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

Abstract

We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) 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. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.

Method of the Year: spatially resolved transcriptomics

“…The research community will soon have cell-type-specific reference atlases onto which they can map their own findings. Among other papers, the BICCN teams recently published a multimodal cell census and atlas of the mammalian primary motor cortex 8 . BICCN phase two is starting, says Zeng.…”

Petabyte-Scale Multi-Morphometry of Single Neurons for Whole Brains

“…Reconstructing the complete 3-D shape or morphology of a neuron, including its dendrites and axons in their entirety, as well as finer structures such as the somata, dendritic spines, and axonal terminal boutons, is recognized as a crucial step to profile the myriad types of neurons in brains [1][2][3][4] . This technique, which we refer to as Multi-Morphometry, has begun to generate intriguing information and hypotheses about brain circuits at the single-neuron / single-synapse level [5][6][7] .…”

MorphoHub: A Platform for Petabyte-Scale Multi-Morphometry Generation

“…Reconstructing the complete 3-D shape or morphology of a neuron, including its dendrites and axons in their entirety, as well as finer structures such as the somata, dendritic spines, and axonal terminal boutons, is recognized as a crucial step to profile the myriad types of neurons in brains [1][2][3][4] . This technique, which we refer to as Multi-Morphometry, has begun to generate intriguing information and hypotheses about brain circuits at the single-neuron / single-synapse level [5][6][7] .…”