Genetics of Chronic Mild Stress and Alcohol Consumption

描述（由申请人提供）：自20世纪80年代发现不同类型的酒精使用障碍以来，出现了两种主要模式。一种通常被称为酒精滥用，而另一种则与酒精依赖有关。虐待类型与反社会行为有关，具有较高的遗传率，而依赖类型与生活压力事件、糟糕的婚姻、困难的工作等有关。后一种类型也被认为具有一定程度的遗传性，但这很难评估，因为并非所有易感基因型都受到压力事件的影响。试图建立应激相关障碍的动物模型的结果并不一致。这是因为压力源往往持续时间较短，并不总是与人类生活事件相似；或者，酒精摄入量的测量可能无法捕捉到人类在压力事件发生之前、期间或之后的消费情况。本提案的主要目的是建立一种压力相关的酒精消耗变化（增加或减少）模型，该模型是在遭受数周不可预测的环境扰动（称为慢性轻度应激（CMS））的遗传参考群体中进行的。该方法是在CMS引起的其他生理变化的框架内对酒精消费进行系统生物学/系统遗传学分析。酒精摄入量将通过黑暗饮酒（DID）模式进行评估，并将在CMS之前，CMS期间和CMS之后进行测量。生理测量包括下丘脑-垂体-肾上腺轴功能，即实验各阶段的粪便皮质酮测定，胸腺和肾上腺重量。所有终点都将进行多变量分析和遗传分析，以确定影响饮酒和其他指标的多态性基因。我们将对海马、下丘脑和肾上腺进行基因表达微阵列分析，以确定哪些基因的表达被CMS改变，哪些基因的表达改变与其他参数有关，尤其是DID。在这项工作的最后，我们将确定与压力相关的酒精消费相关的基因和基因网络，这些基因和基因网络与人类基因组一致。

DESCRIPTION (provided by applicant): Since the discovery of different typologies for alcohol-use disorders in the 1980s, two major patterns have emerged. One type is oftentimes called alcohol abuse, whereas the other is associated with alcohol dependence. The abuse typology is associated with antisocial behavior and has an estimated high heritability, whereas the dependence- based typology is associated with stressful life events, bad marriage, difficult job, etc. This latter type is also supposed to have some degree of heritability, but this is difficult t assess because not all susceptible genotypes are subjected to stressful events. Attempts to develop animal models of the stress-related disorder have yielded inconsistent results. This is because the stressors tend to be short in duration and not always similar to human life events; or, the measure of alcohol drinking may not capture the kind of consumption seen in humans prior, during or following the stressful events. The primary aim of this proposal is to develop a model of stress-related change (increase or decrease) in alcohol consumption in a genetic reference population of mice subjected to several weeks of unpredictable environmental perturbations, termed chronic mild stress (CMS). The approach is a systems biology/systems genetics analysis of alcohol consumption within the framework of other physiological changes caused by CMS. Alcohol consumption will be assessed by the drinking in the dark (DID) paradigm and will be measured prior to CMS, during CMS and following CMS. The physiological measures include hypothalamus-pituitary-adrenal axis function, i.e., fecal corticosterone determinations during all phases of the experiment, thymus and adrenal weights. All endpoints will be subjected to multivariate analysis and genetic analysis to identify polymorphic genes that influence alcohol drinking and the other indices. Gene expression by microarray analysis will be performed on hippocampus, hypothalamus and adrenal glands to identify genes whose expression is altered by CMS and which genes that change expression are related to the other parameters, especially DID. At the end of the work, we will identify genes and gene networks related to stress-related alcohol consumption and that are syntenic with the human genome.