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 Berry; Darren 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

doi:10.1038/s41586-021-03813-8

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^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

The neocortex is disproportionately expanded in human compared with mouse^1,2, 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 disease^4,5. 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 language	English
Pages (from-to)	151-158
Number of pages	8
Journal	Nature
Volume	598
Issue number	7879
DOIs	https://doi.org/10.1038/s41586-021-03813-8
Publication status	Published - 7 Oct 2021

Bibliographical note

Funding Information:
Hungarian Academy of Sciences, the National Research, Development and Innovation Office of Hungary GINOP-2.3.2-15-2016-00018, the Ministry of Human Capacities of Hungary 20391-3/2018/FEKUSTRAT to G.T. Neuropathology support was provided in part by the Nancy and Buster Alvord Endowment to C.D.K. Work was supported by the European Union’s Horizon 2020 Framework Programme for Research and Innovation under the specific grant agreement no. 945539 (Human Brain Project SGA3), ERANET programme iPS&BRAIN, and NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). This work was funded by the Allen Institute for Brain Science. We dedicate this paper to the vision, encouragement, and long-term support of our founder, Paul G. Allen.

Funding Information:
Acknowledgements We thank A. Wanner for providing reconstruction services through A. Szeto and R. Szeto, and Z. Popovic for facilitating the reconstruction work contributed by Mozak.science. We also thank the Mozak citizen scientists for their valuable contribution. The research was partially supported by several grant awards from institutes under the National Institutes of Health (NIH), including award U01MH114812 from National Institute of Mental Health, R01EY023173 from The National Eye Institute, U01MH105982 from the National Institute of Mental Health and Eunice Kennedy Shriver National Institute of Child Health & Human Development, and R011EY023173 from The National Institute of Allergy and Infectious Disease. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH and its subsidiary institutes. Work was supported by the

Publisher Copyright:
© 2021, The Author(s).

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Funding

Hungarian Academy of Sciences, the National Research, Development and Innovation Office of Hungary GINOP-2.3.2-15-2016-00018, the Ministry of Human Capacities of Hungary 20391-3/2018/FEKUSTRAT to G.T. Neuropathology support was provided in part by the Nancy and Buster Alvord Endowment to C.D.K. Work was supported by the European Union’s Horizon 2020 Framework Programme for Research and Innovation under the specific grant agreement no. 945539 (Human Brain Project SGA3), ERANET programme iPS&BRAIN, and NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). This work was funded by the Allen Institute for Brain Science. We dedicate this paper to the vision, encouragement, and long-term support of our founder, Paul G. Allen. Acknowledgements We thank A. Wanner for providing reconstruction services through A. Szeto and R. Szeto, and Z. Popovic for facilitating the reconstruction work contributed by Mozak.science. We also thank the Mozak citizen scientists for their valuable contribution. The research was partially supported by several grant awards from institutes under the National Institutes of Health (NIH), including award U01MH114812 from National Institute of Mental Health, R01EY023173 from The National Eye Institute, U01MH105982 from the National Institute of Mental Health and Eunice Kennedy Shriver National Institute of Child Health & Human Development, and R011EY023173 from The National Institute of Allergy and Infectious Disease. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH and its subsidiary institutes. Work was supported by the

Funders	Funder number
Allen Institute for Brain Science
European Union’s Horizon 2020 Framework Programme for Research and Innovation	945539
National Institute of Mental Health and Eunice Kennedy Shriver National Institute of Child Health & Human Development	R011EY023173
National Institutes of Health
National Institute of Mental Health	U01MH114812, U01MH105982, R01EY023173
National Eye Institute
National Institute of Allergy and Infectious Diseases
Nancy and Buster Alvord Endowment
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	024.004.012
Magyar Tudományos Akadémia
Emberi Eroforrások Minisztériuma	20391-3/2018/FEKUSTRAT
Nemzeti Kutatási Fejlesztési és Innovációs Hivatal	GINOP-2.3.2-15-2016-00018

