Understanding the process by which animals learn to perform specific actions from rewarding experiences is important for identifying the neural and behavioral patterns that indicate system dysregulation; such knowledge can help lead to the development of diagnostics and therapy for conditions where action learning is impaired. Dopaminergic neurons and their targets have been implicated as major contributors to action learning. Though it is well known that stimulation of dopaminergic neurons can reinforce behavior, it is less clear how stimulated dopaminergic activities guide the animal to behaviorally search the world for the action that produces reward. The goal of this proposal is to characterize the role of dopaminergic activity in shaping behavior that hones in on a specific action or action sequences for reward. A key to this proposal is the combination of optogenetics and objective, unsupervised behavioral clustering to develop a closed loop reinforcement system in which reward in the form of dopaminergic stimulation is delivered to the VTA of animals as they learn to perform specific actions or action sequences. The K99 phase of the application will involve characterization of the behavioral patterns underlying single action and action sequence learning, followed by imaging of the dorsolateral striatum (known to represent the action space) in freely moving mice to understand the neural correlates of the action learning process. Functional circuit dissection will also be performed to elucidate which specific VTA projection pathways mediate action learning. Following mastering of these techniques, the applicant will enter the R00 phase and continue studying the role of specific VTA projection pathways on the action learning process. Chemogenetics in combination with closed loop reinforcement will be performed to dissect the pathways necessary for action learning. Neuronal activity imaging will then be performed on dopaminergic targets found to be important for action learning. The training plan, under the joint mentorship of Dr. Rui Costa and Dr. Stefano Fusi at Columbia University, will provide a complete set of neuroscience tools and the necessary career development resources for the applicant to obtain a faculty position and start an independent research program to explore the role of VTA dopaminergic neurons on the action learning process.
The ability to learn to perform specific motor movements is critical for many aspects of life, and is dysregulated in a range of neurological conditions such as Parkinson?s disease, Huntington?s diseases, and dementia. Dopaminergic cells provide a reinforcement signal to promote action learning, but how the brain uses these signals to explore the action space based on past rewarding experiences is not clear. The goal of the proposed project is to broaden our understanding of how dopaminergic cells act to promote action learning in mammals.