A comprehensive understanding of how neural circuits spanning the entire brain generate the full repertoire of perception and behaviors requires a list of brain cell types, as well the means to target each cell type in order to interrogate the functional interactions that give rise to the emergent properties of the whole system. To address these challenges, the ?Center for Epigenomics of the Mouse Brain Atlas? (CEMBA) will focus on ?epigenetic profiling?, for identification, cataloging, characterization and genetic targeting of mammalian brain cell types, an approach that is complementary to RNA expression analysis. The Center will conduct an integrated set of experiments that together will serve to identify, characterize and make genetically accessible, cell types across the entire nervous system. More than 1 million single neurons across the whole brain will be subjected to single cell epigenetic profiling. Cell types emerging from these profiles will be linked to anatomy for detailed characterization of their locations, morphology, and brain-wide connectivity and projections. And genetic profiling data will be used to generate tools to target gene expression to and interrogate the roles of cell types. By focusing on epigenetic profiling, the Center will harness knowledge of gene regulatory mechanisms to identify cell-type specific genetic enhancers. As has been the case in previous efforts to generate mouse lines on the basis of gene expression profiling, efforts will include both bottom up and top down approaches. Knowledge of differences in the connectivity/anatomy of cell types will be used to allow epigenetic profiles to be linked to anatomy. Knowledge of epigenetic differences between cell populations will be used to identify enhancers, which restrict gene expression to neuronal populations that will be subsequently subjected to detailed characterization. The CEMBA-Data Core will collect, manage, analyze, visualize and distribute brain cell-type and anatomical data. Finally, the Administrative Core will effectively coordinate activities within the center and between cooperating centers in the Brain Cell Census Network.

Public Health Relevance

Brain function arises from networks of cells connected to each other in neural circuits. The goal of this project is to understand the identity, location and connectivity of the many different kinds of cells that form a brain, using the laboratory mouse as a model. Determining the cell composition in various regions throughout the brain will create a detailed atlas that will aid in the understanding of a variety of human diseases where these neural circuits may be abnormal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19MH114831-02
Application #
9568015
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Yao, Yong
Project Start
2017-09-20
Project End
2022-05-31
Budget Start
2018-07-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Luo, Liqun; Callaway, Edward M; Svoboda, Karel (2018) Genetic Dissection of Neural Circuits: A Decade of Progress. Neuron 98:256-281
Luo, Chongyuan; Hajkova, Petra; Ecker, Joseph R (2018) Dynamic DNA methylation: In the right place at the right time. Science 361:1336-1340
Mukamel, Eran A; Ngai, John (2018) Perspectives on defining cell types in the brain. Curr Opin Neurobiol 56:61-68
Preissl, Sebastian; Fang, Rongxin; Huang, Hui et al. (2018) Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. Nat Neurosci 21:432-439
Yoon, Young-Sil; Tsai, Wen-Wei; Van de Velde, Sam et al. (2018) cAMP-inducible coactivator CRTC3 attenuates brown adipose tissue thermogenesis. Proc Natl Acad Sci U S A 115:E5289-E5297
Luo, Chongyuan; Rivkin, Angeline; Zhou, Jingtian et al. (2018) Robust single-cell DNA methylome profiling with snmC-seq2. Nat Commun 9:3824
Luo, Liqun; Callaway, Edward M; Svoboda, Karel (2018) Genetic Dissection of Neural Circuits: A Decade of Progress. Neuron 98:865