The transcriptional co-factor LMO4 and ethanol drinking

项目摘要 神经适应性变化的基因表达，由于反复乙醇消费是一个主要的 从适度饮酒到过度饮酒的过渡机制。基因表达 对人类酗酒者和依赖酒精的啮齿动物的分析研究已经确定了许多 乙醇反应基因网络的一部分。人们对这些网络是如何招募的知之甚少 转化为神经适应性反应一种机制可能涉及乙醇调节 结合并调节几种转录因子活性的转录辅助调节因子， 从而协调多样的神经适应性转录网络。但很少 研究已经确定了大脑中对乙醇有反应的转录辅助调节因子， 反过来调节乙醇的消耗。 在正在进行的实验中，我们发现转录辅助调节因子Lim-only 4 （LMO 4）调节乙醇消耗。LMO 4在大脑中的重要区域表达， 成瘾和最近的工作表明，它在可卡因致敏中起着重要作用， 蔗糖的条件奖励我们的初步结果表明，细胞核中的LMO 4水平 在间歇性的，狂欢式的乙醇消耗和基因陷阱期间， Lmo 4基因突变，使LMO 4水平降低50%，增加了 雄性C57 BL/6 J小鼠过量饮酒。 鉴于这些发现，我们认为LMO 4是一种乙醇反应性、神经适应性 转录辅助调节因子，调节乙醇消耗。这一假设将是 在两个具体目标中解决：（1）确定LMO 4是否调节乙醇消耗 在两种性别中，以及（2）确定LMO 4作用于缓和乙醇的大脑区域 消费如果结果显示LMO 4在成人大脑的特定区域调节 乙醇消耗的雄性和雌性小鼠，未来的研究旨在确定乙醇如何 调节LMO 4，LMO 4如何调节乙醇消耗量可以揭示新的光， 乙醇引起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.