Parkinson’s Disease (PD) is one of the most common neurological disorders in the world. Existing treatments for PD do not cure the disease and come with considerable limitations and side effects. This underscores the importance of further study in the mechanisms and treatments for the disease. A hallmark of PD is slowness of movement (“bradykinesia”), which results from changes in basal ganglia activity following dopamine (DA) loss. A recent discovery has demonstrated that optogenetic stimulation of specific cells in the external capsule of the globus pallidus (GPe) results in a persistent rescue of motor impairments in a mouse model of PD. In this rescue, strong optogenetic excitation by channel rhodopsin (ChR2) expressed in inhibitory parvalbumin positive neurons (PV-GPe) allowed mice to regain movement for 6-12H after stimulation. However, how this occurs is entirely unknown. Following DA loss, GPe activity is reduced and output nuclei become overactive. At the same time, DA loss results in pathological bursting in GPe and downstream nuclei, such as the substantia nigra pars reticulata (SNr). Preliminary evidence suggests PV-GPe connections to SNr become stronger, and often excitatory, following DA loss. These changes could offer new insight into the mechanisms that lead to SNr bursting and may serve as key targets of intervention in optogenetic GPe rescue. This proposal will determine the changes in PV-GPe to SNr connectivity caused by DA loss and measure the effects of optogenetic GPe rescue on these connections. The hypothesis is that DA loss changes the strength and sign of PV-GPe to SNr connectivity and that PV-GPe stimulation reduces this connectivity via long-term synaptic depression. The proposal will test these hypotheses by first measuring if DA loss changes the strength of PV- GPe to SNr and determining whether this connectivity is decreased after optogenetic rescue (Aim 1). This will involve in vivo measurements of functional connectivity, as well as acute brain slice measurements of synaptic plasticity that incorporate optogenetics, pharmacology, and cutting edge electrophysiology and histological techniques. The proposal will then test whether DA loss makes PV-GPe to SNr connections excitatory (Aim 2). This is a previously unrecognized change that preliminary evidence now supports. Based on an extensive review of inhibitory literature and preliminary data, the proposed experiments will test whether DA loss causes 1) co-release of glutamate by PV-GPe synapses or 2) a change in the chloride reversal potential of postsynaptic SNr cells. Uncovering the connectivity changes that occur following DA loss will reveal valuable information on neuropathology related to PD and strongly inform network based models of the disease. This proposal provides extensive training opportunities through the inclusion of numerous methodologies that are novel to the applicant, including optogenetics, slice physiology, cell-type specific dissection of circ...