View Program - 63rd Annual Drosophila Research Conference

Dopamine (DA) plays a major role in many animal behaviors, and yet its level is highly variable. It naturally changes over the lifetime in concert with physiological states and environmental stresses. In order to maintain stable expression of many important downstream behaviors, DA level homeostasis needs to be regulated. The way DA homeostasis is achieved on a cellular level has been under extensive investigation, due to its role in Parkinson's disease. However, genetic variation underlying these traits remains relatively unexplored. The extensively characterized genetic diversity existing in the Drosophila melanogaster Genetic Reference Panel, as well as the utility of Drosophila neurogenetic toolkit, enables us to pursue this question in a systematic way.
Here, we use pharmacological interventions to perturb DA level in diverse genetic backgrounds of the DGRP.This enabled us to simulate exogenously induced dopamine perturbations while avoiding confounding the effects of dopamine level with the systemic phenotypic response to a specific environment. We administered L-DOPA (dopamine precursor) and 3IY (dopamine-precursor agonist) to the DGRP lines and then measured changes in locomotion across genotypes. This enabled us to explore the interaction in 193 genotypes and three dopamine states (nominal, elevated and depleted). Using genome-wide association study we then identified new genetic modifiers of perturbed dopamine phenotypes.
These variants point to novel as well as known pathways that affect DA signaling. Namely, we find that the natural genetic variation of enzymes along the cAMP signaling cascade, in the octopamine synthesis, as well as sulfotransferase pathways may play an important role in maintaining locomotion upon perturbation of DA levels. In this study we explore and discuss their functional relevance.

Natural genetic modifiers of sensitivity to dopamine-level perturbations in Drosophila melanogaster