Human neocortical expansion involves glutamatergic neuron diversification
Authors: 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 , Lein Ed S. 
Published: October 2021

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.