Exploring the Role of the Globus Pallidus and its Inhibitory Projections to the Subthalamic Nucleus in the Generation of High Beta Oscillatory Activity in the Parkinsonian Rat

Exploring the Role of the Globus Pallidus and its Inhibitory Projections to the Subthalamic Nucleus in the Generation of High Beta Oscillatory Activity in the Parkinsonian Rat

Stephanie Pistorius
Brigham Young University

Abstract:

Parkinson’s disease (PD) is characterized by the death of dopamine neurons within the basal ganglia. Treatment with deep brain stimulation has made it possible to take recordings from PD patients during electrode implantation. These recordings have shown the presence of increased synchronized beta range (13-35 Hz) oscillatory activity within the basal ganglia. It is hypothesized that this synchronized oscillatory activity may contribute to the motor symptoms of PD. Electrophysiological studies on our hemiparkinsonian rats have shown that synchronized high beta (26-36 Hz) oscillatory activity is found throughout much of the basal ganglia thalamaocortical circuit. However, the origins of this oscillatory activity remain to be determined. It is hypothesized that the reciprocal connections of the external segment of the globus pallidus (GPe) and subthalmamic nucleus (STN) contribute to its generation. Thus, this study explores whether the GPe becomes entrained in this oscillatory activity, as is seen in the STN and motor cortex. This study uses awake, behaving hemiparkinsonian rats to study the spiking and local field potential (LFP) activity of the external segment of the globus pallidus (GPe). Data suggest an increase in LFP spectral power and an increase in coherence with the motor cortex (MCx) 21 days after dopamine depletion. In addition, phase locking data suggests significant phase locking of GPe spikes to GPe and MCx LFP. The results suggest that the GPe is entrained in this synchronized LFP activity and may play a role in its generation. Future studies will seek to characterize the types of GPe neurons projecting to the STN and utilize optogenetics and DREADDs to manipulate these populations and provide direct evidence implicating the GPe-STN reciprocal connections in the generation of this LFP activity. In preparation for these studies, a major goal of this project was to pilot a number of techniques that combine electrophysiological recordings with immunohistochemistry. A successful protocol was developed for the use of Fluorogold to trace the projections targeting the STN. Once projections from the GPe to the STN were confirmed, we immunostained for parvalbumin in efforts to begin separating subpopulations of GPe neurons. In order to take advantage of new technology available to manipulate populations of GPe neurons, pilot studies using DREADDs were performed. Rats were injected with the DREADD pAAV-hSyn –HA-HM3d(Gi)-IRES-mCitrine (N=2). This is a non-specific DREADD that should induce the expression of a novel receptor in the GPe allowing investigators to inhibit activity in all GPe neurons with the administration of clozapine-N-oxide. The rats for this pilot study are currently being analyzed for the expression of this receptor.