Friday, April 4, 2025
4/4/2025
Roles for dopamine signaling modes in striatal circuit modulation and behavior - Summary Dopamine controls movement, learning, motivation and reward, and changes in its signaling are associated with drug addiction and Parkinson’s disease (PD). Dopamine operates through multiple modes, including tonic and phasic signaling, and mechanisms of dopamine in the regulation of behavior continue to be debated. Recent studies on movement, for example, have suggested that rapid, phasic dopamine triggers movement and instructed models on the moment-to-moment roles of dopamine in striatal regulation. These models are contrasted by clinical work that aims at providing stable dopamine levels for PD treatment. The long-term goal of this project is to determine mechanisms of dopamine in the control of behavior. We hypothesize that distinct dopamine signaling modes employ activity-dependent and -independent release mechanisms for producing two-component control of behavioral output. Select roles of dopamine require firing activity, while many permissive roles can be fulfilled by a release mechanism that does not rely on action potential-firing. We have developed mouse mutants and acute manipulations to abolish action potential- induced dopamine release and rapid in vivo dopamine dynamics. In these mutants, movement initiation is unperturbed, and the mice can learn to make easy, binary decisions. In contrast, motivation, invigoration of reward-oriented behavior, and prediction error-based learning are impaired. These data indicate the need for a departure from the model that phasic dopamine triggers movement and justify in-depth analyses of dopamine in reinforcement learning with the new approaches we established. We will study striatal dopamine modulation in movement and reinforcement learning. Using the newly generated tools, we will pursue a range of behavioral assays and simultaneously assess in vivo dopamine dynamics with fluorescent dopamine sensors and neural activity with calcium indicators. In aim 1, we propose to establish relationships between dopamine and striatal output during movement. We measure dopamine dynamics, dopamine axon activity and medium spiny neuron activity during movement initiation and test for the roles of dopamine release in movement and striatal regulation. In aim 2, we dissect mechanisms of dopamine in reinforcement learning. We propose a step-wise, systematic approach to assess the necessity for action potential-induced dopamine release in prediction error-based learning, motivation, motor skill learning, cocaine self-administration and drug seeking. This multiple PI project builds on the expertise of Pascal Kaeser, an expert in the biology of dopamine transmission, and Naoshige Uchida, an expert in behavioral dopamine research. Our work will solve central discrepancies in models of dopamine action in movement control and will likely establish roles for precise dopamine signaling in reinforcement learning. The knowledge we generate may ultimately help revise strategies for treating diseases with altered dopamine function, for example drug addiction.
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