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

描述（由申请方提供）：从长期乙醇暴露中退出会导致许多生理反应。其中两种反应是睡眠参数改变和焦虑增加。然而，很少有人知道的因素，影响睡眠参数的变化的严重程度或是否有睡眠之间的关系：唤醒特征和焦虑在乙醇戒断。两个因素已被证明会影响睡眠：觉醒特征和乙醇戒断效应的严重程度是生物体的遗传学或性别，因此，第一个实验将测试遗传学和/或性别或两个变量的组合影响乙醇引起的睡眠变化的严重程度的假设。这些假设的测试将通过使用PI Dr. O 'Hara开发的新型系统（压电系统）来促进。该系统具有以非侵入性方式评估睡眠模式的优点，这也需要最少的劳动力投资。为了检验这些假设，将检查DBA/2 J（D2）和C57 BL/6 J（B6）小鼠以及通过使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假设，而且还能够鉴定介导任何差异反应的基因组区域。将使用蒸汽吸入并在Veatch（2006）的多个戒断和暴露周期后给予乙醇暴露，这是一种允许快速诱导酒精依赖的技术。将比较乙醇暴露前（基线）与停药期间的睡眠：清醒参数。第二个实验将检查动物的焦虑表型与乙醇戒断期间睡眠改变的严重程度之间是否存在关系，以确定焦虑水平最高的小鼠是否也在戒断期间表现出最严重的睡眠中断。将使用几种不同的行为范例来解决小鼠的焦虑表型，包括高架十字迷宫和活动室中的运动活动。将小鼠暴露于乙醇，并以与第一次实验相同的方式监测睡眠：觉醒参数。将在乙醇暴露前和戒断期间评估焦虑表型。这些实验将提供深入了解在为特定患者设计治疗方案或了解介导治疗结果差异的因素时需要考虑的变量。 公共卫生相关性：睡眠中断是酒精戒断过程中发生的生理反应之一，已被证明是酒精戒断成功的负面预测因素。该提案将深入了解性别和遗传学在酒精暴露和戒断后睡眠中断中的作用，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.