Genetic Analysis of Stress Response on EtOH Sensitivity

描述(申请人提供)：心理压力对社会具有惊人的影响，并在酗酒中扮演重要角色。本研究的目的是探索ILS和ISS小鼠暴露于应激和随后的乙醇敏感性之间关系的机制基础。我假设应激对酒精敏感性的影响取决于个体的遗传背景，这些遗传差异与边缘-下丘脑-垂体-肾上腺轴(LHPA)激活的个体差异有关。为了研究酒精和压力之间的复杂相互作用，我将利用酒精敏感性表型，包括乙醇诱导的翻正反射丧失、-低温和-低剂量激活。LHPA活性的外周和中枢成分将通过测量皮质酮和促肾上腺皮质激素水平以及原位杂交下丘脑室旁核相关基因的表达来评估。对小鼠暴露在酒精和压力下后细胞活动发生变化的神经区域和路径的表征，将进一步为人类群体研究提供信息，以建立人类酒精中毒的预测指标，并最终开发更有效的治疗方法。

DESCRIPTION (provided by applicant): Psychological stress has a staggering impact on society and plays a major role in alcoholism. The goal of the present study is to explore the mechanistic basis of the relationship between exposure to stress and subsequent sensitivity to ethanol in ILS and ISS mice. I hypothesize that the effects of stress on ethanol sensitivity are dependent on the genetic background of the individual, and that these genetic differences are related to individual differences in limbic-hypothalamic-pituitary-adrenal axis (LHPA) activation. To study the complex interactions between alcohol and stress, I will utilize ethanol sensitivity phenotypes including ethanol induced -loss of righting reflex, -hypothermia, and -low dose activation. Peripheral and central components of LHPA activity will be assessed by measurement of corticosterone and adrenocorticotropic hormone levels, and in situ hybridization of related gene expression in the paraventricular nucleus of the hypothalamus. The characterization of neural regions and pathways in which cellular activity is changed after exposure to alcohol and stress in mice will further inform studies in human populations to establish predictors of alcoholism in humans and ultimately develop more effective treatments.