Defining Genes and Circuits Affecting Naïve and Experience-Dependent Alcohol Preference in Drosophila melanogaster
Ojelade, Shamsideen Adeniyi
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Despite alcohol being one of the most used and abused drugs in the world, the molecular mechanisms underlying alcohol abuse disorders remain largely unknown. In this dissertation, I utilized the model system Drosophila melanogaster to identify genes and circuits affecting ethanol-induced behaviors. From an unbiased genetic screen, I identified a novel gene that affects ethanol consumption in both flies and humans. Ras suppressor 1 (Rsu1) is required in the adult Drosophila nervous system for normal sensitivity to ethanol-induced sedation, and acts upstream of Rac1 and downstream of integrin to regulate the actin cytoskeleton. In a two bottle choice assay called the capillary feeding (Café) assay, loss of Rsu1 causes immediate heightened alcohol preference compared to wild type's initial naïve aversion. In contrast, flies specifically lacking Rsu1 in the mushroom bodies show normal initial aversion to alcohol, but then fail to acquire ethanol preference like normal flies do. Our data show that not only is Rsu1 required for normal alcohol responses, it suggests that different anatomical brain structures in flies control distinct alcohol behavioral responses. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption in flies and humans. Using a modified Café paradigm, we investigated whether dopamine plays a role in both the aversive and experience-dependent properties of alcohol. I show that distinct subsets of DA neurons innervating the Fan-shaped body (FSB) and Mushroom body (MB) mediate naïve alcohol aversion (NAA) and experience-dependent alcohol preference (EDAP) respectively in flies. Furthermore, Rac1-dependent actin alteration in these anatomical structures (FSB and MB) also mirror dopaminergic-induced neuronal activity in these circuits suggesting that dopamine functions upstream of Rac1-signaling to affect alcohol preference in flies. Taken together, my dissertation suggests a conserved role for dopamine and the integrin/Rsu1/Rac1/Cofilin/Actin signaling pathway in modulating drug-induced behavioral plasticity across phyla, and highlights Drosophila as an effective model for integrative translational research.