The mammalian brain consists of millions to billions of cells that are organized into many cell types with specific spatial distribution patterns and structural and functional properties1-3. Here we report a comprehensive and high-resolution transcriptomic and spatial cell-type atlas for the whole adult mouse brain. The cell-type atlas was created by combining a single-cell RNA-sequencing (scRNA-seq) dataset of around 7 million cells profiled (approximately 4.0 million cells passing quality control), and a spatial transcriptomic dataset of approximately 4.3 million cells using multiplexed error-robust fluorescence in situ hybridization (MERFISH). The atlas is hierarchically organized into 4 nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, to visualize the mouse whole-brain cell-type atlas along with the single-cell RNA-sequencing and MERFISH datasets. We systematically analysed the neuronal and non-neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell-type organization in different brain regions-in particular, a dichotomy between the dorsal and ventral parts of the brain. The dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. Our study also uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types. Finally, we found that transcription factors are major determinants of cell-type classification and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole mouse brain transcriptomic and spatial cell-type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development and evolution of the mammalian brain. 

A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain

The mammalian brain is composed of millions to billions of cells that are organized into numerous cell types with specific spatial distribution patterns and structural and functional properties. An essential step towards understanding brain function is to obtain a parts list, i.e., a catalog of cell types, of the brain. Here, we report a comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain. The cell type atlas was created based on the combination of two single-cell-level, whole-brain-scale datasets: a single- cell RNA-sequencing (scRNA-seq) dataset of ∼7 million cells profiled, and a spatially resolved transcriptomic dataset of ∼4.3 million cells using MERFISH. The atlas is hierarchically organized into five nested levels of classification: 7 divisions, 32 classes, 306 subclasses, 1,045 supertypes and 5,200 clusters. We systematically analyzed the neuronal, non-neuronal, and immature neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain: the dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. We also systematically characterized cell-type specific expression of neurotransmitters, neuropeptides, and transcription factors. The study uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types across the brain, suggesting they mediate a myriad of modes of intercellular communications. Finally, we found that transcription factors are major determinants of cell type classification in the adult mouse brain and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole-mouse-brain transcriptomic and spatial cell type atlas establishes a benchmark reference atlas and a foundational resource for deep and integrative investigations of cell type and circuit function, development, and evolution of the mammalian brain.

/pdf/a-high-resolution-transcriptomic-and-spatial-atlas-of-cell-2797pvc8.pdf

The mammalian cortex is composed of a highly diverse set of cell types and develops through a series of temporally regulated events1, 2–3. Single-cell transcriptomics enables a systematic study of cell types across the entire timeline of cortical development. Here we present a comprehensive and high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex. The atlas is built from a single-cell RNA sequencing dataset of 568,654 high-quality single-cell transcriptomes and a single-nucleus Multiome dataset of 200,061 high-quality nuclei, which were densely sampled across the embryonic and postnatal developmental stages (from embryonic day 11.5 to postnatal day 56). We computationally reconstructed a transcriptomic developmental trajectory map of all excitatory, inhibitory and non-neuronal cell types in the visual cortex. Branching points that mark the emergence of new cell types at specific developmental ages and molecular signatures of cellular diversification are identified. The trajectory map shows that neurogenesis, gliogenesis and early postmitotic maturation in the embryonic stage give rise to all cell classes and nearly all subclasses in a staggered parallel manner. Increasingly refined cell types emerge throughout the postnatal differentiation process, including the late emergence of many cell types during the eye-opening stage and the onset of critical period, suggesting that there is continuous cell-type diversification at different stages of cortical development. Throughout development, there are cooperative dynamic changes in gene expression and chromatin accessibility in specific cell types. We identify cell-type-specific and temporally resolved gene regulatory networks that link transcription factors and downstream target genes through accessible chromatin motifs. Collectively, our study provides a detailed dynamic molecular map directly associated with individual cell types and specific temporal events that can reveal the molecular logic underlying the complex and multifaceted cortical cell type and circuit development. A high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex from embryonic to postnatal development is presented, providing a real-time dynamic molecular map associated with individual cell types and specific developmental events.

Continuous cell-type diversification in mouse visual cortex development

The telencephalon of the mammalian brain contains multiple regions and circuits that have adaptive and integrative roles in a variety of brain functions. GABAergic neurons in the telencephalon are diverse; they have many circuit functions, and dysfunction of these neurons has been implicated in various brain disorders1, 2–3. Here we conducted a systematic and in-depth analysis of the transcriptomic and spatial organization of GABAergic neuronal types in all regions of the mouse telencephalon and their developmental origins. This was accomplished using 611,423 young adult single-cell transcriptomes and 614,569 single-cell transcriptomes collected from multiple prenatal and postnatal developmental timepoints. We present a hierarchically organized adult telencephalic GABAergic neuronal cell-type taxonomy of 7 classes, 52 subclasses, 284 supertypes and 1,051 clusters, as well as a corresponding developmental taxonomy of 1,688 clusters across ages from embryonic day 7 to postnatal day 14. Detailed charting efforts reveal extraordinary complexity whereby relationships among cell types reflect both spatial locations and developmental origins. Transcriptomically and developmentally related cell types are often found in distant and diverse brain regions, indicating that long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons. Moreover, we find various spatial dimensions of both discrete and continuous variation among related cell types that are correlated with gene expression gradients. Lastly, we find that cortical, striatal and some pallidal GABAergic neurons undergo extensive postnatal diversification, whereas septal, preoptic and most pallidal GABAergic neuronal types emerge in a burst during the embryonic stage with limited postnatal diversification. Overall, the telencephalic GABAergic cell-type taxonomy will serve as a foundational reference for molecular, structural and functional studies of cell types and circuits by the entire community. Long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons, which diversify extensively after birth in the cortex and striatum, but show limited postnatal changes in the septum, preoptic area and pallidum.

Transcriptomic and spatial organization of telencephalic GABAergic neurons

This protocol is used for the rapid generation of 3’ transcriptomic-NGS-ready- single-cell-libraries from pools of cells. Note: Research reported in this publication was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number's 1U01MH114812-01 and 1U19MH114830-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 

10Xv3.1 Genomics Sample Processing v2

Protocol is used to profile all the open chromatin regions at a single nuclei level through the rapid generation of NGS-ready libraries, and for rapid generation of 3' transcriptomic-NGS-ready-single-cell-libraries from the same pool of transposed nuclei. 

10x Multiome Sample Processing v1

Isolation of nuclei from frozen adult human brain tissue or thawed and microdissected brain tissue sections for FPCR and/or RNA-seq analysis. Note: Research reported in this publication was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number U01MH114812. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 

Isolation of Nuclei from Adult_Human_Brain_Tissue v2

This protocol describes how to isolate tissue from various ROI’s of the mouse brain followed by preparation of a highly concentrated single cell suspension for transcriptomic profiling on 10x Genomics platform. Note: Research reported in this publication was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number U19MH114830. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 

Mouse Whole Cell Tissue Processing for 10x Genomics Platform v9

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10Xv3.1 Genomics Sample Processing v2

10x Multiome Sample Processing v1

Isolation of Nuclei from Adult_Human_Brain_Tissue v2

Mouse Whole Cell Tissue Processing for 10x Genomics Platform v9

Isolation of Nuclei from Adult_Human_Brain_Tissue v2