Genetic analysis of effort discounting in C. elegans

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PROJECT SUMMARY/ABSTRACT Substance abuse causes immeasurable personal suffering and exacts a devastating toll on society. Most ad- dictive disorders have a significant genetic basis. Thus, a deeper understanding of the genetic pathways in- volved in addiction, coupled with genome sequencing, could yield individualized treatment and prevention pro- grams tailored to a person's addiction liability genotype. Unfortunately, substance abuse disorder (SUD) is an extremely broad diagnosis that likely subsumes a multi- tude of deficits. It has proved difficult to link variants of individual genes to such a broad disorder, even when using powerful approaches such as human genome-wide association (GWA) mapping. In response, research- ers are now shifting their focus to bio-behavioral markers of substance abuse, including several forms of impul- sivity, which are simpler to identify, yet well correlated with substance abuse, and likewise heritable. Initial GWA mappings of impulsivity genes with large effects, though successful, indicate that the cost of the next step – of finding the many genes with small but nevertheless essential effects – may be prohibitive. More- over, there remains the problem of functional analysis, translating lists of mapped genes into predictive models of how they interact to produce the disorder. Both concerns could be addressed if bio-behavioral markers of SUD could be demonstrated in genetically tractable, small-animal models, which are amenable to inexpensive GWA mappings and functional genetic analysis. This project seeks to establish a model of addiction related impulsivity in one such a model, the nematode worm C. elegans. The research focuses on a form of impulsivity called effort discounting, the tendency to choose low-effort, low- value rewards over high-effort, high-value rewards. We have shown that C. elegans assigns values to food re- wards based on their inherent quality and the physical costs of ingesting them. Capitalizing on this, we will opti- mize methods of increasing the physical costs of specific foods in high-throughput assays. Then, we will use these assays to ascertain whether the strength of signaling by the neurotransmitter dopamine is correlated with selection of high-effort options, as it is in mammalian models. Finally, we will estimate the heritability of effort discounting in C. elegans by quantifying this phenotype in a small collection of wild-caught, genetically diver- gent C. elegans strains. If successful, the research will establish a rapid, cost-effective method for accelerating gene discovery related to substance abuse disorders.