Dissertation Defense Announcement:

A novel dopamine depletion paradigm: Investigation of progressive circuit dysfunction in Parkinson’s disease

Amanda Willard
Carnegie Mellon University
Department of Biological Sciences

Monday, August 20th, 2018
10:00 AM
Mellon Institute Social Room (328)

Abstract
The development of animal models of Parkinson’s disease (PD) and assessing their electrophysiological differences has played a critical role in our understanding of basal ganglia function and the underlying mechanisms of PD. The wide range of animal models available and the quest to explore new ways to recover motor function have greatly enhanced our understanding of the remarkable reorganization that occurs in the brain following dopamine neurodegeneration. However, it remains unclear how and when pathophysiological features develop during the progression of the disease; information that could be critical to advancing the development of disease-modifying therapies. In order to address this question, we developed a novel paradigm for modeling progressive dopamine loss and used this paradigm, in addition to other well-studied animal models of PD, to investigate how and when basal ganglia activity changes in PD. First, we developed a gradual dopamine depletion mouse model by injecting multiple low doses of 6-OHDA over months to better recapitulate the slow progression of dopamine loss seen in PD. Behavioral assessment revealed a differential degradation of motor symptoms, with vertical movement declining linearly while horizontal movement remained robust until late stages. Interestingly, we found that motor coordination was significantly less impaired in animals that had undergone gradual depletions as opposed to acute depletions. These results establish a gradual depletion paradigm that can be used to study changes at various stages of dopamine loss, while modeling the progressive degeneration in PD so as not to preclude any compensatory plasticity that may be missing in more acute models. Next, we demonstrated a stereotyped, hierarchical progression of pathophysiology in the output nucleus of the basal ganglia using a number of animal models of PD. Briefly, firing rate changes occurred first at early stages of dopamine loss, followed by changes in firing pattern at more intermediate stages. The progression of pathophysiology was similar between two mechanistically different models of PD and end stage pathophysiology was similar regardless of the rate or lateralization of depletion. These results provide the first quantitative analysis of the trajectory with which the basal ganglia output breaks down over the course of progressive dopamine depletion. Taken together, these results demonstrate the complex interplay between the onset and progression of various motor deficits and pathological basal ganglia activity that develop due to the progressive degeneration of dopamine.

Committee:
Dr. Aryn Gittis (Advisor)
Dr. Sandra Kuhlman
Dr. Alison Barth
Dr. Robert Turner