MicroRNA-137 drives epigenetic reprogramming in the adult amygdala and behavioral changes after adolescent alcohol exposure

Abstract Adolescent binge drinking is a serious public health concern and a risk factor for alcohol use disorder (AUD) and comorbid anxiety in adulthood. Chromatin remodeling mediated by epigenetic enzymes including lysine-specific demethylase 1 (LSD1) due to adolescent alcohol exposure may play a role in adult psychopathology. The mechanism by which adolescent alcohol exposure mechanistically regulates epigenetic reprogramming and behavioral changes in adulthood is unknown. We investigated the role of microRNA-137 (miR-137), which is crucial for normal neurodevelopment and targets LSD1, in adolescent intermittent ethanol (AIE) exposure-induced anxiety-like and alcohol-drinking behaviors and related epigenetic reprogramming in the amygdala in adulthood. Adolescent rats were exposed to 2g/kg ethanol (2 days on/off; AIE) or intermittent n-saline (AIS) during postnatal days (PND) 28-41 and allowed to grow to adulthood for analysis of behavior, miRNA expression, and epigenetic measures in the amygdala. Interestingly, miR-137 was increased and its target genes Lsd1 and Lsd1 + 8a were decreased in the AIE adult amygdala. Infusion of miR-137 antagomir directly into the central nucleus of the amygdala (CeA) rescues AIE-induced alcohol drinking and anxiety-like behaviors via normalization of decreased Lsd1 expression, decreased LSD1 occupancy, and decreased Bdnf IV expression due to increased H3K9 dimethylation in AIE adult rats. Further, concomitant Lsd1 siRNA infusion into the CeA prevents the miR-137-mediated reversal of AIE-induced adult anxiety and chromatin remodeling at the Bdnf IV promoter. These novel results highlight miR-137 as a potential therapeutic target for anxiety and AUD susceptibility after adolescent alcohol exposure in adulthood. Significance Statement Adolescent alcohol exposure is a serious public health problem and contributes to alcohol use and anxiety disorders later in life. In this study, we identify microRNA-137, a small non-coding RNA, in the central nucleus of amygdala (CeA) as a crucial regulator of increased alcohol consumption and anxiety-like behavior in adult rats after adolescent intermittent ethanol (AIE) exposure. Inhibition of microRNA-137 in the CeA reverses increased alcohol intake and anxiety-like behavior, and this effect is mediated by lysine-specific demethylase 1 (LSD1), a microRNA-137 target gene that regulates epigenetic programming. Thus, we have identified microRNA-137 and its target LSD1, in the CeA that play a mechanistic role in the pathogenesis of increased adult anxiety and alcohol consumption after adolescent alcohol exposure.