Dissecting the Synaptic and Cellular Actions of Dopamine in Vivo - Diversity Supplement

Project Summary Dopamine (DA) is a neuromodulator that is implicated in motivating, producing and reinforcing actions. Although phasic increases and decreases in DA response to different stimuli have been extensively studied, our understanding of their impact on downstream neural activity remains limited, constituting a major impediment to the treatment of psychiatric disease. The parent R01 to this supplement is focused on understanding how DA release influences the activity of these downstream neurons by measuring the effect of behaviorally and optogenetically-evoked DA transients on D1- and D2-SPNs. However, dopamine signaling occurs concomitantly with other neuromodulators that are also thought to play key roles in these processes. The serotonin (5HT) system, in particular, projects to overlapping brain areas and, together, the two neuromodulators are the target of many neuropsychiatric drugs. Like DA neurons, 5HT neurons exhibit tonic firing at baseline and transiently increase or decrease their firing depending on behavioral state changes or environmental stimuli. While both DA and 5HT have been implicated in reward processing, the relationship of their activity during behavior remains largely unexplored. Defining distinct patterns of DA and 5HT signaling during reward driven behaviors is a first crucial step toward understanding how these neuromodulators act in concert to mediate behaviors associated with psychiatric disease states, such as depression and anxiety. In this proposal, we seek to understand the dynamics between 5HT and DA during behavior, and how these neuromodulators together influence the activity of downstream neurons. To do this, we will first characterize 5HT and DA dynamics in the Nucleus Accumbens (NAc), leveraging recent methods that have been developed to simultaneously record the release of these neuromodulators in behaving mice (Aim 1). Next, we will image 5HT, DA, and neuron activity simultaneously to understand how the activity of these two neuromodulators correlates with, and modulates neural activity in the NAc (Aim 2). Overall, we hypothesize that DA and 5HT have stereotyped release dynamics relative to one another and that each neuromodulator plays a distinct role in shaping activity of downstream neurons.