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Berg, J., Sorensen, S. A., Ting, J. T., Miller, J. A., Chartrand, T., Buchin, A., Bakken, T. E., Budzillo, A., Dee, N., Ding, S. L., Gouwens, N. W., Hodge, R. D., Kalmbach, B., Lee, C., Lee, B. R., Alfiler, L., Baker, K., Barkan, E., Beller, A., ... Lein, E. S. (2021). Human neocortical expansion involves glutamatergic neuron diversification. Nature, 598(7879), 151-158. https://doi.org/10.1038/s41586-021-03813-8

@article{df908a46b18241b3b732326dddbab23b,

title = "Human neocortical expansion involves glutamatergic neuron diversification",

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{\textquoteright}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.",

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

note = "Funding Information: Hungarian Academy of Sciences, the National Research, Development and Innovation Office of Hungary GINOP-2.3.2-15-2016-00018, the Ministry of Human Capacities of Hungary 20391-3/2018/FEKUSTRAT to G.T. Neuropathology support was provided in part by the Nancy and Buster Alvord Endowment to C.D.K. Work was supported by the European Union{\textquoteright}s Horizon 2020 Framework Programme for Research and Innovation under the specific grant agreement no. 945539 (Human Brain Project SGA3), ERANET programme iPS&BRAIN, and NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). This work was funded by the Allen Institute for Brain Science. We dedicate this paper to the vision, encouragement, and long-term support of our founder, Paul G. Allen. Funding Information: Acknowledgements We thank A. Wanner for providing reconstruction services through A. Szeto and R. Szeto, and Z. Popovic for facilitating the reconstruction work contributed by Mozak.science. We also thank the Mozak citizen scientists for their valuable contribution. The research was partially supported by several grant awards from institutes under the National Institutes of Health (NIH), including award U01MH114812 from National Institute of Mental Health, R01EY023173 from The National Eye Institute, U01MH105982 from the National Institute of Mental Health and Eunice Kennedy Shriver National Institute of Child Health & Human Development, and R011EY023173 from The National Institute of Allergy and Infectious Disease. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH and its subsidiary institutes. Work was supported by the Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = oct,

day = "7",

doi = "10.1038/s41586-021-03813-8",

language = "English",

volume = "598",

pages = "151--158",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7879",

}

Berg, J, Sorensen, SA, Ting, JT, Miller, JA, Chartrand, T, Buchin, A, Bakken, TE, Budzillo, A, Dee, N, Ding, SL, Gouwens, NW, Hodge, RD, Kalmbach, B, Lee, C, Lee, BR, Alfiler, L, Baker, K, Barkan, E, Beller, A, Berry, K, Bertagnolli, D, Bickley, K, Bomben, J, Braun, T, Brouner, K, Casper, T, Chong, P, Crichton, K, Dalley, R, de Frates, R, Desta, T, Lee, SD, D’Orazi, F, Dotson, N, Egdorf, T, Enstrom, R, Farrell, C, Feng, D, Fong, O, Furdan, S, Galakhova, AA, Gamlin, C, Gary, A, Glandon, A, Goldy, J, Gorham, M, Goriounova, NA, Gratiy, S, Graybuck, L, Gu, H, Hadley, K, Hansen, N, Heistek, TS, Henry, AM, Heyer, DB, Hill, DJ, Hill, C, Hupp, M, Jarsky, T, Kebede, S, Keene, L, Kim, L, Kim, MH, Kroll, M, Latimer, C, Levi, BP, Link, KE, Mallory, M, Mann, R, Marshall, D, Maxwell, M, McGraw, M, McMillen, D, Melief, E, Mertens, EJ, Mezei, L, Mihut, N, Mok, S, Molnar, G, Mukora, A, Ng, L, Ngo, K, Nicovich, PR, Nyhus, J, Olah, G, Oldre, A, Omstead, V, Ozsvar, A, Park, D, Peng, H, Pham, T, Pom, CA, Potekhina, L, Rajanbabu, R, Ransford, S, Reid, D, Rimorin, C, Ruiz, A, Sandman, D, Sulc, J, Sunkin, SM, Szafer, A, Szemenyei, V, Thomsen, ER, Tieu, M, Torkelson, A, Trinh, J, Tung, H, Wakeman, W, Waleboer, F, Ward, K, Wilbers, R, Williams, G, Yao, Z, Yoon, JG, Anastassiou, C, Arkhipov, A, Barzo, P, Bernard, A, Cobbs, C, de Witt Hamer, PC, Ellenbogen, RG, Esposito, L, Ferreira, M, Gwinn, RP, Hawrylycz, MJ, Hof, PR, Idema, S, Jones, AR, Keene, CD, Ko, AL, Murphy, GJ, Ng, L, Ojemann, JG, Patel, AP, Phillips, JW, Silbergeld, DL, Smith, K, Tasic, B, Yuste, R, Segev, I, de Kock, CPJ , Mansvelder, HD, Tamas, G, Zeng, H, Koch, C & Lein, ES 2021, 'Human neocortical expansion involves glutamatergic neuron diversification', Nature, vol. 598, no. 7879, pp. 151-158. https://doi.org/10.1038/s41586-021-03813-8

