Genetics of Chronic Mild Stress and Alcohol Consumption

描述(申请人提供)：自20世纪80年代发现酒精使用障碍的不同类型以来，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相关，具有较高的遗传度，而基于依赖的类型与应激生活事件、糟糕的婚姻、困难的工作等相关。后者也被认为具有一定的遗传性，但这一点很难评估，因为并不是所有的易感基因都会受到应激事件的影响。建立压力相关障碍的动物模型的尝试产生了不一致的结果。这是因为压力源的持续时间往往很短，并不总是与人类的生活事件相似；或者，酒精饮酒的衡量标准可能不包括人类在压力事件之前、期间或之后看到的那种饮酒情况。这项建议的主要目的是建立一个与压力相关的饮酒量变化(增加或减少)的模型，在遗传参考种群的小鼠受到几周的不可预测的环境扰动，称为慢性轻度应激(CMS)。这种方法是在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。酒精消耗量将通过在黑暗中饮酒(DID)范式进行评估，并将在CMS之前、CMS期间和之后进行测量。生理指标包括下丘脑-垂体-肾上腺轴功能，即在实验的所有阶段测定粪便皮质酮、胸腺和肾上腺重量。所有终点将接受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基因。基因芯片分析将在海马体、下丘脑和肾上腺进行基因表达分析，以找出CMS改变表达的基因，以及哪些改变表达的基因与其他参数相关，尤其是DID。在这项工作结束时，我们将识别与压力相关的饮酒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是同步的。

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.