Project Summary The external segment of the globus pallidus (GPe) is a neuronally diverse and highly interconnected nucleus within the basal ganglia. Under conditions of low dopamine, plasticity in the GPe promotes the emergence of pathological firing patterns that contribute to widespread basal ganglia dysfunction. In Parkinson’s disease (PD), deep brain stimulation (DBS) in the GPe can alleviate motor symptoms, suggesting there is a mechanistic link between neuronal dysfunction in the GPe and motor symptoms of PD. Using optogenetics to target neuronal subpopulations in the GPe, we discovered that persistent behavioral rescue could be induced by interventions that excited parvalbumin-expressing GPe neurons (PV-GPe) and inhibited Lim homeobox 6-expressing GPe neurons (Lhhx6-GPe). Differences in the synaptic inputs onto these neuronal subpopulations enabled us to develop a human-translatable electrical DBS protocol that could achieve the same cell-type specificity of optogenetics. In parkinsonian mice, these circuit-inspired burst DBS protocols provided superior therapeutic benefit over conventional protocols, extending the therapeutic duration for hours beyond the period of active stimulation. We are now collaborating with neurosurgeons at Allegheny General in Pittsburgh to test the therapeutic efficacy of circuit-inspired DBS protocols in humans. Results from in vivo physiological recordings revealed that GPe interventions reverse parkinsonian pathophysiology in the basal ganglia for hours following stimulation, raising the intriguing possibility that GPe interventions induce therapeutic plasticity that restores circuit function in disease. This would represent a transformative advance in PD therapeutics. But a number of questions still remain about how transient interventions in the GPe translate into long-lasting therapeutic effects at the behavioral level. This proposal will use electrophysiological, optogenetic, and behavioral approaches to identify the therapeutic mechanisms of persistent behavioral rescue by achieving three main goals: (1) We will map the neural pathways required for persistent behavioral rescue, including testing an innovative hypothesis that both motor and arousal circuits are involved (2) We will identify short-term and long-term effects of GPe interventions on basal ganglia physiology, testing the hypothesis that GPe interventions drive therapeutic plasticity in dopamine depleted mice, and (3) We will assess the therapeutic efficacy of GPe interventions delivered at different stages of dopamine depletion on both motor and non-motor symptoms to further study the neural circuits involved, as well as to advance preclinical testing of GPe interventions for continued therapeutic development. These studies will advance the development of circuit-inspired approaches that repair, rather than mask circuit dysfunction for long-term recovery of brain function in disease.

Project Narrative The identification of distinct cell-types throughout the basal ganglia has been essential in advancing our understanding of network function and improving neurological therapies. This proposal seeks to understand the cellular mechanisms by which cell-type specific interventions in the external segment of the globus pallidus (GPe) restore basal ganglia function in mouse models of Parkinson’s disease to provide long-lasting therapeutic effects.