Impact of striatal dopamine and acetylcholine on motor skill variability in rats - the neural mechanisms driving individual differences in motor skill are poorly understood

While current therapies are effective at the population level, they often fail in individuals. Understanding the neurological basis of individual differences in motor skill will provide US with fundamental insights into motor control and enable targeted therapeutic strategies. Dopamine (DA) and acetylcholine (ACH) activity within the striatum are crucial for motor control, and bidirectionally regulate each other via striatal AXO-axonal synapses. The striatum forms several anatomically and functionally analogous circuits with cortical regions, each regulating different types of behavior. Motor behavior is regulated by a dorsal striatal-motor cortical circuit, while reward and motivation-related behavior is regulated by a ventral striatal-prefrontal cortical circuit. Variation in reward-related behavior is causally related to DA signaling in the ventral striatum. Given the similar architecture of dorsal motor and ventral motivational cortical-striatal circuits, we hypothesize that variation in dorsal striatal DA signaling, modulated by ACH, drive individual differences in motor skill analogously to ventral striatal DA control of reward-related behavior. The goal of this proposal is to determine the relationships between dorsal striatal DA, dorsal striatal ACH, and individual differences in motor skill. We will use dual-color photometry and optogenetics to monitor and manipulate DA and ACH within the striatum of rats as they perform a dexterous motor task to determine the role of striatal DA and ACH in individual differences in motor skill (aim 1). We will use dual-color photometry, high-density electrophysiology, and computational approaches to determine the relationship between neuromodulators, corticostriatal dynamics, and differences in motor skill between individuals (aim 2). These experiments will provide US with fundamental insights into how striatal DA-ACH interactions influence broader cortical and striatal circuit dynamics and allow precise finely- tuned motor control. The experiments and training activities outlined in this proposal will expand my skillset from primarily molecular and behavioral techniques to circuit-level and computational approaches, preparing me to lead a research group using a combination of strategies to address critical translational neuroscience questions.