TY - JOUR

T1 - Human neocortical expansion involves glutamatergic neuron diversification

AU - Berg, Jim

AU - Sorensen, Staci A.

AU - Ting, Jonathan T.

AU - Miller, Jeremy A.

AU - Chartrand, Thomas

AU - Buchin, Anatoly

AU - Bakken, Trygve E.

AU - Budzillo, Agata

AU - Dee, Nick

AU - Ding, Song Lin

AU - Gouwens, Nathan W.

AU - Hodge, Rebecca D.

AU - Kalmbach, Brian

AU - Lee, Changkyu

AU - Lee, Brian R.

AU - Alfiler, Lauren

AU - Baker, Katherine

AU - Barkan, Eliza

AU - Beller, Allison

AU - Berry, Kyla

AU - Bertagnolli, Darren

AU - Bickley, Kris

AU - Bomben, Jasmine

AU - Braun, Thomas

AU - Brouner, Krissy

AU - Casper, Tamara

AU - Chong, Peter

AU - Crichton, Kirsten

AU - Dalley, Rachel

AU - de Frates, Rebecca

AU - Desta, Tsega

AU - Lee, Samuel Dingman

AU - D’Orazi, Florence

AU - Dotson, Nadezhda

AU - Egdorf, Tom

AU - Enstrom, Rachel

AU - Farrell, Colin

AU - Feng, David

AU - Fong, Olivia

AU - Furdan, Szabina

AU - Galakhova, Anna A.

AU - Gamlin, Clare

AU - Gary, Amanda

AU - Glandon, Alexandra

AU - Goldy, Jeff

AU - Gorham, Melissa

AU - Goriounova, Natalia A.

AU - Gratiy, Sergey

AU - Graybuck, Lucas

AU - Gu, Hong

AU - Hadley, Kristen

AU - Hansen, Nathan

AU - Heistek, Tim S.

AU - Henry, Alex M.

AU - Heyer, Djai B.

AU - Hill, Di Jon

AU - Hill, Chris

AU - Hupp, Madie

AU - Jarsky, Tim

AU - Kebede, Sara

AU - Keene, Lisa

AU - Kim, Lisa

AU - Kim, Mean Hwan

AU - Kroll, Matthew

AU - Latimer, Caitlin

AU - Levi, Boaz P.

AU - Link, Katherine E.

AU - Mallory, Matthew

AU - Mann, Rusty

AU - Marshall, Desiree

AU - Maxwell, Michelle

AU - McGraw, Medea

AU - McMillen, Delissa

AU - Melief, Erica

AU - Mertens, Eline J.

AU - Mezei, Leona

AU - Mihut, Norbert

AU - Mok, Stephanie

AU - Molnar, Gabor

AU - Mukora, Alice

AU - Ng, Lindsay

AU - Ngo, Kiet

AU - Nicovich, Philip R.

