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

Author:

Berg JimORCID,Sorensen Staci A.ORCID,Ting Jonathan T.ORCID,Miller Jeremy A.ORCID,Chartrand ThomasORCID,Buchin AnatolyORCID,Bakken Trygve E.ORCID,Budzillo AgataORCID,Dee NickORCID,Ding Song-LinORCID,Gouwens Nathan W.ORCID,Hodge Rebecca D.ORCID,Kalmbach BrianORCID,Lee ChangkyuORCID,Lee Brian R.ORCID,Alfiler LaurenORCID,Baker KatherineORCID,Barkan ElizaORCID,Beller AllisonORCID,Berry KylaORCID,Bertagnolli DarrenORCID,Bickley KrisORCID,Bomben JasmineORCID,Braun ThomasORCID,Brouner KrissyORCID,Casper TamaraORCID,Chong PeterORCID,Crichton KirstenORCID,Dalley RachelORCID,de Frates RebeccaORCID,Desta TsegaORCID,Dingman Lee SamuelORCID,D’Orazi FlorenceORCID,Dotson NadezhdaORCID,Egdorf TomORCID,Enstrom RachelORCID,Farrell ColinORCID,Feng DavidORCID,Fong Olivia,Furdan SzabinaORCID,Galakhova Anna A.ORCID,Gamlin ClareORCID,Gary AmandaORCID,Glandon AlexandraORCID,Goldy JeffORCID,Gorham Melissa,Goriounova Natalia A.ORCID,Gratiy SergeyORCID,Graybuck LucasORCID,Gu Hong,Hadley KristenORCID,Hansen NathanORCID,Heistek Tim S.ORCID,Henry Alex M.ORCID,Heyer Djai B.,Hill DiJonORCID,Hill ChrisORCID,Hupp MadieORCID,Jarsky TimORCID,Kebede SaraORCID,Keene LisaORCID,Kim LisaORCID,Kim Mean-HwanORCID,Kroll MatthewORCID,Latimer CaitlinORCID,Levi Boaz P.ORCID,Link Katherine E.ORCID,Mallory MatthewORCID,Mann RustyORCID,Marshall DesireeORCID,Maxwell MichelleORCID,McGraw MedeaORCID,McMillen DelissaORCID,Melief EricaORCID,Mertens Eline J.ORCID,Mezei LeonaORCID,Mihut NorbertORCID,Mok Stephanie,Molnar GaborORCID,Mukora AliceORCID,Ng LindsayORCID,Ngo Kiet,Nicovich Philip R.ORCID,Nyhus JulieORCID,Olah GasparORCID,Oldre AaronORCID,Omstead VictoriaORCID,Ozsvar AttilaORCID,Park DanielORCID,Peng HanchuanORCID,Pham TrangthanhORCID,Pom Christina A.ORCID,Potekhina LydiaORCID,Rajanbabu RamkumarORCID,Ransford Shea,Reid DavidORCID,Rimorin ChristineORCID,Ruiz AugustinORCID,Sandman DavidORCID,Sulc JosefORCID,Sunkin Susan M.ORCID,Szafer Aaron,Szemenyei ViktorORCID,Thomsen Elliot R.ORCID,Tieu MichaelORCID,Torkelson AmyORCID,Trinh JessicaORCID,Tung HermanORCID,Wakeman WayneORCID,Ward KatelynORCID,Wilbers RenéORCID,Williams GraceORCID,Yao ZizhenORCID,Yoon Jae-GeunORCID,Anastassiou CostasORCID,Arkhipov AntonORCID,Barzo PalORCID,Bernard AmyORCID,Cobbs CharlesORCID,de Witt Hamer Philip C.ORCID,Ellenbogen Richard G.ORCID,Esposito LukeORCID,Ferreira ManuelORCID,Gwinn Ryder P.ORCID,Hawrylycz Michael J.ORCID,Hof Patrick R.ORCID,Idema Sander,Jones Allan R.ORCID,Keene C.DirkORCID,Ko Andrew L.ORCID,Murphy Gabe J.ORCID,Ng LydiaORCID,Ojemann Jeffrey G.,Patel Anoop P.ORCID,Phillips John W.ORCID,Silbergeld Daniel L.ORCID,Smith KimberlyORCID,Tasic BosiljkaORCID,Yuste RafaelORCID,Segev IdanORCID,de Kock Christiaan P.J.ORCID,Mansvelder Huibert D.ORCID,Tamas GaborORCID,Zeng HongkuiORCID,Koch ChristofORCID,Lein Ed S.ORCID

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.

Publisher

Cold Spring Harbor Laboratory

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