Genetics of Chronic Mild Stress and Alcohol Consumption

摘要 自从20世纪80年代发现了酒精使用障碍的不同类型以来，有两种 主要模式已经出现。一种类型通常被称为酗酒，而 另一种与酒精依赖有关。虐待类型与 反社会行为，估计有很高的遗传力，而依赖- 基于类型学的分类与紧张的生活事件、糟糕的婚姻、困难的工作等有关。 后一种类型也被认为具有某种程度的遗传性，但这很难 进行评估，因为并不是所有的易感基因都会受到应激事件的影响。 建立应激相关障碍的动物模型的尝试取得了成果 结果不一致。这是因为压力源往往持续时间较短，而不是 总是与人的生活事件相似；或者，酒精饮酒的衡量标准可能不包括 在压力事件之前、期间或之后在人类身上看到的那种消耗。 这项提议的主要目的是开发一个与压力相关的变化模型。 (增加或减少)小鼠遗传参考人群的饮酒量 经历了数周不可预测的环境扰动，称为慢性 轻度应激(CMS)。该方法是一种系统生物学/系统遗传学分析 在饮酒框架内引起的其他生理变化 不育系CMS。酒精消费将通过在黑暗中饮酒(DID)范例进行评估 并将在CMS之前、CMS期间和之后进行测量。生理学 措施包括下丘脑-垂体-肾上腺轴功能，即粪便皮质酮 在实验的所有阶段测定胸腺和肾上腺重量。全 将对终点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基因。基因 基因芯片分析将在海马区、下丘脑区进行表达 和肾上腺来识别CMS改变其表达的基因，以及 改变表达的基因与其他参数有关，尤其是DID。在… 在工作的最后，我们将确定与应激相关的基因和基因网络 饮酒和与人类基因组同步的基因。

Abstract 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 to 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.