Systems Genetics of Alcohol Response and Stress Effects in CNS

描述（由申请人提供）：乙醇和压力发挥广泛的神经药理学和神经生理学作用，在中枢神经系统中留下分子和细胞印记。虽然已经确定了乙醇和应激在大脑中的一些靶点，特别是神经递质张力的变化，但乙醇的大部分影响是通过变构相互作用和下游事件的微妙和非特异性修饰介导的，这些修饰仍然难以确定和操纵。乙醇和压力的共同作用也因基因差异而有很大差异。在这次INIA更新中，我们将使用新的基因组方法来更多地了解对酒精、压力和分子靶点的不同易感性。我们利用一组不同的小鼠菌株（BXDs）来模拟人类遗传复杂性的许多方面。在目的1中，我们评估了基因表达和剪接的易感性差异，以及个体差异对应激反应和最终饮酒的影响。在目标2中，我们将研究慢性间歇性乙醇暴露（以及狂饮动物模型）对自愿饮酒的影响。在这里，我们要问的是，压力和酒精的结合是如何以一种几乎永久的方式改变基因表达模式，从而在获得乙醇的情况下诱发快速复发的。在目标3中，我们将整合、测试和翻译目标1和目标2的结果，以更多地了解导致脑功能易感性和适应性变化的复杂分子和细胞网络。我们将利用广泛的人类数据集来测试在小鼠种群中发现的翻译相关性。

DESCRIPTION (provided by applicant): Ethanol and stress exert a wide spectrum of neuropharmacological and neurophysiological effects that leave both molecular and cellular imprints in the CNS. While some targets of ethanol and stress in the brain have been defined, particularly shifts in neurotransmitter tone, much of the influence of ethanol is mediated by subtle and non-specific modification of allosteric interactions and downstream events that will remain hard to pinpoint and manipulate. The joint effects of ethanol and stress also vary a great deal depending on genetic differences. In this INIA renewal we will use new genomic methods to understand much more about differential vulnerability to alcohol and stress and molecular targets. We exploit a diverse group of strains of mice (BXDs) that model many aspects of human genetic complexity. In Aim 1 we evaluate predisposing differences in gene expression and splicing and the effects that individual differences have on responses to stress and to eventual alcohol consumption. In aim 2 we will study the effects of chronic intermittent ethanol exposure (and animal model of binge drinking) on voluntary alcohol consumption. Here we are asking how the combination of stress and alcohol alters gene expression patterns in an almost permanent way to induce quick relapse when access to ethanol is provided. In aim 3 we will integrate, test, and translate our results from aims 1 and 2 to understand more about the complex molecular and cellular networks that contribute to both vulnerability and allostatic changes in brain function. We will exploit extensive human data sets to test the translational relevance of finding in murine populations.