Sex-Dependent Effect of Stress on Alcohol Consumption

描述(申请人提供)：这项研究的目的是为了更好地了解性别依赖因素对酒精中毒发展的影响。最重要的假设是，酗酒的风险存在性别差异。更具体地说，我们假设性别差异部分源于性腺激素和可遗传的b-内啡肽水平的影响，以影响神经和行为应激反应，并改变酒精(Etoh)带来的快感。在具体目标1中，我们将使用小鼠模型来表征男性和女性性腺激素在应激对乙醇自我给药影响中的作用。我们的假设是压力会增加 乙醇的自我给药依赖于性腺激素，因此雌性小鼠的卵巢切除将抵消这种影响，而对雄性小鼠的阉割将促进这种作用。具体目标2将集中在b-内啡肽(b-E)和内源性阿片肽在应激对乙醇自我给药的性别依赖效应中的作用。由于应对行为和应激易感性的差异在HPA轴功能中具有生物学基础，并受到b-E的调节，我们将使用合成b-E能力不足的转基因小鼠来验证这样的假设，即促成应激反应异位化的行为反应(即乙醇自我给药)将随着这种多肽的变化而变化。最后，具体目标3是雇用至少12名本科生，包括女性和代表性不足的少数族裔学生，在高度指导的环境中与首席调查员合作开展这些研究项目。作为一名HHMI杰出导师，在实验室与本科生合作的典范记录，PI长期致力于这些动手技能为未来神经科学家提供的教育好处。

DESCRIPTION (provided by applicant): The goal of this research is to better understand the influence of sex-dependent factors on the development of alcoholism. The overarching hypothesis is that there are sex differences in the liability toward alcohol abuse. More specifically, we hypothesize that sex differences partially derive from the effects of gonadal hormones and heritable levels of b-endorphin to influence the neural and behavioral stress response and modify the pleasure derived from alcohol (EtOH) administration. In Specific Aim 1, we will use mouse models to characterize the role of male versus female gonadal hormones in the effects of stress on EtOH self-administration. Our hypothesis here is that stress will increase the self-administration of EtOH, dependent upon gonadal hormones, such that an ovariectomy of female mice will counter this effect and that castration of male mice will promote it. Specific Aim 2 will focus on the role of b-endorphin (b-E) and endogenous opioid peptide in the sex-dependent effect of stress on the self-administration of EtOH. As differences in coping behavior and vulnerability to stress have a biological basis in HPA axis function and are modulated by b-E, we will use transgenic mice deficient in the capacity to synthesize b-E to test the hypothesis that behavioral responses contributing to allostasis of the stress response (i.e., EtOH self-administration) will vary as a function of this peptide. Finally, Specific Aim 3 is to employ at lest a dozen undergraduates, including female and underrepresented minority students, to work with the principle investigator on these research projects in a highly mentored environment. As an HHMI Distinguished Mentor with an exemplary record of collaborating with undergraduate students in the laboratory, the PI has a longstanding commitment to the educational benefit that these hands-on skills provide to future neuroscientists.