The epigenetic link between environmental exposure and adult onset depression

University Of New Mexico Health Scis Ctr, Albuquerque NM

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Abstract

DESCRIPTION (provided by applicant): The training proposal outlined in this grant application was designed specifically for the applicant, primarily focusing on the acquisition of several cutting edge techniques, research skills, professional development, and improving biomedical knowledge base. The research component of the training program seeks to determine the mechanism by which arsenic exposure during development increases susceptibility to depression in adulthood and the contribution of altered epigenetic regulation of adult neurogenesis to onset of depression. Depression is a leading cause of disability worldwide, affecting more than 350 million people; despite several pharmacological treatments more than 30% of individuals never receive full remission of symptoms. Arsenic, a ubiquitous metal found in drinking water in low doses, has been shown to result in cognitive deficits and depressive-like symptoms in both animal models and in humans. The mechanism by which arsenic induces these effects is unknown. A goal of this research proposal is to increase understanding about the molecular etiology of arsenic-associated depression by elucidating complex gene by environment interactions during development that influence the functionality of hippocampal neurons. The experiments in this proposal are designed to test the hypothesis that arsenic exposure during development interferes with the epigenetic environment of the hippocampus leading to susceptibility to depression in adulthood. Aim 1 will evaluate depressive-like behavior and hippocampal deficits using several behavioral tasks with and without antidepressant treatment in mice exposed to arsenic in the perinatal period. Additional assessments of hippocampal neurogenesis (proliferation and differentiation) will be done using immunohistochemistry, confocal microscopy, and unbiased stereology with and without antidepressant treatment to confirm the link with depression. Aim 2 will evaluate the impact of perinatal arsenic exposure and subsequent antidepressant treatment on the epigenetic programming of neurogenesis-related genes using qRT-PCR on a neurogenesis microarray and chromatin histone modifications on genes identified by the microarray using chromatin immunoprecipitation. The expected outcome of these aims is the identification of novel epigenetic molecular targets for therapeutic treatment of MDD. This proposal will contribute to the applicant's predoctoral training in neuroepigenetics of mental disorders.