PROJECT SUMMARY A major limitation of dopaminergic therapy for Parkinson’s disease (PD) is motor response “wearing-off” within a few hours after the dose. Although the field has focused on prolonging the short-duration (acute) response of each dose using more persistent drug preparations and delivery methods, these pharmacological approaches have limited and short-term benefits. Wearing-off is driven by a decline in the duration of benefit of each dose, due to the decay of the long-duration response (LDR) that lowers the trough level performance. We recently showed the importance of task-specific learning and the striatopallidal pathway in LDR induction and decay. Interestingly, our preliminary data suggest that repeated optogenetic stimulations of globus pallidus externa (GPe) parvalbumin (PV)-expressing neurons – part of the striatopallidal pathway – induced long-term rescue: mice showed improved locomotion when reintroduced to the same open-field environment ≥24 h after the final stimulation session. This resembled LDR induced by repeated L-DOPA treatments. However, while LDR induced by L-DOPA was selective to the induction context, LDR induced by stimulation of GPe PV+ neurons transferred to a new context. Thus, repeated stimulation of GPe PV+ neurons conferred long-term motoric benefits but may also reduce discrimination learning. This project aims to uncover the mechanisms underlying these properties of LDR. GPe PV+ neurons consist of two subpopulations: those that project to substantia nigra vs. to parafasicular thalamus. We will establish how the activities of these two GPe subpopulations are altered during parkinsonian locomotion impairment and during different phases of LDR, both for LDR induced by L-DOPA and by GPe PV+ neuronal stimulation. We will also examine whether perturbing these two GPe subpopulations results in dissociable effects on long-lasting locomotion rescue vs. its context selectivity. This project will advance our knowledge in the role of the striatopallidal pathway in mediating LDR, and elucidate both therapeutic utility and potential side effects of GPe deep brain stimulation.