UCSF

MicroRNAs (miRNAs) induce messenger RNA (mRNA) degradation and repress mRNA translation. Several miRNAs control the expression of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC). The BDNF signaling pathway is activated by moderate intake of alcohol to prevent escalation to excessive drinking. Here, we present data to suggest that the transition from moderate to uncontrolled alcohol intake occurs, in part, upon a breakdown of this endogenous protective pathway via a miRNA-dependent mechanism. Specifically, a mouse paradigm that mimics binge alcohol drinking in humans produced a robust reduction in BDNF mRNA levels in the medial PFC (mPFC), which was associated with increased expression of several miRNAs including miR-30a-5p. We show that miR-30a-5p binds the 3' untranslated region of BDNF, and that overexpression of miR-30a-5p in the mPFC decreased BDNF expression. Importantly, overexpression of miR-30a-5p in the mPFC produced an escalation of alcohol intake and a preference over water. Conversely, inhibition of miR-30a-5p in the mPFC using a Locked Nucleic Acid sequence that targets miR-30a-5p restored BDNF levels and decreased excessive alcohol intake. Together, our results indicate that miR-30a-5p plays a key role in the transition from moderate to excessive alcohol intake.