Interneurons tune the neural circuits mediating the anxiolytic effects of alcohol

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Project Summary Excessive alcohol consumption leads to alcohol use disorders in approximately 7% of individuals and is associated with numerous health conditions, substantial economic burden, and is the third leading cause of preventable deaths in the United States. Despite the fact that alcohol misuse is a serious health and economic concern worldwide, we still do not fully understand the basic mechanisms contributing to alcohol consumption. One primary factor thought to drive consumption is the anxiolytic effects of alcohol. However, the specific cell types and networks mediating the anxiolytic effects of alcohol are unknown. Recent studies have elucidated connections between the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in the network communication of anxiety. Oscillations within the BLA and mPFC and the coupling between these regions is thought to be driven by parvalbumin (PV) interneurons in the BLA. PV interneurons in the BLA express the GABAAR δ subunit at a high density, which is thought to be a target of action for alcohol. We hypothesize that alcohol acts preferentially on PV interneurons in the BLA, modulating local oscillations and frequency coupling between the BLA and mPFC, thereby mediating the anxiolytic effects. This proposal represents the first attempt to examine the cell type-specific effects of alcohol on the network communication of anxiety. The current application will explore the cell type-specific targets of alcohol in the BLA and determine whether the GABAAR δ subunit on PV interneurons plays a role in mediating the anxiolytic effects of low dose alcohol (Specific Aim 1). This application will determine whether the anxiolytic effects of alcohol involve modulation of the local oscillations in the BLA and mPFC as well as the frequency coupling between the mPFC and BLA (Specific Aim 2). Further, we will determine whether driving the network communication of safety recapitulates the anxiolytic effects of alcohol and whether disruption of the pro-safety communication reduces the anxiolytic effects of alcohol (Specific Aim 3). This proposal will define specific cell types and associated neural pathways that are most sensitive to alcohol and how these circuits orchestrate sensitivity to alcohol. This application will determine whether the anxiolytic effects of alcohol are mediated by GABAAR δ subunit containing receptors on PV interneurons in the BLA through the coordination of activity between the mPFC and BLA.