AU - Nyhus, Julie

AU - Olah, Gaspar

AU - Oldre, Aaron

AU - Omstead, Victoria

AU - Ozsvar, Attila

AU - Park, Daniel

AU - Peng, Hanchuan

AU - Pham, Trangthanh

AU - Pom, Christina A.

AU - Potekhina, Lydia

AU - Rajanbabu, Ramkumar

AU - Ransford, Shea

AU - Reid, David

AU - Rimorin, Christine

AU - Ruiz, Augustin

AU - Sandman, David

AU - Sulc, Josef

AU - Sunkin, Susan M.

AU - Szafer, Aaron

AU - Szemenyei, Viktor

AU - Thomsen, Elliot R.

AU - Tieu, Michael

AU - Torkelson, Amy

AU - Trinh, Jessica

AU - Tung, Herman

AU - Wakeman, Wayne

AU - Waleboer, Femke

AU - Ward, Katelyn

AU - Wilbers, René

AU - Williams, Grace

AU - Yao, Zizhen

AU - Yoon, Jae Geun

AU - Anastassiou, Costas

AU - Arkhipov, Anton

AU - Barzo, Pal

AU - Bernard, Amy

AU - Cobbs, Charles

AU - de Witt Hamer, Philip C.

AU - Ellenbogen, Richard G.

AU - Esposito, Luke

AU - Ferreira, Manuel

AU - Gwinn, Ryder P.

AU - Hawrylycz, Michael J.

AU - Hof, Patrick R.

AU - Idema, Sander

AU - Jones, Allan R.

AU - Keene, C. Dirk

AU - Ko, Andrew L.

AU - Murphy, Gabe J.

AU - Ng, Lydia

AU - Ojemann, Jeffrey G.

AU - Patel, Anoop P.

AU - Phillips, John W.

AU - Silbergeld, Daniel L.

AU - Smith, Kimberly

AU - Tasic, Bosiljka

AU - Yuste, Rafael

AU - Segev, Idan

AU - de Kock, Christiaan P.J.

AU - Mansvelder, Huibert D.

AU - Tamas, Gabor

AU - Zeng, Hongkui

AU - Koch, Christof

AU - Lein, Ed S.

N1 - Funding Information: Hungarian Academy of Sciences, the National Research, Development and Innovation Office of Hungary GINOP-2.3.2-15-2016-00018, the Ministry of Human Capacities of Hungary 20391-3/2018/FEKUSTRAT to G.T. Neuropathology support was provided in part by the Nancy and Buster Alvord Endowment to C.D.K. Work was supported by the European Union’s Horizon 2020 Framework Programme for Research and Innovation under the specific grant agreement no. 945539 (Human Brain Project SGA3), ERANET programme iPS&BRAIN, and NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). This work was funded by the Allen Institute for Brain Science. We dedicate this paper to the vision, encouragement, and long-term support of our founder, Paul G. Allen. Funding Information: Acknowledgements We thank A. Wanner for providing reconstruction services through A. Szeto and R. Szeto, and Z. Popovic for facilitating the reconstruction work contributed by Mozak.science. We also thank the Mozak citizen scientists for their valuable contribution. The research was partially supported by several grant awards from institutes under the National Institutes of Health (NIH), including award U01MH114812 from National Institute of Mental Health, R01EY023173 from The National Eye Institute, U01MH105982 from the National Institute of Mental Health and Eunice Kennedy Shriver National Institute of Child Health & Human Development, and R011EY023173 from The National Institute of Allergy and Infectious Disease. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH and its subsidiary institutes. Work was supported by the Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/10/7

Y1 - 2021/10/7

N2 - 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.

AB - 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.

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U2 - 10.1038/s41586-021-03813-8

DO - 10.1038/s41586-021-03813-8

M3 - Article

AN - SCOPUS:85116429019

SN - 0028-0836

VL - 598

SP - 151

EP - 158

JO - Nature

JF - Nature

IS - 7879

ER -

Human neocortical expansion involves glutamatergic neuron diversification

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