Striatal Dopamine's Role in Associative Learning and Behavior

Project Summary Cognitive impairments are pervasive in psychiatric disease. These symptoms impact patient outcomes and typ- ically resist treatment. Striatal dopamine dysfunction often contributes to these cognitive deficits, suggesting it may be a therapeutic target. Associative learning tasks, where subjects learn that a cue predicts reward, provide several advantages for pursuing this topic. First, learning and performance are heavily dependent on striatal dopamine. Second, these tasks translate easily from humans to rodents, allowing for detailed circuit-interroga- tion. Third, extensive data suggests that the underlying dopaminergic mechanisms are preserved across spe- cies, adding translational value. Specifically, during these tasks, dopamine neurons fire transiently to cues and/or the rewards they predict. ‘Cue-transients’ purportedly reflect a cue’s ‘value’ and guide decision-making by mod- ulating striatal firing. In contrast, ‘reward-transients’ presumably reflect the difference between a trial’s actual and expected reward-outcome and guide learning by triggering plasticity at corticostriatal synapses. These assump- tions underly most theories of dopamine’s role in associative learning, yet key knowledge-gaps remain. For ex- ample, cues can signal reward at a certain rate, probability, number, and several other factors. Due to confounds in many associative learning tasks, whether dopamine transients preferentially track one or some combination of these variables is unclear. Moreover, few studies have directly measured how dopamine affects striatal firing in behaving animals, preventing us from getting a detailed picture of how these transients guide behavior. Here, we will target these knowledge gaps. Based on prior work and our pilot data, our central hypothesis is that dopamine transients preferentially track a cue’s reward-rate, and this coding guides behavior by tuning striatal neurons to task-related cortical inputs. In Aim 1, we will focus on establishing whether dopamine tracks reward- rate over other variables (e.g., number, probability, etc.). To assess this, we will measure striatal dopamine- binding via photometry during behavioral tasks that are tailored for answering this question. In Aim 2, we will ask how dopamine impacts the firing of striatal neurons to guide learning and decision-making. Specifically, using combined dopamine-sensor photometry and tetrode electrophysiology, we will correlate dopamine-binding levels with single-neuron firing in the striatum, as mice learn and ultimately perform during our tasks. Furthermore, using combined tetrode electrophysiology and optogenetics, we will test the causal impact of dopamine on stri- atal-firing and behavior. These data will provide fundamental insight into striatal dopamine’s role in cognition and, ideally, help guide future treatments for cognitive deficits in psychiatric disease. Furthermore, the lab train- ing, mentoring, and writing skills I obtain will serve me well throughout my career.