PROJECT SUMMARY Parkinson’s disease (PD) is a debilitating neurological disorder affecting up to 10 million people worldwide with symptoms of tremor, bradykinesia, and rigidity that severely limit the quality of life of patients. Deep brain stimulation (DBS) is an effective treatment used in patients who demonstrate symptoms that are inadequately controlled by medications. This treatment involves the delivery of continuous high frequency stimulation to either the subthalamic nucleus (STN) or the globus pallidus interna (GPi), two modulatory nuclei in the basal ganglia (BG). DBS improves motor symptoms acutely but does not differentiate between neuronal circuits, and its effects decay rapidly when stimulation is turned off. The need for constant stimulation increases the risk of side effects and the frequency of battery replacement. Hence the investigation of alternative patterns of stimulation that produce long-lasting recovery is critical. Such stimulation paradigms could minimize adverse outcomes caused by constant current delivery while also inducing therapeutic plasticity in the form of reversal of the aberrant synchronous activity of the BG seen in PD patients. Since the cellular mechanism of action of DBS is unknown, the clinical advances in identifying these patterns have been limited. Recent findings in the Gittis lab suggest that optogenetically manipulating distinct neuronal subpopulations (specifically, activating PV neurons and inhibiting Lhx6 neurons) in the external globus pallidus (GPe), a central nucleus of the BG, provides long-lasting reduction in immobility in dopamine-depleted mice that show bradykinesia or akinesia at baseline. In an effort to make this finding translatable, using insights from the synaptic features of these cell-types, we identified that electrical stimulation delivered in the entopeduncular nucleus (EPN, rodent homolog of the GPi) as bursts can produce the same cell-type modulation described above. Such a DBS protocol when tested in vivo produced motor recovery that lasted for hours after stimulation was stopped. These findings could hugely impact the standard of care for Parkinson’s disease patients that show a narrow therapeutic window, by maximizing their therapeutic duration, minimizing side effects, and potentially altering their pathological circuitry. The goal of this proposal is to demonstrate a clinically translatable optimized burst DBS protocol which can produce long-lasting motor recovery by reversing the underlying pathological activity in the BG. In an effort to optimize burst DBS from a translational standpoint, Aim 1 will establish the combination of stimulation frequency and duration required to see prolonged therapeutic benefits. To potentially accelerate the translation to PD patients with DBS implants in the STN, the effect of burst DBS in the STN will be compared to burst DBS in the EPN. Since patients show motor vs. non-motor symptoms at varying stages of the disease, Aim 2 will charac...