Title Understanding the Epigenetic Mechanisms Underlying Stress-related Neuropsychiatric Disorders Abstract Epidemiological studies provide mounting evidence supporting that environmental and experiential influences, such as stressful life events, interact with genetic variations and compound the risks for neuropsychiatric disorders, such as major depressive disorder (MDD). MDD afflicts about 6.7% of the United States adults, but treatment options for MDD are limited and not effective. The objective of this proposal is to define the global epigenetic landscape associated with stress experience and assess the effect of locus-specific epigenetic changes on the manifestation of depression-like phenotypes. We propose to first establish sex-specific stress paradigms to apply in male and female mice. We will then take a genomic approach to identify the stress responsive epigenetic code in targeted neuronal cell types in the brain. Finally, we will modify and apply CRISPR/Cas9 technology to address the causal relationship between the identified epigenetic code to the expression of depression-like behaviors. With currently available state-of-the-art technologies and our newly developed, genetically modified mouse tools, we hope to gain an insight into the epigenetic mechanisms through which stress interacts with susceptibility genes and confers increased risk to MDD. Our proposed study will also allow greater understanding of the underlying causes of stress-related neuropsychiatric disorders and provide the necessary foundation for improved diagnosis and intervention.
According to a recent estimate by the National Institute of Mental Health, each year about 6.7% of adults in the U.S experience major depressive disorder (MDD), and women are 70% more likely than men to experience depression during their lifetime. Currently, the treatment options are limited with low efficacy. The underlying cause of MDD is largely unknown, but epidemiology studies have pointed to the influence of adverse life events and stressful experiences. Therefore, we propose to address the molecular mechanisms by which stress experience induces long-lasting changes in the epigenome and causes alterations in gene expression that may contribute to the etiology of MDD. An improved understanding of the molecular basis of stress-related psychiatric disorders will lead to improved treatments and diagnostic tests - a high priority for the National Institutes of Health.
