The gestational and postpartum maternal environment plays an important role in developing susceptibility to psychiatric disorders later in life. Although the societal cost of prenatal and postnatal adversity, such as maternal infection and childhood adversity and trauma, is recognized, our understanding of the pathogenesis of these conditions is very limited. By using animal models of maternal adversity, we identified modifications in DNA methylation in specific neurons in the central nervous system that, via the modulation of gene expression, predispose the offspring to anxiety and increased stress responsiveness. These modifications occur at genes that encode proteins involved in synaptogenesis and synaptic functions indicating that the behavioral abnormalities are caused by multiple functional deficits at the synapse. This application will explore the spectrum, specificity, distribution and functional significance of DNA methylation in three different models of maternal adversity with construct validity and how these modifications derail the normal developmental trajectory of neuronal differentiation, synaptogenesis and emotional behavior. These studies will help identifying key neurodevelopmental genes and proteins that can be pharmacologically targeted to prevent or reverse the negative effects of early life adversity.

Public Health Relevance

Exposure to adversity early in life can have a permanent impact on emotional and cognitive behavior. Here we will map the molecular correlates of this impact in neuronal DNA that, by modulating gene expression, alter the normal development of the brain and emotional/cognitive behavior. These studies will help to better understand the molecular mechanism underlying early life adversity and could facilitate the development of interventions to prevent or reverse its negative effects.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH100894-02
Application #
8683251
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065