Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Mice Consuming Alcohol Attenuates Glycolysis

Abstract

SUMMARYmTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use and abuse. We report that activation of mTORC1 in the nucleus accumbens (NAc) of mice consuming alcohol promotes the translation of microRNA (miR) machinery components and the upregulation of microRNAs (miRs) expression including miR34a-5p. In parallel, we detected a paradoxical mTORC1-dependent repression of translation of transcripts including Aldolase A, an essential glycolytic enzyme. We found that miR34a-5p in the NAc targets Aldolase A for translation repression and promotes alcohol intake. Our data further suggest that glycolysis is inhibited in the NAc manifesting in an mTORC1-dependent attenuation of L-lactate, the end product of glycolysis. Finally, we show that systemic administration of L-lactate attenuates mouse excessive alcohol intake. Our data suggest that alcohol promotes paradoxical actions of mTORC1 on translation and glycolysis which in turn drive excessive alcohol use.Abstract FigureGraphical abstract(A)Alcohol activates mTORC1 signaling in D1+ NAc neurons which in turn increases the translation of GW182, Trax and CNOT4 and represses the translation of Aldolase A, Rbfox2 and PPM1E. In parallel, alcohol increases the levels of miR15b-5p, miR25-3p, miR92-3p and miR34a-5p which are predicted to target Aldolase A, Rbfox2 and PPM1E.(B)Alcohol activates mTORC1 signaling in the NAc which increases the level of miR34a-5p repressing the translation of Aldolase A and decreasing the level of L-lactate, promoting further drinking.