A high-resolution transcriptomic and spatial atlas of cell types in the whole
mouse brain
Authors: Yao Zizhen , van Velthoven Cindy T. J. , Kunst Michael , Zhang Meng , McMillen Delissa , Lee Changkyu , Jung Won , Goldy Jeff , Abdelhak Aliya , Baker Pamela , Barkan Eliza , Bertagnolli Darren , Campos Jazmin , Carey Daniel , Casper Tamara , Chakka Anish Bhaswanth , Chakrabarty Rushil , Chavan Sakshi , Chen Min , Clark Michael , Close Jennie , Crichton Kirsten , Daniel Scott , Dolbeare Tim , Ellingwood Lauren , Gee James , Glandon Alexandra , Gloe Jessica , Gould Joshua , Gray James , Guilford Nathan , Guzman Junitta , Hirschstein Daniel , Ho Windy , Jin Kelly , Kroll Matthew , Lathia Kanan , Leon Arielle , Long Brian , Maltzer Zoe , Martin Naomi , McCue Rachel , Meyerdierks Emma , Nguyen Thuc Nghi , Pham Trangthanh , Rimorin Christine , Ruiz Augustin , Shapovalova Nadiya , Slaughterbeck Cliff , Sulc Josef , Tieu Michael , Torkelson Amy , Tung Herman , Cuevas Nasmil Valera , Wadhwani Katherine , Ward Katelyn , Levi Boaz , Farrell Colin , Thompson Carol L. , Mufti Shoaib , Pagan Chelsea M. , Kruse Lauren , Dee Nick , Sunkin Susan M. , Esposito Luke , Hawrylycz Michael J. , Waters Jack , Ng Lydia , Smith Kimberly A. , Tasic Bosiljka , Zhuang Xiaowei , Zeng Hongkui 
Published: March 2023

ABSTRACT
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.