Alcohol use disorders (AUD) are a significant health burden on society, yet the underlying molecular mechanisms are still not well understood. People at risk for AUDs can be more sensitive to the rewarding aspects of ethanol, and/or more resistant to the aversive intoxicating effects. Although AUDs have significant genetic etiology, few genes are known that significantly contribute to the development of these disorders. Molecular understanding of these effects will allow the design of rational interventional strategies, Drosophila melanogaster has become an increasingly useful model to understand the molecular mechanisms of the behavioral responses to alcohol. The goal of this proposal is to study genes regulating the actin cytoskeleton, and the molecular mechanisms by which they do so, to regulate ethanol-induced behaviors in Drosophila. The proposed experiments build on our previous findings that Rsu1, a negative regulator of the small Rho-family GTPase Rac1, is required in distinct neurons to mediate nave aversion to alcohol, or experience-dependent preference for alcohol. First, we will study the dopaminergic neurons, and neural circuits that mediate nave alcohol aversion and experience-dependent alcohol preference. Second, we will investigate the target neurons of these dopamine neurons, and test their involvement in alcohol aversion and preference. This will include the study of actin regulators, and their role, in these dopaminergic neurons. Third, we will investigate the molecular mechanism that link dopaminergic signaling to the regulation of Rac1. This will include an investigation of dopamine receptors, and of known Rac1 regulator proteins for their role in alcohol preference and aversion. The genes we propose to investigate are highly conserved from Drosophila to mammals, and some of the ones we have already characterized have human variants that are associated with alcohol consumption and dependence. The proposed research will advance our understanding of the genetic basis for the development of AUDs. This in turn, will result in the identification of new risk factors and potential therapeutic targets for the treatment of alcohol abuse disorders.
Alcohol abuse disorders are a chronic human condition where initial consumption leads to long lasting behavioral changes, including compulsive consumption despite adverse consequences. The results of the proposed studies will provide valuable mechanistic insight into the way initial ethanol exposure causes these long lasting behavioral changes, and could thus generate new therapeutic targets for the treatment of alcohol addiction for which there are currently very limited treatment options.
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