GABAergic cortico-limbic circuit mechanisms of ethanol dependence

大量研究表明，GABA信号的适应是脑血管病发病的主要因素。 酒精依赖。尽管乙醇在抑制控制和GABAA受体上的作用已经确立， 酒精对中枢GABAA受体表达和信号转导的适应作用知之甚少。 前额叶皮质(MPFC)和中央杏仁核(CEA)，这两个相互关联的脑区参与了 酒精依赖的发展。以前的工作已经证明在GABAA中有显著的适应 大脑皮层、培养的皮质神经元和CEA神经元中受体的表达 这些改变对mPFC和CEA的局部微电路和功能连接仍不清楚。这个 这一部分的主要目标是研究GABAA受体适配在整个回路中的作用 慢性酒精暴露后mPFC和CEA功能的电生理、生化和超微结构研究 分子方法。我们将进一步研究组蛋白脱乙酰酶(HDAC)作为基础的影响 控制GABAA受体适应性的机制以确定HDAC抑制作为一种潜在的作用 选择性逆转GABAA受体表达和通路病理改变的治疗靶点 功能。我们还将研究慢性酒精暴露对mPFC之间功能连接的影响。 静息状态功能磁共振成像(FMRI)检测CEA。总的来说，建议的 研究将描绘酒精依赖的分子和细胞机制在局部mPFC和 杏仁核微回路以及mPFC向杏仁亚区的投射。这些研究可能 导致微电路特异的分子靶点逆转酒精依赖的病理。

Numerous studies have implicated adaptations in GABA signaling as a major factor in the pathogenesis of alcohol dependence. Despite the established actions of ethanol on inhibitory control and GABAA receptors, little is known about ethanol adaptations in GABAA receptor expression and signaling that occur in the medial prefrontal cortex (mPFC) and central amygdala (CeA), interconnected brain regions that are implicated in the development of alcohol dependence. Previous work has demonstrated significant adaptations in GABAA receptor expression in cerebral cortex, cultured cortical neurons and CeA neurons, however the impact of these changes on local microcircuitry and functional connectivity of the mPFC and CeA remain unclear. The overarching goal of this component is to examine the role of GABAA receptor adaptations in overall circuit function of mPFC and CeA following chronic ethanol exposure using electrophysiological, biochemical, and molecular methods. We will further investigate the impact of histone deacetylases (HDACs) as the underlying mechanism governing the GABAA receptor adaptations to determine the utility of HDAC inhibition as a potential therapeutic target to selectively reverse pathological changes in GABAA receptor expression and circuit function. We will also examine the effect of chronic ethanol exposure on functional connectivity between mPFC and CeA using resting state functional magnetic resonance imaging (fMRI). Collectively, the proposed studies will delineate molecular and cellular mechanisms of ethanol dependence in local mPFC and amygdalar microcircuits as well as the mPFC projection to amygdalar subregions. These studies may lead to microcircuit-specific molecular targets for reversal of ethanol dependence pathology.