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障碍是脆弱基因和环境因素相互作用的结果。同卵双胞胎精神障碍的不完全外显(不协调)被认为是环境影响的结果。同样，基因差异被认为是暴露在类似环境中的受试者出现精神症状的似乎韧性或脆弱性的原因。虽然精神障碍的这种基因-环境因素具有直观的吸引力，但无论是导致易感性的基因还是增加精神疾病发病风险的环境因素都不是很清楚。最近，在识别可能影响重度抑郁症预后的易感基因和环境因素方面取得了一些进展。重度抑郁症是一种最常见的精神障碍，对个人、家庭和社会造成巨大损失。Caspi的一项极具影响力的研究表明，5-羟色胺转运体基因(5HTT)的某些启动子变体与早期生活压力(童年虐待)或成年压力(失业、离婚等)相互作用。调整抑郁症状的可能性，诊断出重度抑郁症，并在研究对象中进行自杀行为。具体地说，研究发现，降低5HTT转录效率的启动子变异会增加抑郁症相关的表型，而表达水平较高的变异会增强对儿童或成人压力的韧性。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与抑郁相关的行为的表达的积极和消极方式。此外，老鼠模型提供了研究调节环境对行为影响的神经底物的可能性。这一研究为我们对抑郁症的发病机制获得新的认识提供了可能。

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.