Project Summary Dopamine plays a central role in motivation and reinforcement learning, allowing animals to take advantage of their current circumstances to optimize both present and future behavior. Yet reconciling the diverse roles of dopamine has remained a challenge, in part due to the difficulty of understanding how a single neuromodulator can convey different signals to its cellular targets in distinct behavioral contexts. One prominent model is that different patterns of dopamine release engage distinct molecular pathways in downstream circuits, such that tonic fluctuations in dopamine regulate motivation while phasic bursts of dopamine convey reward prediction errors for learning. However, recent work has suggested that phasic firing patterns can both instruct learning and convey motivational signals that promote movement, challenging this simple dichotomy. Here we propose to use the Drosophila mushroom body as a powerful model to dissect dopamine’s diverse roles in modulating behavior. Recent work from our lab has shown that the same mushroom body dopaminergic neurons (DANs) responsive to rewards that instruct learning also reflect an animal’s purposive actions, underscoring how the dual representation of reward and locomotion is a conserved feature of dopaminergic systems from flies to mammals. Taking advantage of the mushroom body’s simple circuit architecture and unparalleled genetic toolkit, we will build on these observations to reveal how reward and locomotor signals are directly translated to different patterns of dopamine release and engage distinct dopamine receptor signaling cascades to shape circuit processing and behavior. In Aim 1, we will perform multicolor functional imaging as animals navigate in a virtual olfactory environment and reveal how tonic and phasic patterns of DAN activity are propagated to their post- synaptic targets. In Aim 2 we will use a suite of optical sensors to measure dopamine release and dopamine receptor signaling to understand how the same neuromodulator engages different sub-cellular cascades in different behavioral contexts. In Aim 3 we will test how animals use tonic DAN activity to regulate their ongoing behavior. Dysfunction in dopaminergic signaling is at the core of a wide array of neuropsychiatric conditions, from the severe motor deficits of Parkinsonian patients to motivational disorders like depression and drug addiction. By applying a multidisciplinary approach to interrogate the relatively simple dopaminergic circuitry of the fly, we hope to provide an integrative understanding of dopamine’s diverse actions with important implications to understanding neuromodulation in both healthy and diseased states.

Project Narrative Dysfunction in dopaminergic signaling is associated with a wide array of neuropsychiatric conditions including depression, schizophrenia and addiction. Developing a mechanistic understanding of how dopamine acts on specific molecular signaling pathways to shape circuit function will lay the foundation for the development of novel therapeutic treatments.