Gender and Genetic effects on sleep:wake parameters following ethanol exposure

描述(由申请人提供)：从慢性酒精暴露中戒除会导致许多生理反应。其中两个反应是睡眠参数改变和焦虑增加。然而，关于影响睡眠参数变化严重程度的因素，以及睡眠特征与戒酒期间的焦虑之间是否存在关系，人们知之甚少。已被证明影响睡眠的两个因素：觉醒特征和酒精戒断影响的严重程度是生物的遗传或性别，因此，第一个实验将测试遗传和/或性别或两个变量的组合影响酒精引起的睡眠变化严重程度的假设。这些假说的检验将通过使用由Pi Dr.O‘Hara开发的新型系统--Piezo系统来实现。该系统的优势是以一种非侵入性的方式评估睡眠模式，而且需要最少的劳动力投资。为了验证这些假设，将检验DBA/2J(D2)和C57BL/6J(B6)小鼠以及由D2和B6小鼠杂交产生的BXD重组近交系小鼠。BXD菌株的加入将使我们不仅能够解决这些假说，而且还可以确定基因组中调节任何差异反应的区域(S)。酒精暴露将使用蒸汽吸入，并在Veatch(2006)的多次戒断和暴露之后进行，这是一种允许快速诱导酒精依赖的技术。睡眠的比较：酒精暴露前的清醒参数(基线)将与戒酒期间的参数进行比较。第二个实验将检查动物的焦虑表型与酒精戒断期间睡眠改变的严重程度之间是否存在关系，以确定焦虑程度最高的小鼠在戒酒期间是否也表现出最严重的睡眠中断。将使用几种不同的行为范式来处理小鼠的焦虑表型，包括高架加迷宫和活动室中的运动活动。小鼠将被暴露在酒精和睡眠中：以与第一个实验相同的方式监测觉醒参数。焦虑表型将在酒精暴露之前和戒断期间进行评估。这些实验将提供对在为特定患者设计治疗方案时需要考虑的变量的洞察，或者在理解调节治疗结果差异的因素时需要考虑的变量。 与公共健康相关：睡眠中断是戒酒过程中发生的一种生理反应，已被证明是戒酒成功的负面预测因素。这项提议将深入了解性别和遗传学在酒精暴露和戒酒后睡眠障碍中的作用，并确定这些差异背后的基因组区域。

DESCRIPTION (provided by applicant): Withdrawal from chronic ethanol exposure results in a number of physiological responses. Two of those responses are altered sleep parameters and increased anxiety. However, little is known about either the factors that influence the severity of the alterations in sleep parameters or about whether there is a relationship between sleep: wake characteristics and anxiety during ethanol withdrawal. Two factors that have been shown to affect both sleep: wake characteristics and the severity of ethanol's withdrawal effects are the genetics or gender of the organism, and thus, the first experiment will test the hypotheses that genetics and/or gender or a combination of the two variables influences the severity of ethanol-induced changes in sleep. Testing of these hypotheses will be facilitated by the use of a novel system, the Piezo system, developed by the PI Dr. O'Hara. This system has the advantage of evaluating sleep patterns in a non-invasive fashion that also requires minimal labor investment. To test these hypotheses, DBA/2J (D2) and C57BL/6J (B6) mice as well as the BXD recombinant inbred mice generated by intercrossing the D2 and B6 mice will be examined. The addition of the BXD strains will allow us to not only address the hypotheses, but also to identify the region(s) of the genome that mediate any differential responses. Ethanol exposure will be given using vapor inhalation and following the multiple cycles of withdrawal and exposure of Veatch (2006), a technique that allows for the rapid induction of alcohol dependence. Comparisons of the sleep: wake parameters before ethanol exposure (baseline) will be compared to those during withdrawal. The second experiment will examine whether there is a relationship between the anxiety phenotypes of the animal and the severity of sleep alterations during ethanol withdrawal to determine whether the mice with the highest level of anxiety also show the most severe sleep disruptions during withdrawal. The anxiety phenotype of the mice will be addressed using several different behavioral paradigms including the elevated plus maze and locomotor activity in an activity chamber. Mice will be exposed to ethanol and the sleep: wake parameters monitored in the same manner as in the first experiment. Anxiety phenotypes will be assessed prior to ethanol exposure and during withdrawal. These experiments will provide insights into variables that need to be considered in the design of treatment programs for particular patients or in understanding the factors that mediate differences in treatment outcomes. PUBLIC HEALTH RELEVANCE: Sleep disruptions are one of the physiological responses that occur during alcohol withdrawal and have been shown to be a negative predictor of success in alcohol withdrawal. This proposal will provide insight into the role of gender and genetics in sleep disruptions following alcohol exposure and withdrawal as well as identify regions of the genome that underlie these differences.