Human neocortical expansion involves glutamatergic neuron diversification

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

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


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.

Original languageEnglish
Pages (from-to)151-158
Number of pages8
Issue number7879
StatePublished - 7 Oct 2021


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