Our ability to learn and produce action sequences underlies much of what we do: be it communicating through writing, playing instruments, or simply tying shoelaces. Our reliance on these skills leaves us vulnerable to a wide range of brain disorders such as obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, Parkinson’s, and Huntington’s diseases which affect the basal ganglia circuits involved in their acquisition and execution. Our ability to help patients critically depends on a better understanding of basal ganglia function. Yet the principles of basal ganglia function and dysfunction in health and disease conditions remain elusive. The goal of this proposal is to combine objective, unsupervised behavioral clustering, cell-type-specific Cal-light tagging, and closed-loop optogenetic manipulation to test the hypothesis that activities of action-specific striatal ensembles are channeled through unique sets of output neurons that project to different target areas; therefore, modulating specific behaviors (e.g. locomotion, turning, reaching, rearing, etc.). During the K99 phase, I will test the hypothesis that the striatopallidal pathway can function as an action promoting pathway via direct output channels from the external globus pallidus (GPe) to parafascicular nucleus in the thalamus (GPe¿Pf) and pedunculopontine nucleus in the brainstem (GPe¿PPN). I will test the hypothesis that the GPe¿PPN projection is mainly involved in the control of locomotion whereas GPe¿Pf projection contributes to the initiation and execution of learned lever press. During the R00 phase, I will use a novel Cal-light system to tag action-specific spiny projection neurons (SPNs) and parse out diverse action-specific SPNs that go beyond the conventional view of direct versus indirect pathways. I will test the hypothesis that different subpopulations of GPe neurons receive input from unique action-specific SPNs, such that GPePPN neurons receive biased input from locomotion- specific SPNs while GPePf neurons are preferentially innervated by lever-pressing-specific SPNs. This work and career development plan will be conducted in the vibrant research community at Columbia University under the supervision of Dr. Rui Costa and Dr. Hyungbae Kwon from Johns Hopkins University. In addition to technical expertise, both Drs. Costa and Kwon have an impressive track record of successful trainees. The candidate has also assembled a team of expert collaborators, including Dr. Darcy Peterka, Dr. Luke Hammond, Dr. Tanya Tabachnik, and Dr. David Ng. The entire mentoring team will guide the candidate in technical and professional training. Together, the proposed experiments will provide a mechanistic, circuit-level understanding of action-specific basal ganglia subcircuits that goes beyond the classical model. This work will have profound implications for a range of psychiatric and neurodegenerative diseases, with the potential to identify novel therapeutic targets. Additionally, all viral reagents, the new Cal-light tagging platform, mouse lines, and the computational tools developed and tested in this proposal will be shared with the broader neuroscience community to accelerate discoveries in other labs.
