Wednesday, April 2, 2025
4/2/2025
Acetylcholine determines dopamine's role in learning versus moving - Project Summary The neuromodulator dopamine is implicated in most neuropsychiatric disorders, and also several movement disorders. A wealth of data has implicated dopamine release in the striatum -the input structure of the basal ganglia- in both learning and motor control. Therefore, a major outstanding question for the field is understanding how dopamine can satisfy these dual functions within the same brain area, using the same neural machinery. For the most part, previous studies have either focused on movement or learning in separate experiments. The proposed work has two main goals: (1) to relate dopamine release in the striatum to both learning and motor control on single trials in the same animal, at task events occurring at distinct timepoints; (2) to test the hypothesis that the neuromodulator acetylcholine dynamically gates whether dopamine in the striatum is used for learning or moving on a moment-by-moment basis. This proposal will use a novel behavioral paradigm in rats; critically, the task involves several sequential events on single trials that differentially elicit movements, or convey information about offered rewards, enabling dissociation of motor and reward-related dynamics at distinct timepoints. High-throughput behavioral training will generate dozens of trained subjects for experiments in parallel, accelerating the rate of research progress. We will use optical dopamine sensors to measure release in the striatum at distinct timepoints, testing the hypothesis that dopamine promotes learning versus moving at distinct timepoints (Aim 1). We will also perform electrophysiological recordings in the striatum to identify neural correlates of learning (i.e., neural plasticity) at certain timepoints but not others (Aim 1). We will next use optogenetics to manipulate dopamine release at distinct timepoints, and evaluate the effects on learning versus moving (Aim 2). Finally, previous experiments suggest that another neuromodulator in the striatum, acetylcholine, might influence the effect of dopamine on neurons. We will use optical methods to measure and manipulate acetylcholine at specific trial events and evaluate effects on trial-by-trial learning and movement (Aim 3). These experiments will test the hypothesis that acetylcholine gates whether striatal dopamine is used for learning or moving. This will address a major outstanding question in the field: how can dopamine support multiple distinct functions via the same circuit elements? Neuromodulatory systems including dopamine and acetylcholine are implicated in myriad neuropsychiatric disorders including schizophrenia and depression. A greater understanding of the circuit mechanisms by which they coordinate different aspects of behavior holds promise for revealing novel therapeutic targets for these disorders.
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