Molecular regulation of CeA glutamate and binge drinking

摘要/项目摘要 酗酒是美国境内最普遍的酒精中毒形式，但 狂欢饮酒并没有得到很好的理解。来自我的实验室的大量功能数据表明 酒精诱导核内mGluR5/Hmer 2途径活性增加(通过PI3K和PKC？) 伏隔核(NAC)对酗酒小鼠饮酒倾向的重要作用 喝酒。NAC壳与NAC的其他成员在细胞结构、解剖和功能方面具有相同的特征 扩展的杏仁核亚回路，包括杏仁中央核(CEA)，这是一个高度大脑区域 与酒精中毒的神经生物学有关。Hmer 2在CEA中丰富，其水平在 与mGluR1/5在慢性酒精饮酒模型中的一致性。初步的功能数据表明， 正如在NAC外壳中观察到的那样，抑制CEA mGluR5以及PI3K的活性可以减少小鼠酗酒的情况，a 发现与现有报告一致，在CEA PKC？击倒后减少有限的酒精摄入量。 这些数据表明，mGluR5通过PI3K和PKC介导的信号转导也发挥了重要作用 CEA在对狂饮的监管中发挥着重要作用，或许还有遗传上的脆弱性。这个项目将扩大到 这些最新的观察并使用了我们的行为药理学和遗传学方法的组合 测试特发性或酒精诱导mGluR介导的信号转导增加的总体假设 通过它的Q亚基到PKC，以及它的亚基到扩展的杏仁核结构中的PI3K，特别是CEA， 对酗酒的表现和遗传易感性很重要。本提案的目标1 将使用药理学和遗传学方法的组合来测试完整的特定假设 CEA内通过mGluR5-Hmer 2-PI3K和mGluR5-Hmer 2-PKC？通路的信号转导 对维持小鼠过量饮酒来说是必要的和/或充分的。目标2将与这些功能相关 暴饮史对神经细胞表达和激活状态的短期和长期影响的研究 杏仁核延伸结构及其前额叶皮质内mGluR5介导的信号通路 地区。AIM 3将基础和酒精刺激的mGluR5-Hmer 2-Kinase通路激活与基因 狂饮的倾向，使用了几个动物模型。预计取得的成果将大大 加深对mGluR/Hmer 2介导的信号在杏仁核扩展中的作用的理解 对过度饮酒的维持和脆弱性进行监管。这样的知识将指向 酒精对mGluR5/Hmer介导的谷氨酸突触后调节的影响 杏仁核扩展结构及其前额叶皮质连接内的信息传递是关键 神经适应调节狂饮倾向，这与理解 酒精中毒的脆弱性及其谷氨酸靶向药物治疗。

Abstract/Project Summary Binge alcohol drinking is the most prevalent form of alcoholism within the United States yet the neurobiology of binge drinking is not well-understood. A significant body of functional data from my laboratory demonstrates that alcohol-induced increases in mGluR5/Homer2 pathway activity (via PI3K and PKC¿) within the nucleus accumbens (NAC) shell as important for the propensity to consume alcohol in murine models of binge alcohol drinking. The NAC shell shares cytoarchitectural, anatomical and functional features with other members of the extended amygdala subcircuit, including the central nucleus of the amygdala (CeA) - a brain region highly implicated in the neurobiology of alcoholism. Homer2 is enriched in the CeA and its levels are up-regulated in concert with those of mGluR1/5 in models of chronic alcohol drinking. Preliminary functional data indicates that, as observed for the NAC shell, inhibiting CeA mGluR5, as well as PI3K, activity reduces binge alcohol drinking in mice, a finding consistent with existing reports for a reduction in limited access alcohol intake upon CeA PKC¿ knock-down. Such data point to an important role also for mGluR5-mediated signaling through both PI3K and PKC¿ within the CeA in the regulation of, and perhaps genetic vulnerability to, binge drink. This project will expand upon these recent observations and employ our combination of behavioral pharmacological and genetic approaches to test the over-arching hypothesis that idiopathic or alcohol-induced increases in mGluR-mediated signaling through its ¿q subunit to PKC¿ and its ¿¿ subunit to PI3K within extended amygdala structures, notably the CeA, is important for the manifestation of, and genetic vulnerability to, binge alcohol drinking. Aim 1 of this proposal will employ a combination of pharmacological and genetic approaches to test the specific hypothesis that intact signaling through the mGluR5-Homer2-PI3K and mGluR5-Homer2-PKC¿ pathways within the CeA is necessary and/or sufficient for maintaining excessive alcohol intake in mice. Aim 2 will relate these functional studies to the short- and long-term effects of a history of binge drinking upon the expression and activational state of mGluR5-mediated signaling pathways within extended amygdala structures and their prefrontal cortical interconnected regions. Aim 3 will relate basal and alcohol-stimulated mGluR5-Homer2-kinase pathway activation to genetic propensity to binge drink, using several animal models. It is anticipated that the results obtained will greatly increase our understanding of the role for mGluR/Homer2-mediated signaling within the extended amygdala regulates the maintenance of, and vulnerability to, excessive alcohol drinking. Such knowledge will point to alcohol-induced alterations in mGluR5/Homer-mediated regulation of post-synaptic aspects of glutamate transmission within extended amygdala structures and their prefrontal cortical interconnections as critical neuroadaptations regulating the propensity to binge drink, which has high relevance for understanding of alcoholism vulnerability and its treatment with glutamate-targeting pharmacotherapies.