Thomsen, Medea McGraw, Emma Garren, Christine Rimorin, Lydia Ng, Boudewijn P. F. Lelieveldt, C. Dirk Keene, Amy Bernard, Richard G. Ellenbogen, Rafael Yuste, David Feng, Boaz P. Levi, Trygve E. Bakken, Tamara Casper, Bosiljka Tasic, Aaron Szafer, Nick Dee, Nadiya V. Shapovalova, Kanan Lathia, Lucas T. Graybuck, Charles Cobbs, Julie Nyhus, Thomas Höllt, Zizhen Yao, Krissy Brouner, and Andrew L. Ko

Subjects
0303 health sciences, Cell type, Neocortex, Cellular architecture, Middle temporal gyrus, Cell, Human brain, Biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Cerebral cortex, medicine, Neuroscience, Nucleus, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Elucidating the cellular architecture of the human neocortex is central to understanding our cognitive abilities and susceptibility to disease. Here we applied single nucleus RNA-sequencing to perform a comprehensive analysis of cell types in the middle temporal gyrus of human cerebral cortex. We identify a highly diverse set of excitatory and inhibitory neuronal types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to a similar mouse cortex single cell RNA-sequencing dataset revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of human cell type properties. Despite this general conservation, we also find extensive differences between homologous human and mouse cell types, including dramatic alterations in proportions, laminar distributions, gene expression, and morphology. These species-specific features emphasize the importance of directly studying human brain.

Published
2018
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6. Neuropathological and transcriptomic characteristics of the aged brain

Author

Terri L. Gilbert, Thomas J. Montine, Aaron Szafer, Eiron Cudaback, Nick Dee, Christine Cuhaciyan, Xianwu Li, Kimberly A. Smith, Samuel R Josephsen, Tim A. Dolbeare, Paul K. Crane, Amy Bernard, Nadezhda Dotson, Michael Tieu, Fiona Griffin, Shannon E. Rose, Ed S. Lein, Jeff Goldy, Laura E. Gibbons, Julie Pendergraft, Felix Lee, Nivretta Thatra, Elaine Shen, Elizabeth Rha, Susan M. Sunkin, Garrett Gee, Lydia Potekhina, Nadia Postupna, Darren Bertagnolli, Andy J. Sodt, Nikolas L. Jorstad, Angela L. Guillozet-Bongaarts, Samantha Rice, Jeremy A. Miller, Natalie M Coleman, Zeb Haradon, Tsega Desta, David Rosen, Angela M. Wilson, Justin Johal, Shubhabrata Mukherjee, Kristopher Bickley, Anne Renz, Abharika Sapru, Robert Howard, Desiree A. Marshall, Tracy Lemon, Nika Hejazinia, Rachel A. Dalley, Shu Shi, Steve Horvath, Mindy L Chua, Aimee Schantz, Eric B. Larson, Allison Beller, Michael S. Fisher, Julie Nyhus, C. Dirk Keene, Lydia Ng, Kim Howard, Caroline Habel, Nathalie Gaudreault, Krissy Brouner, Leanne L Hellstern, Shiella Caldejon, Jose Melchor, Emily Sherfield, Chihchau L. Kuan, Mike Chapin, Richard G. Ellenbogen, Chris Barber, Florence Lai, and Eric Lee

Subjects
0301 basic medicine, Male, Amyloid beta, QH301-705.5, Science, Hippocampus, Disease, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Dementia, Humans, Biology (General), Gene, Pathological, Aged, Aged, 80 and over, Cerebral Cortex, General Immunology and Microbiology, biology, business.industry, General Neuroscience, Gene Expression Profiling, aging, Cognition, General Medicine, Alzheimer's disease, medicine.disease, 3. Good health, Tools and Resources, 030104 developmental biology, biology.protein, gene expression, Medicine, Female, business, Neuroscience, 030217 neurology & neurosurgery, Human, dementia
Abstract

As more people live longer, age-related neurodegenerative diseases are an increasingly important societal health issue. Treatments targeting specific pathologies such as amyloid beta in Alzheimer’s disease (AD) have not led to effective treatments, and there is increasing evidence of a disconnect between traditional pathology and cognitive abilities with advancing age, indicative of individual variation in resilience to pathology. Here, we generated a comprehensive neuropathological, molecular, and transcriptomic characterization of hippocampus and two regions cortex in 107 aged donors (median = 90) from the Adult Changes in Thought (ACT) study as a freely-available resource (http://aging.brain-map.org/). We confirm established associations between AD pathology and dementia, albeit with increased, presumably aging-related variability, and identify sets of co-expressed genes correlated with pathological tau and inflammation markers. Finally, we demonstrate a relationship between dementia and RNA quality, and find common gene signatures, highlighting the importance of properly controlling for RNA quality when studying dementia.

Published
2017

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