GABAergic cortico-limbic circuit mechanisms of ethanol dependence

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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.