The epigenetic link between environmental exposure and adult onset depression

描述（由申请人提供）：本资助申请中概述的培训计划是专门为申请人设计的，主要侧重于获得几种尖端技术，研究技能，专业发展和提高生物医学知识基础。培训计划的研究部分旨在确定在发育过程中砷暴露增加成年期抑郁症易感性的机制，以及成年神经发生的表观遗传调节改变对抑郁症发作的贡献。抑郁症是全球残疾的主要原因，影响超过3.5亿人;尽管有几种药物治疗，但超过30%的人从未完全缓解症状。砷是一种普遍存在于低剂量饮用水中的金属，已被证明会导致动物模型和人类的认知缺陷和抑郁样症状。砷引起这些效应的机制尚不清楚。本研究的一个目标是通过阐明复杂的基因与环境在发育过程中的相互作用，影响海马神经元的功能，以增加对砷相关抑郁症的分子病因学的理解。本提案中的实验旨在验证以下假设：发育期间的砷暴露干扰海马体的表观遗传环境，导致成年后易患抑郁症。目的1将评估抑郁样行为和海马功能障碍，在围产期砷暴露的小鼠在抗抑郁治疗和不抗抑郁治疗的几个行为任务。将使用免疫组织化学、共聚焦显微镜和无偏体视学（伴和不伴抗抑郁药治疗）对海马神经发生（增殖和分化）进行额外评估，以确认与抑郁症的联系。目的2将评估围产期砷暴露和随后的抗抑郁药治疗对神经发生相关基因的表观遗传编程的影响，使用qRT-PCR的神经发生微阵列和染色质组蛋白修饰的微阵列使用染色质免疫沉淀法确定的基因。这些目标的预期结果是鉴定用于MDD治疗的新型表观遗传分子靶点。该提案将有助于申请人在精神障碍神经表观遗传学方面的博士前培训。

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.