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.
Major depressive disorder is a common but debilitating mental health issue affecting a sizable percentage of the global population. Environmental exposure to arsenic, a heavy metal present in drinking water all around the world, results in deficits in learning and memory and increased susceptibility to depression in human populations. The research component of the proposed training program aims to determine a mechanism by which this environmental toxin causes damage to the brain resulting in adult onset depression. Since depression is a costly mental health disease impacting millions of people, identifying and understanding underlying mechanisms of environmentally induced depression would be extremely beneficial and may provide new therapeutic targets that could be used for prevention or treatment.
|Tyler, Christina R; Allan, Andrea M (2014) The Effects of Arsenic Exposure on Neurological and Cognitive Dysfunction in Human and Rodent Studies: A Review. Curr Environ Health Rep 1:132-147|
|Tyler, Christina R; Solomon, Benjamin R; Ulibarri, Adam L et al. (2014) Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism. Neurotoxicology 44:98-109|
|Tyler, Christina R; Allan, Andrea M (2013) Adult hippocampal neurogenesis and mRNA expression are altered by perinatal arsenic exposure in mice and restored by brief exposure to enrichment. PLoS One 8:e73720|