Gene-Environment Interactions and Vulnerability to Neuropsychiatric Disorders

描述（由申请人提供）：不同的证据支持精神疾病是易感性基因和环境因素相互作用的结果。精神疾病在同卵双胞胎中的不完全外显率（不一致）被假设是环境影响的结果。同样，基因差异也被认为是暴露在类似环境下的受试者对精神症状的恢复能力或脆弱性的原因。虽然这种精神疾病的基因-环境素质具有直观的吸引力，但赋予易感性的基因和增加精神疾病发病率的环境因素都没有得到很好的理解。重性抑郁症是一种最常见的精神疾病，对个人、家庭和社会都造成了巨大的损失。最近，在确定可能影响重性抑郁症结果的易感基因和环境因素方面取得了一些进展。Caspi的一项极具影响力的研究表明，血清素转运基因（5HTT）的某些启动子变异与早期生活压力（童年虐待）或成年压力（失业、离婚等）相互作用，从而调节研究对象出现抑郁症状、诊断为重度抑郁症和自杀行为的可能性。具体来说，该研究发现降低5HTT转录效率的启动子变异增加了抑郁症相关表型，而高表达的启动子变异赋予了对儿童或成人压力的弹性。5htt -环境相互作用的小鼠模型的可用性使我们能够提出几个具体的问题，关于环境可能被操纵以减少或增加抑郁相关行为表达的积极和消极方式。此外，小鼠模型为研究介导环境对行为影响的神经基质提供了可能性。这条调查路线提供了获得关于抑郁症发病机制的新认识的可能性。

DESCRIPTION (provided by applicant): Different lines of evidence support the notion that psychiatric disorders result from the interaction of vulnerability genes and environmental factors. The incomplete penetrance (discordance) of psychiatric disorders in identical twins has been hypothesized to be the result of environmental influences. Likewise, genetic differences have been postulated to be responsible for the seeming resilience or vulnerability to psychiatric symptoms seen in subjects exposed to similar environmental situations. Although this gene- environment diathesis of psychiatric disorders has intuitive appeal, neither the genes conferring susceptibility nor the environmental factors that increase the risk of psychiatric morbidity are well understood. Recently some progress has been made in identifying both susceptibility genes and environmental factors that may influence the outcome in major depression, the most common psychiatric disorder that takes an enormous toll on individuals, their families, and society. A highly influential study by Caspi demonstrated that certain promoter variants of the serotonin transporter gene (5HTT) interact with either early life stress (childhood maltreatment) or adult stresses (job loss, divorce, etc.) to modulate the likelihood of depressive symptoms, diagnosed major depression, and suicidal behavior in the study subjects. Specifically, the study found that promoter variants that reduce transcriptional efficiency of the 5HTT increase depression-related phenotypes whereas variants that have higher expression confer resilience to childhood or adult stresses. The availability of a mouse model of a 5HTT-environment interaction allows us to ask several specific questions regarding the positive and negative ways that the environment may be manipulated to reduce or increase the expression of depression-related behaviors. In addition, a mouse model offers the possibility to investigate the neural substrates that mediate the environmental impact on behavior. This line of investigation offers the possibility of gaining new understanding regarding the pathogenesis of depressive disorders.