UC Merced

Ethanol tolerance is the first type of behavioral plasticity and neural plasticity that is induced by ethanol intake, and yet its molecular and circuit bases remain largely unexplored. Here, we characterize distinct forms of ethanol tolerance in Drosophila: rapid and chronic tolerance. Chronic tolerance, induced by continuous exposure, lasts for two days and depends on new protein synthesis and CREB. Unlike rapid, chronic tolerance is independent of the immediate early gene Hr38/Nr4a. Chronic tolerance is suppressed by the Sirtuin HDAC Sirt1, whereas rapid tolerance is enhanced by Sirt1. Moreover, rapid tolerance is composed of both labile and consolidated traces. Repeated ethanol exposures induce another type of chronic tolerance that is separately represented in the brain. Interestingly, rapid and chronic tolerance map to anatomically distinct regions of the Drosophila mushroom body learning and memory center, where they rely on mutually exclusive inhibitory circuits with large interneurons. Thus, depending on the initial dosage and pattern of intake, ethanol-induced neural plasticity underlies the longer-term brain changes associated with alcohol-use disorder.