(Overall) For the brain (or any other biological systems), cells are a fundamentally important level of organization between genes/molecules and networks/systems. The mammalian brain is composed of millions to billions of neurons and non-neuronal cells with diverse properties and extremely intricate connections to form highly specific and hierarchically organized circuits and networks. To unravel the principles of information processing in brain circuits, it is essential to have a systematic understanding of its components ? the cell types, and to have tools to monitor and manipulate them in the living brain to probe their roles in the circuits. However, it is still unclear how many cell types there are in the brain and how to even define them. Recent high-throughput technology advancement, especially in the areas of sequencing and imaging, has created an unprecedented opportunity to collect comprehensive information about individual cells in large scales to enable data-driven cell type classification. We will form a Comprehensive Center on Mouse Brain Cell Atlas, and our goal is to create a comprehensive whole-brain atlas of cell types in the mouse encompassing molecular, anatomical and functional annotations of cell types. We will conduct large-scale single-cell transcriptomic analysis across the entire mouse brain, as well as systematic sampling of neuronal morphology and connectivity in a wide range of brain areas. In selected proof-of-principle cases, we will examine the correspondence among the transcriptomic, morphological, connectional and/or functional properties of the same cells, to gain an understanding what defines a cell type. Finally, we will generate a census of the number and location of cells for each type, and new genetic tools targeting selected cell types. We will establish a Data Core to provide data management systems for integrating the diverse data collections and to provide data processing and mapping infrastructure and expertise to transform raw data into quantitative cell characterization features. We will also establish an Administrative Core to address the operational management of the Center, including fiscal management, project management, strategic planning, progress reporting, and support for collaboration and communication. Altogether this project will create a first version of a comprehensive cell type atlas for an entire mammalian brain with enduring values to the community towards the understanding of brain function in healthy and diseased states.

Public Health Relevance

(Overall) For the brain (or any other biological systems), cells are a fundamentally important level of organization between genes/molecules and networks/systems. To unravel the principles of information processing in brain circuits, it is essential to have a systematic understanding of its components ? the cell types, and to have tools to monitor and manipulate them in the living brain to probe their roles in the circuits. We will create a first version of a comprehensive cell type atlas for an entire mammalian brain, the mouse brain, which encompasses molecular, anatomical and functional annotations of cell types as a valuable resource to the community towards the understanding of brain function in healthy and diseased states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19MH114830-02
Application #
9568008
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
Allen Institute
Department
Type
DUNS #
137210949
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Risso, Davide; Purvis, Liam; Fletcher, Russell B et al. (2018) clusterExperiment and RSEC: A Bioconductor package and framework for clustering of single-cell and other large gene expression datasets. PLoS Comput Biol 14:e1006378
Luo, Chongyuan; Hajkova, Petra; Ecker, Joseph R (2018) Dynamic DNA methylation: In the right place at the right time. Science 361:1336-1340
Zeng, Hongkui (2018) Mesoscale connectomics. Curr Opin Neurobiol 50:154-162
Ecker, Joseph R; Geschwind, Daniel H; Kriegstein, Arnold R et al. (2017) The BRAIN Initiative Cell Census Consortium: Lessons Learned toward Generating a Comprehensive Brain Cell Atlas. Neuron 96:542-557