Improving our understanding of the mechanisms by which environmental signals during sensitive early-life periods contribute to mental illness will have profound impact on human health. In concert with the Center approach. Project 1 will test the overarching hypothesis that exposure to fragmented / unpredictable patterns of maternal signals promotes adolescent emotional and cognitive vulnerabilities that can be predicted and detected early in their trajectory. In accord with the constructive suggestions of the Reviewers of the original submission and supported by strong preliminary data, the studies proposed for the revised Project 1 will employ rodent models and viral / genetic and epigenetic tools to address the underlying mechanisms at molecular, cellular and network levels. These studies will inform and be shaped by Projects 2.3. and carried out in tight integration with Project 4 and the imaging and computational Cores Project 1 will aim to: (1) analyze patterns of maternal behaviors in an established model of fragmented care, and, building on new data showing vulnerabilities to emotional and cognitive problems already In adolescent rats. identify the onset and trajectories of these vulnerabilities to adulthood;(2) In concert with Project 4. test the hypothesis that the basis of altered emotional and cognitive functions resulting from fragmented patterns of maternal signals derives from shifts in the functional connectivity of the involved brain networks;(3) examine for sex dependence of the consequences of fragmented patterns of maternal care, guided by human data. The results, in turn will influence timing and types of human testing in Projects 3.4: (4) Probe causal molecular mechanisms in defined brain regions that may underlie the emotional and cognitive consequences of fragmented maternal care patterns. Building on new data and novel technologies, we will look for mechanisms of broad enduring gene expression changes, using Crh as a marker qene. Regulating expression in space and time, we will also test if enhanced CRH expression is necessary and sufficient to mediate the effects of fragmented care; finally, we will determine identities of other involved genes, and the mechanisms regulating enduring changes in gene expression at the chromatin level. In summary. Project 1 will focus on a crucial clinical problem and will test an innovative concept, that fragmented patterns of maternal signals might be a common denominator of the established, profound influence of the mother on the emotional and cognitive outcome of her progeny. It will use innovative viral-genetic methods and epigenetic tools to probe the underlying mechanisms, and integrate single-neuron discoveries with structural and network analyses of Projects 2. 3 and 4. The resulting discoveries will inform and guide behavioral and imaging studies in the other projects, contributing to identification of potential biomarkers and generation of predictive models for adolescent vulnerabilities. Hence, the potential impact of the proposed studies is tremendous.

Public Health Relevance

Depression, anxiety and learning problems affect one in five American adolescents (UNICEF, 2012). While we know that early-life experience might contribute to the emergence of these problems, we know little about the mechanisms. We will use animal models and cutting-edge technology to figure out how brain cells change their function in response to disorganized maternal signals, and if the sex of the child makes a difference. The discoveries made in animals will dramatically increase our understanding of human disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-L (02))
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University of California Irvine
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