Neuron- and Circuit-Specific Mechanisms and Adaptations Regulating Motor Function in Parkinson Disease Models

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ABSTRACT Parkinson's disease (PD) is the second most common neurodegenerative disease (after Alzheimer's disease), afflicting tens of millions worldwide. The characteristic disease symptoms arise from basal ganglia dysfunction that occurs secondary to loss of dopamine neurons in the substantia nigra pars compacta. Symptomatic treatment is focused either on replacing dopamine or disrupting aberrant activity through deep- brain stimulation in the subthalamic nucleus or the primary basal ganglia output nucleus in the primate, internal globus pallidus (GPi). This proposal is aimed at understanding the function and dysfunction of basal ganglia circuitry in mice, at the output of the basal ganglia to motor thalamus. In Aim 1, we will develop strategies to identify basal ganglia-recipient motor thalamus neurons in ventral anterior/ventral lateral thalamus (VA/VL), and characterize their projection targets and cortical inputs in awake, behaving animals. In Aim 2, we will use sophisticated in vivo strategies to record from posterior EP neurons and VA/VL neurons as animals move their limbs during locomotion, a fixed repetitive behavior. We will perturb activity in this pathway using optogenetics to determine the contribution of activity in these neurons to forelimb movements, and we will examine how activity in this pathway is altered after loss of striatal dopamine. In Aim 3, we will perform similar experiments in mice performing a lever-pulling task, a flexible forelimb movement. We will examine both cued and uncued versions of this task to distinguish activity generated internally vs. externally. Finally, we will examine how loss of striatal dopamine impacts EP and VA/VL activity during flexible forelimb movements. Our overarching goal is to understand how loss of striatal dopamine in PD leads to disruptions in basal ganglia circuit function and motor deficits, in order to develop novel therapeutic strategies for treating PD motor symptoms.