Whole Mouse Brain Atlas Publication Package Highlights

The recording of this webinar is now available: https://www.youtube.com/watch?v=l5NHSLk6O-A

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The millions to billions of cells that comprise mammalian brains are organized into many highly specialized cell types. Previous studies have demonstrated that known and novel cell types can be identified by their single-cell gene expression profiles. However, the actual number of cell types in the brain and the degree of diversity among these cell types has been unknown. 

This webinar presents a new collection of studies from the BRAIN Initiative Cell Atlas Network (biccn.org) and published in Nature that report the first complete cell type atlas of a mammalian brain, with over 30 million cells profiled from the adult mouse brain using a combination of single-cell transcriptomic, epigenomic, and spatial transcriptomic approaches, identifying over 5,300 cell types in the entire mouse brain. 

These studies uncover multitudes of organizing principles of the extraordinary cell type diversity across the brain. This collective body of work represents a landmark achievement that will have far-reaching impact on understanding cell type-based brain circuit function across the neuroscience field.

More about the collection of studies, published in Nature on December 13, 2023: https://www.biccn.org/science/whole-mouse-brain

Event program:

10:00am Overview - Hongkui Zeng https://www.biccn.org/science/whole-mouse-brain

• Understanding the extraordinary diversity of the individual cells in the brain by classifying them into an organized census has been a multi-generational endeavor since Ramon y Cajal. Now, as reported in ten articles published in Nature on Dec 14, 2023, researchers from the BRAIN Initiative Cell Census Network (BICCN) have used single-cell transcriptomic, epigenomic and spatial transcriptomic characterization of more than 32 million cells to comprehensively define and localize cell types in the entire brain of the mouse, the most widely used laboratory model in vertebrate neuroscience. Integration of these datasets has resulted in the first complete cell census and atlas of a mammalian brain with exceptionally high molecular and spatial resolution.

10:10am A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain - Zizhen Yao https://www.nature.com/articles/s41586-023-06812-z

• A comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain was created by combining a scRNA-seq dataset of ~7 million cells profiled (~4.0 million cells passing quality control) and a spatial transcriptomic dataset of ~4.3 million cells using MERFISH. The atlas is hierarchically organized into four nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. A high degree of correspondence between transcriptomic identity and spatial specificity for each cell type was observed. The study reveals unique characteristics of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain. The study shows that transcription factors are major determinants of cell type classification in the adult mouse brain and identifies a combinatorial transcription factor code that defines cell types across all brain regions.

10:20 am Molecularly defined and spatially resolved cell atlas of whole mouse brain - Xingjie Pan https://www.nature.com/articles/s41586-023-06808-9

• We imaged a panel of more than 1,100 genes in approximately 10 million cells across the entire adult mouse brains using MERFISH and performed spatially resolved, single-cell expression profiling at the whole-transcriptome scale by integrating MERFISH and scRNA-seq data. This approach generated a comprehensive cell atlas of more than 5,000 transcriptionally distinct cell clusters, belonging to more than 300 major cell types, in the whole mouse brain with high molecular and spatial resolution. Using this atlas, we systematically characterized cell-type composition, organization, and cell-cell communication in all brain regions.

10:30 am The molecular cytoarchitecture of the adult mouse brain - Jonah Langlieb https://www.nature.com/articles/s41586-023-06818-7 

• As part of the BICCN consortium, this study unveils a comprehensive atlas of mouse brain cell types, using high-throughput single-nucleus RNA sequencing (> 6 million nuclei) combined with Slide-seq unbiased spatial transcriptomics (> 4 million spatial pixels). It highlights the exceptional diversity of cell types in the midbrain and hindbrain and extends to characterizing neuropeptide and neurotransmitter signaling, exploring region-specific activity-regulated gene expression, and examining the heritability of neurological and psychiatric traits. These data are additionally available as an online resource at www.BrainCellData.org.

10:40 am Single-cell DNA methylome and 3D multi-omic atlas of the adult mouse brain - Hanqing Liu https://www.nature.com/articles/s41586-023-06805-y

• Cytosine DNA methylation plays a crucial role in brain development and has been associated with several neurological disorders. In our study, we employed cutting-edge techniques such as single-nucleus methylome and 3D multiome sequencing to analyze the DNA methylation patterns in nearly half a million individual cells obtained from 117 distinct regions across the adult mouse brain. I will present an overview of our cellular and genomic analysis approaches, as well as highlight the major insights and discoveries made possible by this extensive dataset.

