Sex differences in the alcohol-mediated modulation of BLA network states

Abstract

About 85% of adults in the United States report drinking alcohol in their lifetime. Mood disorders, like generalized anxiety disorder and major depression, are highly comorbid with alcohol use. The basolateral amygdala (BLA) is an area of the brain that is heavily implicated in both mood disorders and alcohol use disorder. Importantly, modulation of BLA network/oscillatory states via parvalbumin-positive (PV) GABAergic interneurons has been shown to control the behavioral expression of fear and anxiety. Further, PV interneurons express a high density of {delta}-subunit-containing GABAA receptors (GABAARs), which are sensitive to low concentrations of alcohol. Our lab previously demonstrated that {delta}-subunit-containing GABAARs on PV interneurons in the BLA influence voluntary ethanol intake and anxiety-like behavior in withdrawal. Therefore, we hypothesized that the effects of alcohol may modulate BLA network states that have been associated with fear and anxiety behaviors via {delta}-GABAARs on PV interneurons in the BLA. Given the impact of ovarian hormones on the expression of {delta}-GABAARs, we examined the ability of alcohol to modulate local field potentials (LFPs) in the BLA from male and female C57BL/6J and Gabrd-/- mice after acute and repeated exposure to alcohol. Here, we demonstrate that acute and repeated alcohol can differentially modulate oscillatory states in male and female C57BL/6J mice, a process which involves {delta}-GABAARs. This is the first study to demonstrate that alcohol is capable of altering network states implicated in both anxiety and alcohol use disorders. Significance StatementAlcohol use disorder and mood disorders are highly comorbid. The basolateral amygdala (BLA) is implicated in both of these disorders, but the mechanisms contributing to their shared pathophysiology remain uncertain. Here we demonstrate that acute and repeated alcohol exposure can alter network oscillations in the BLA which control the behavioral expression of fear and anxiety. These data suggest that alcohol may directly influence network states associated with mood. Further, we demonstrate sex differences in alcohols ability to modulate BLA network states, an effect involving {delta}-GABAA receptors, which may contribute to sex differences in alcohol intake and comorbid mood disorders. These data potentially point to a novel mechanism mediating the effects of alcohol on affective states. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY