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Identification of distinct neuronal subpopulations has been essential for understanding brain function, but clinical applications struggle to access specific neurons in heterogeneously mingled populations. Recently, optogenetic protocols targeting neuronal subpopulations in the external globus pallidus (GPe) were shown to provide long-lasting therapeutic effects in dopamine depleted mice.

Here, we leverage underlying synaptic differences between Parvalbumin (PV) and Lim homeobox 6 (Lhx6) subpopulations to drive population-specific neuromodulation in the GPe, using brief bursts of electrical stimulation. We then apply these findings to strategically design a clinically appropriate deep brain stimulation (DBS) protocol, which we show induces long-lasting therapeutic effects that far exceed those of conventional DBS, extending for hours beyond stimulation. These results establish the feasibility of transforming knowledge about circuit architecture into quickly translatable therapeutic approaches.

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