10:50 am Single-cell analysis of chromatin accessibility in adult mouse brain - Songpeng Zu https://www.nature.com/articles/s41586-023-06824-9

• We report a comprehensive atlas of candidate cis-regulatory DNA elements (cCREs) in the adult mouse brain, generated through examination of the chromatin accessibility in 2.3 million individual brain cells from 117 anatomical dissections. The atlas includes approximately 1 million cCREs and their chromatin accessibility across 1482 distinct brain cell populations. We infer the gene regulatory networks in over 260 subclasses of mouse brain cells and develop deep learning models to predict the activities of gene regulatory elements in different brain cell types from DNA sequence alone.

11:00 am Brain-wide correspondence of neuronal epigenomics and distant projections - Jingtian Zhou https://www.nature.com/articles/s41586-023-06823-w

• Anatomical and single-cell genomic analyses parse the neurons into cell-type clusters by either their connectivity or molecular signatures, but how the cell types defined by these two different data types are associated with each other remains unknown. In this talk, I will describe our effort using Epi-Retro-Seq to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets across the whole mouse brain. We highlight uses of these data for interrogating a complicated but predictable relationship between neural projection and epigenome, and linking ~1k molecular cell types with distal projection and spatial location through integrative analysis.

11:10 am A transcriptomic taxonomy of mouse brain-wide spinal projecting neurons - Carla Winter https://www.nature.com/articles/s41586-023-06817-8

• The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord; however, a comprehensive molecular characterization of brain wide SPNs is still lacking. Here, we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain1. We use this atlas to uncover novel aspects of SPN biology, including (1) a transcription factor code defining the composition and spatial location of reticulospinal neurons, (2) transcriptomic differences between cervical- & lumbar- projecting SPNs, and (3) electrophysiologically distinct types of rubrospinal neurons. Together, this study establishes a comprehensive taxonomy of brain wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.

11:20 am Spatial atlas of the mouse central nervous system at molecular resolution - Hailing Shi https://www.nature.com/articles/s41586-023-06569-5

• A spatial atlas of the mouse central nervous system with molecular resolution was generated with the in situ spatial transcriptomics method STARmap PLUS, composed of 1.09 million high-quality single cells profiled with 1,022-gene expression and recombinant adeno-associated viral transduction mapped at 194 x 194 x 345 nm3. Integration with single-cell RNA-seq datasets allowed the imputation of ~12,000 genes in spatially mapped single cells. In addition to clustering single-cell gene expression for spatial maps of hundreds of molecular cell types, we defined molecular tissue regions by clustering spatial niche gene expression constructed from spatially resolved single cells, refining tissue architectures in previously established anatomical definitions.

11:30 am Conserved and divergent gene regulatory programs of the mammalian neocortex - Ethan Armand https://www.nature.com/articles/s41586-023-06819-6

• Evolution is a power lens to understand gene regulation; diverging patterns of gene regulation drive evolution across species, while conserved patterns are representative of core functions that are preserved across evolution. We present an unprecedented dataset of chromatin accessibility, gene expression, 3D genome information, and DNA methylation across 21 cell types in humans, macaques, marmosets, and mice. These data allow us to identify functional conserved elements, diverging elements driving changes in gene expression, and build powerful deep learning models of regulatory syntax.

11:40 am Evolution of neuronal cell classes and types in the vertebrate retina - Karthik Shekhar https://www.nature.com/articles/s41586-023-06638-9

• I will describe our efforts to analyze the conservation of retinal cell types across 17 vertebrate species using single cell transcriptomics. We find a remarkable degree of conservation of retinal cell types, suggesting that they originated in the vertebrate ancestor 500 million years ago. We have identified mammalian orthologs of the so-called "midget" cells which comprise >80% of the retinal output in humans, subserve high acuity vision, and were hitherto believed to be specific to primates. The orthology relationship is surprising, and provokes an intriguing hypothesis connecting the evolution of the retina to the evolution of the cerebral cortex. Knowing the orthologs of midget cells in several accessible models will aid efforts to slow their degeneration in blinding diseases such as glaucoma.

11:50 am Q&A - all speakers