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Role of Candidate Gene Networks in Behavioral Responses to Ethanol in C. elegans

Andrew Davies and Jill Bettinger

Ethanol acts through multiple targets to bring about its intoxicating effects. Normal physiological responses to intoxication lead to the development of acute functional tolerance (AFT). The collection of genes that are required for ethanol to generate its effects and to produce tolerance are of particular interest because genetic variation in those genes in humans is likely to contribute to an individual’s level of predisposition to develop alcohol use disorders. The overall goal of this project is to better understand the identity of those genes and how they function individually and in groups (or networks) to mediate ethanol responses. We use C. elegans to take an in vivo genetic approach to identify novel ethanol response genes and to validate candidate genes that have been hypothesized to have a role in ethanol responses. To determine if candidate genes play a role in ethanol responses in C. elegans, we use quantitative assays that assess two behaviors under independent neuromuscular control to measure initial sensitivity to ethanol and the development of AFT. Mutant strains with altered function for genes of interest are tested and any altered responses are identified. We also make use of the amenable genetics of C. elegans to perform forward genetic screens to identify mutations in genes that act in the process of AFT development. In doing so, we are isolating suppressor mutations that restore AFT to an otherwise AFT-defective mutant. We expect that some genes identified by this screen will be novel ethanol response genes. A central theme of this research is the expansion of the focus from single genes to networks of interacting genes to produce a better biological understanding of the mechanisms of action for the intoxicating effects of ethanol and the development of AFT. Bioinformatic resources are used to propose potential interacting genes for each validated ethanol response gene. These genes are assessed as described above with the idea that genes that do act together are more likely to share an altered ethanol response phenotype. Based on previous findings and the overall genome conservation between C. elegans and mammals, we expect that genes we identify will also play roles in mammalian ethanol responses. The identity of multiple genes that act in concert to mediate ethanol responses will then be shared with other components of this Center. That knowledge will prioritize candidate genes for further study in rodents and/or humans and bring power to analyses by allowing the network of genes be considered as a unit rather than as a group of individual genes.