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Human neocortical expansion involves glutamatergic neuron diversification.

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.

SUBMITTER: Berg J

PROVIDER: S-EPMC8494638 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Human neocortical expansion involves glutamatergic neuron diversification.

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

Nature 20211006 7879

The neocortex is disproportionately expanded in human compared with mouse<sup>1,2</sup>, 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 ...[more]

PMID: 34616067

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Project description:UnlabelledThe amygdala serves as emotional center to mediate innate fear behaviors that are reflected through neuronal responses to environmental aversive cues. However, the molecular mechanism underlying the initial neuron responses is poorly understood. In this study, we monitored the innate defensive responses to aversive stimuli of either elevated plus maze or predator odor in juvenile mice and found that glutamatergic neurons were activated in amygdala. Loss of EphB2, a receptor tyrosine kinase expressed in amygdala neurons, suppressed the reactions and led to defects in spine morphogenesis and fear behaviors. We further found a coupling of spinogenesis with these threat cues induced neuron activation in developing amygdala that was controlled by EphB2. A constitutively active form of EphB2 was sufficient to rescue the behavioral and morphological defects caused by ablation of ephrin-B3, a brain-enriched ligand to EphB2. These data suggest that kinase-dependent EphB2 intracellular signaling plays a major role for innate fear responses during the critical developing period, in which spinogenesis in amygdala glutamatergic neurons was involved.Significance statementGeneration of innate fear responses to threat as an evolutionally conserved brain feature relies on development of functional neural circuit in amygdala, but the molecular mechanism remains largely unknown. We here identify that EphB2 receptor tyrosine kinase, which is specifically expressed in glutamatergic neurons, is required for the innate fear responses in the neonatal brain. We further reveal that EphB2 mediates coordination of spinogenesis and neuron activation in amygdala during the critical period for the innate fear. EphB2 catalytic activity plays a major role for the behavior upon EphB-ephrin-B3 binding and transnucleus neuronal connections. Our work thus indicates an essential synaptic molecular signaling within amygdala that controls synapse development and helps bring about innate fear emotions in the postnatal developing brain.

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Human neocortical expansion involves glutamatergic neuron diversification.

Publications

Human neocortical expansion involves glutamatergic neuron diversification.

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