Ethanol Mechanisms in GABAAR Gene Targeted Mice

该项目在目前资助期间的目标是使用基因工程小鼠品系。 这些研究的首要目标是阐明有助于脑出血的神经生物学机制。 酒精使用障碍的易感性增加，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)。正如早些时候的进度报告中指出的那样，一些 在重新建立全球和非洲的繁育群体时遇到了方法学上的挑战 条件性K1小鼠。由于在建立所需的小鼠品系方面的延迟，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(AIM 3)将继续重点研究乙醇对以下小鼠组蛋白修饰的影响 急性和慢性酒精暴露和酒精戒断后。 PI对酒精诱导的行为和行为的跨代改变的挑衅性发现 在父亲先入为主的酒精暴露后饮酒提供了一种显著扩大 这笔赠款的实验重点是一个令人兴奋的新方向。我们的结果表明，一个人的乙醇 表型在一定程度上是由他父亲在怀孕前接触酒精的历史决定的。 值得注意的是，乙醇的这些跨代效应似乎只影响男性后代。这些令人兴奋的东西 观察表明，乙醇是一种影响细菌的表观诱变剂(即，它改变了表观遗传程序)。 细胞以经久不衰的方式。为了进一步调查假设一个人饮酒和 神经生物学对酒精的敏感性部分是由于父母先入为主的酒精暴露，我们将(1) 更详细地刻画模型，(2)进行研究揭示调解这些问题的机制(S 影响，(3)检查这些影响是否代表真正的跨代表观遗传，(4)发育大鼠 父亲先孕酒精暴露的模型，以及(5)进行神经生物学研究，以更好地 了解表型。 相关性(请参阅说明)： 乙醇成瘾仍然是我们社会的一个严重的医疗和社会经济问题。澄清 乙醇成瘾的分子和神经生理基础以及父亲的后果 先入为主的酒精暴露将有助于制定更有效的治疗策略 酗酒。

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.