In Parkinson's disease (PD), the basal ganglia (BG), a set of highly interconnected subcortical structures, are fundamentally altered due to the chronic loss of dopamine in the system. A leading hypothesis places the globus pallidus externa (GPe) as major component in this circuit dysfunction. The GPe is a central nucleus in the motor-suppressing pathway that has historically has been identified as a homogenous population of neurons and thus a uniform role in BG function. Cell type diversity in BG nuclei is common and uncovering the role of cell-types has significantly improved our understanding of circuit function and dysfunction. Recent studies have revealed pallidal populations based on anatomical projections, in vivo spike activity, and post- mortem tissue analysis that challenge classical models and provide functional roles for pallidal neurons based on connectivity differences. Though these classifications have been largely beneficial, they have been difficult to generalize across models and preparations. Therefore, we have identified two genetically distinct populations of neurons that differ in their topographic distribution, intrinsic physiology and axonal projections. The GPe population that expresses parvalbumin (PV-GPe) projects more strongly to the subthalamic nucleus (STN) and sends a distinct output projection to the parafascicular nucleus of the thalamus (pf). Most notably, optical stimulation of PV-GPe projections does not alter gross locomotion in health animals but recues motor impairments in conditions of low dopamine. Thus, the primary objective of this proposal is to identify behavioral and synaptic correlates of a genetically distinct population of GPe neurons in health and disease.
Aim 1 will investigate the role of two distinct output projections to brain areas importan for movement initiation (STN) and behavioral flexibility (pf) during control (saline) and dopamine-depleted (6-OHDA) conditions. Here, we will optically stimulate the PV-GPe projections to access the behavioral effect in these defined regions in health and determine which projection is most important to target for the restoration of motor control in disease. To understand how the circuit is altered after dopamine loss, Aim 2 will determine the anatomical and synaptic alterations in these two projection targets by measuring the evoked synaptic response of PV-GPe axons in the STN and pf using optical stimulation. To test whether the alterations in synaptic inputs is differential altered based on the genetically-defined populations, Aim 3 will use a combination of electrical and optical stimulation to identify sources of change in PV-GPe synaptic inputs in control and dopamine-depleted conditions. Together, we will test the hypothesis that PV-GPe neurons play a critical role in the behavioral and synaptic dysfunction associated with movement impairments. The long-term goal is to uncover the therapeutic potential of targeting a distinct neuronal population in the treatment of debilitating movement dysfunction in Parkinson's.
Parkinson's disease (PD) is a debilitating movement disorder that affects millions of individuals worldwide and is characterized by dysfunction in the basal ganglia. The external segment of the globus pallidus (GPe) is a central nucleus in the basal ganglia that has been heavily implicated in the development, maintenance and progression of neurodegenetive disorders such as PD. This study aims to determine how a distinct population of GPe neurons participate during health and disease that would provide the basis for therapeutic treatments to specifically influence this subset of neurons and treat aspects of movement dysfunction in Parkinson's.
| Mastro, Kevin J; Zitelli, Kevin T; Willard, Amanda M et al. (2017) Cell-specific pallidal intervention induces long-lasting motor recovery in dopamine-depleted mice. Nat Neurosci 20:815-823 |
