PROJECT SUMMARY The neuromodulator dopamine is important for many brain functions: loss of dopamine neurons causes movement disorders, such as Parkinson's disease; dopamine signaling is targeted by drugs of abuse and integral to the neurobiology of reward and addiction; and dopamine signaling is a therapeutic target for the treatment of many neuropsychiatric disorders. Despite its importance in the brain, relatively little is known about mechanisms that regulate dopamine release in vivo or are otherwise required for the function of dopamine neurons. To directly address this question, we have used a simple invertebrate model – the nematode C. elegans - to identify molecules required in vivo for dopamine signaling. We have identified genes whose expression is highly enriched in dopamine neurons, and by testing the corresponding mutants for defects in a behavior that requires endogenous dopamine we have identified five evolutionarily conserved genes that are likely required for the function of dopamine neurons. Using live-cell imaging and studies of dopamine neuron physiology we will determine the function of these genes. We will also use genetic analyses to determine how these genes interact with known components of dopamine signaling pathways. We expect that these studies will identify new therapeutic targets for the treatment of neurological and psychiatric disorders. Importantly, because extant therapeutic targets act downstream of dopamine release (they are receptors, transporters and dopamine-degrading enzymes), we also anticipate that our studies will identify targets with fundamentally new mechanisms of action in dopamine signaling.

PROJECT NARRATIVE Many neurological and neuropsychiatric disorders - for example Parkinson's Disease and schizophrenia – are linked to defects in brain circuits that use the neuromodulator dopamine. Using an animal model that is amenable to large-scale molecular-genetic studies and high-throughput behavioral analysis, we have identified genes that are (1) highly expressed by dopamine neurons, (2) required for a dopamine-driven behavior, and (3) have counterparts in the human genome. We will determine the functions of these genes in dopamine neurons with the goal of identifying new therapeutic targets in dopamine signaling.