The transcriptional co-factor LMO4 and ethanol drinking

项目总结 反复饮酒引起的基因表达的神经适应性改变是一个主要原因 从适量饮酒向过度饮酒过渡的基础机制。基因表达 对人类酗酒者和依赖酒精的啮齿动物进行的特征研究发现， 酒精反应基因网络。关于这些网络是如何招募的，人们知之甚少 转化为神经适应性反应。一种机制可能涉及乙醇对 转录共调节因子结合并调节几个转录因子的活性， 从而编排了一个不同的神经适应性转录网络。然而，很少有人 研究已经确定了大脑中对乙醇和乙醇做出反应的转录协同调节因子 反过来，监管乙醇的消费。 在正在进行的实验中，我们发现有证据表明，转录辅助调节因子LIM-Only 4 (LMO4)调节乙醇的消耗。LMO4在大脑中重要的脑区表达 成瘾和最近的研究表明，它在可卡因敏化和 有条件的蔗糖奖励。我们的初步结果表明，LMO4在细胞核中的水平 在间歇性的、狂欢的酒精消费和基因陷阱期间，伏隔减少 LMO4基因突变使LMO4水平降低50%，增加了糖尿病的发生 雄性C57BL/6J小鼠过量饮酒。 鉴于这些发现，我们认为LMO4是一种酒精反应、神经适应性 调节乙醇消耗的转录共调节因子。这一假设将是 涉及两个具体目标：(1)确定LMO4是否管制乙醇消费 在两性中，以及(2)识别LMO4对中等酒精起作用的大脑区域 消费。如果结果显示成人大脑特定区域的LMO4调节 雄性和雌性小鼠的乙醇消费，未来的研究旨在确定乙醇如何 监管LMO4以及LMO4如何监管乙醇消耗可能会为 乙醇引发神经适应性反应的基本机制 过度饮酒。

PROJECT SUMMARY Neuroadaptive changes in gene expression due to repeated ethanol consumption is a major mechanism that underlies the transition from moderate to excessive drinking. Gene expression profiling studies of human alcoholics and ethanol dependent rodents have identified a multitude of ethanol-responsive gene networks. Little is known about how these networks are recruited into a neuroadaptive response. One mechanism could involve ethanol regulation of transcriptional co-regulators that bind and modulate the activity of several transcription factors, thereby orchestrating a diverse neuroadaptive transcriptional network. However, very few studies have identified transcriptional co-regulators in the brain that respond to ethanol and in turn regulate ethanol consumption. In ongoing experiments we found evidence that the transcriptional co-regulator Lim-only 4 (LMO4) regulates ethanol consumption. LMO4 is expressed in brain regions important for addiction and recent work indicates that it plays an important role in cocaine sensitization and conditioned reward for sucrose. Our initial results show that LMO4 levels in the nucleus accumbens decrease during intermittent, binge-like ethanol consumption, and a gene trap mutation in the Lmo4 gene, which reduces LMO4 levels by 50%, increases the development of excessive ethanol consumption in male C57BL/6J mice. Given these findings we propose that LMO4 is an ethanol-responsive, neuroadaptive transcriptional co-regulator that regulates ethanol consumption. This hypothesis will be addressed in two Specific Aims: (1) to determine whether LMO4 regulates ethanol consumption in both sexes, and (2) to identify brain regions in which LMO4 acts to moderate ethanol consumption. Should the results show that LMO4 in specific regions of the adult brain regulates ethanol consumption in male and female mice, future studies aimed at determining how ethanol regulates LMO4 and how LMO4 regulates ethanol consumption could shed new light on a fundamental mechanism by which ethanol provokes a neuroadaptive response that leads to excessive drinking.