Ethanol Mechanisms in GABAAR Gene Targeted Mice

本项目在目前供资期间的目标是采用基因工程小鼠品系。 这些研究的总体目标是阐明导致神经系统疾病的神经生物学机制。 酒精使用障碍的脆弱性增加，重点是海马/杏仁核GABA能 突触传递（目标1-2）和表观遗传学（目标3）。如前几份进度报告所述， 在重新建立全球和非洲的繁殖群体方面遇到了方法上的挑战， 条件性K1小鼠。由于在建立所需的鼠标线方面的延迟，目标1和2将继续 基本上如最初描述的那样进入扩展阶段。乙醇的表观遗传效应研究 3)将继续关注乙醇对小鼠组蛋白修饰的影响， 急性和慢性乙醇暴露以及乙醇戒断后。 PI关于乙醇诱导行为的跨代改变的挑衅性发现， 在父亲怀孕前接触乙醇后饮酒， 这项资助的实验重点是一个令人兴奋的新方向。我们的研究结果表明，一个人的乙醇 表型部分取决于他父亲在怀孕之前的乙醇暴露史。 值得注意的是，乙醇的这些跨代效应似乎只影响雄性后代。这些令人兴奋 观察表明乙醇是表诱变剂（即，它改变了表观遗传程序）， 细胞以一种持久的方式。为了进一步研究一个人的饮酒和 神经生物学对乙醇的敏感性部分是由于父母的孕前乙醇暴露，我们将（1） 更详细地描述模型，（2）进行研究以揭示介导这些的机制 影响，（3）检查这些影响是否代表真正的跨代表观遗传，（4）培养大鼠 模型的父亲孕前乙醇暴露，（5）进行神经生物学研究，以更好地 了解phenotype。 相关性（参见说明）： 乙醇成瘾仍然是我们社会的一个令人印象深刻的医疗和社会经济问题。阐明 分子和神经生理学底物的基础乙醇成瘾和后果的父亲 孕前乙醇暴露将有助于开发更有效的治疗策略， 酒精中毒

The aims of this project for the currently funded period employed genetically engineered mouse lines. The overarching goal of these studies was to elucidate neurobiological mechanisms that contribute to an increased vulnerability to alcohol use disorders, with a focus on both hippocampal/amygdala GABAergic synaptic transmission (Aims 1-2) and epigenetics (Aim 3). As noted in earlier progress reports, some methodological challenges were encountered in re-establishing the breeding colonies of global and conditional Kl mice. Because of the delays in establishing the needed mouse lines, Aims 1&2 will continue essentially as originally described into the extension phase. Studies of the epigenetic effects of ethanol (Aim 3) will continue to focus on characterizing the effects of ethanol on histone modifications in mice following acute and chronic ethanol exposure and following ethanol withdrawal. The provocative discovery by the PI of transgenerational alterations in ethanol-induced behaviors and drinking following paternal preconception ethanol exposure has provided a need to significantly expand the experimental focus of this grant in an exciting new direction. Our results suggest that an individual's ethanol phenotype is dictated in part by his father's history of ethanol exposure prior to conceiving that individual. Remarkably, these transgenerational effects of ethanol appear to only affect male offspring. These exciting observations suggest that ethanol is an epimutagen (i.e., it alters the epigenetic program) that impacts germ cells in an enduring fashion. To further investigate the hypothesis that an individual's drinking and neurobiological sensitivity to ethanol are due in part to parental preconception ethanol exposure, we will (1) characterize the model in greater detail, (2) undertake studies to reveal the mechanism(s) that mediate these effects, (3) examine if these effects represent true transgenerational epigenetic inheritance, (4) develop a rat model of paternal preconception ethanol exposure, and (5) conduct neurobiological studies to better understand the phenotype. RELEVANCE (See instructions): EtOH addiction remains an imposing medical and socio-economic concern for our society. Elucidating the molecular and neurophysiological substrates that underlie EtOH addiction and the consequences of paternal preconception ethanol exposure will facilitate the development of more effective treatment strategies for alcoholism.