Brain development involves the organized differentiation of neural progenitors into neurons and glia, tightly orchestrated in both temporal and spatial domains. Alterations in embryonic brain development can manifest as altered post-natal brain structure and function, leading to neuropsychiatric illness. Recent advances in tissue clearing technology and light-sheet microscopy have allowed for rapid cellular resolution image acquisition in intact whole brains. The ability to analyze these large datasets has lagged behind the ability to acquire them, resulting in their most common use as visual anecdotes rather than quantified results. In this proposal, we will develop computational tools to specifically quantify the developmental trajectories of individual cell-types in the entire brain. We will apply tissue clearing technology and light-sheet microscopy to study how development is altered in autism-associated CHD8 heterozygous mutant mice. Heterozygous CHD8 loss of function mutations result in macrocephaly in both human patients and mouse models. We will first acquire whole brain cellular resolution images of neural progenitor and neuronal cell-types across critical time- periods of neocortical neurogenesis in wild-type and Chd8+/- mice. We will then develop longitudinal image registration algorithms to map the developmental trajectories of neocortical development. Finally, we will quantify cell-type distributions within annotated areas of the developing neocortex. Completing the aims of this proposal will elucidate the cellular basis and spatial localization of brain overgrowth in autism.

Public Health Relevance

Alterations in embryonic brain development can manifest as altered post-natal brain structure and function, leading to neuropsychiatric illness. We will develop computational tools to specifically quantify the developmental trajectories of individual cell-types in the brain of an autism mouse model. Our experiment will allow us to directly probe the developmental cellular mechanisms leading to early brain overgrowth, providing a mechanistic understanding of a key autism biomarker, which could serve in part to guide therapeutics to an appropriate developmental time period and cell-type.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH121433-02
Application #
10022336
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Panchision, David M
Project Start
2019-09-23
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599