Stimulation of the Medial SNr Promotes Sustained Motor Recovery and Counteracts Parkinsonian Pathophysiology in Dopamine Depleted Mice

Dopamine loss alters the activity of neural circuits in the basal ganglia, contributing to motor symptoms of Parkinsons disease and catalepsy. Treatments that reduce basal ganglia pathophysiology alleviate motor symptoms but require maintenance. Cell-type specific interventions can reduce pathophysiology and provide sustained therapeutic benefits, but a lack of understanding of pathways involved limits translation. Here, we establish patterns of neuromodulation and electrophysiological biomarkers at the level of basal ganglia output that predict the duration of therapeutic effects. Focal activation of neurons in the ventromedial substantia nigra reticulata (SNr) engaged a gradual recovery of movement that persisted for hours after treatment, accompanied by a persistent reduction in parkinsonian pathophysiology. Global SNr inhibition, as prescribed by the classic rate model, provided only transient effects on movement and did not reverse network pathophysiology. These findings represent important steps towards developing therapeutic strategies that aim to repair, rather than simply mask, circuit dysfunction in disease.