PROJECT SUMMARY
Patients with Parkinson’s disease (PD) experience progressive motor impairments that lead to severe disability.
The motor impairments of PD are associated with abnormal neuronal activity in the basal ganglia, a group of
brain structures involved in movement planning and execution. The long-term goal of our research is to elucidate
how the abnormal activity of the basal ganglia relates to the motor deficits in PD, with the goal of developing
novel therapies to treat parkinsonism with improved specificity and fewer unwanted side effects. The proposed
studies are focused on the external segment of the globus pallidus (GPe), a key structure in the basal ganglia
circuitry. Traditionally, the GPe was thought to be composed of a single neuron type; it is now established that
this nucleus contains different types of neurons that can be classified based on their projection targets
(‘upstream’ to the striatum, or ‘downstream’ to the subthalamic nucleus or internal pallidum). In rodent models of
PD, there is evidence that PD-related abnormalities occur selectively in specific types of GPe neurons, raising
the possibility that different GPe neuron populations might make distinct contributions to the normal and
pathological roles of the GPe. However, the translational relevance of these findings is limited by functional and
anatomical differences between the rodent and primate GPe. Our experiments will define functional differences
between classes of GPe neurons in normal rhesus monkeys and in monkeys rendered parkinsonian by treatment
with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Monkeys are an excellent animal
model for studying PD-related changes in brain activity, because their basal ganglia and connected brain
structures closely resemble those in humans, and because MPTP-treated monkeys show the majority of the
motor impairments seen in PD patients. We will use electrophysiological in vivo recordings to evaluate
differences in the firing rates and patterns of GPe-upstream and GPe-downstream neurons. The projections of
individual GPe neurons will be identified by their antidromic responses to electrical stimulation of the target
structures (aim 1). To determine how GPe neurons modulate the activity in the striatum, subthalamic nucleus or
internal pallidum, we will selectively silence GPe axonal terminals in each of these nuclei, using optogenetic
methods. We will also determine whether selective silencing of GPe terminals alters PD-motor impairments in
monkeys (aim 2). Finally, we will use histologic techniques to identify proteins whose expression reveals specific
GPe neuron projection patterns (aim 3). Our studies will begin to determine how the activities of primate GPe
neuron subtypes differ, how they regulate the activity in other basal ganglia neurons in the normal and
parkinsonian states, and whether they are involved in the pathophysiology of parkinsonism. The knowledge
gained from these studies is significant, as it may enable us to develop new treatments for PD that harness
functional and anatomical differences of GPe neuron types.
