A multimodal cell census and atlas of the mammalian primary motor cortex

Abstract

Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.

Morphological diversity of single neurons in molecularly defined cell types

“…L2/3 cells have local axons branching in L2/3 and downward into L5, whereas L4 cells have local axons mainly projecting up to L2/3 68 . We also found 4 cells from MOp and MOs with these L4-like features -minimal apical dendrites and upward-projecting local axons, suggesting that these are the L4-like cells located in motor cortex 69 that can also be identified transcriptomically 70 . Consistent with prior notion 67 , all but two SSp L4 cells have only local axons but no long-range projections.…”

A method to estimate the cellular composition of the mouse brain from heterogeneous datasets

“…Over the past century, numerous studies have reported a great variety of cells in the mouse brain according to their morphological, electrical, and molecular features. Several groups such as the BRAIN Initiative® have launched ambitious projects to undertake a comprehensive census of all brain cells, determining their molecular, structural and functional properties [1][2][3][4]. Building a catalogue of the vast diversity of neuron types in the brain is a challenge for modern neuroscience.…”

Spindle-Shaped Neurons in the Human Posteromedial (Precuneus) Cortex

“…Notably, thick-tufted layer V pyramidal neurons are a heterogeneous class of cells, but are morphologically different from their neighboring VENs ( Watson et al, 2006 ; compare with Ramaswamy and Markram, 2015 ; Cembrowski and Spruston, 2019 ; Rasia-Filho et al, 2021 ); see also comments on the likely coexistence of discrete and continuous variations that underlie cell-type diversity in BRAIN Initiative Cell Census Network (BICCN), 2021 . VENs emerge mainly after birth, increase in number until age 4 years ( Allman et al, 2005 ), and can be susceptible to alterations in some neuropsychiatric disorders (as described below).…”