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 synaptic dopamine release in vivo. And although the effects of dopamine on individual cells have been extensively studied, how dopamine signals are processed to change the dynamics of post synaptic neurons to execute changes of behavior is not well understood. The microscopic roundworm C. elegans offers the opportunity to study these aspects of dopamine signaling using powerful tools of molecular genetics and in vivo circuit analysis. Using behavioral genetics and newly developed methods for analysis of neural circuits in behaving animals we will (1) determine mechanisms that regulate dopamine release in response to appetitive stimuli and postsynaptic and (2) determine circuit mechanisms that transform dopamine signaling events into lasting changes in behavior. Because of the ancient and conserved functions of dopamine signaling in the animal nervous system, we propose that our studies will also advance understanding of pre- and postsynaptic mechanisms in dopamine systems of the human brain and accelerate discovery of new approaches to understanding and treating diseases linked to dysfunction of dopaminergic systems.

The neurotransmitter dopamine plays critical roles in circuits that generate voluntary movement and process rewarding stimuli; because these circuits have large influence on behavior, affect, and cognition, dopamine signaling is targeted for the treatment of many neurological and psychiatric diseases, including Parkinson's Disease, schizophrenia, attention disorders, and obsessive-compulsive disorder. We will use a powerful experimental model - a microscopic animal that uses dopamine to generate simple behaviors - to discover genes required for the proper regulation of dopamine release and to determine how dopamine causes lasting changes in neural circuits that control behavior. Understanding the molecular and circuit mechanisms required for dopamine signaling will advance understanding of diseases linked to dysfunction of dopamine signaling in the brain and will generate opportunities to develop new approaches for their treatment.