A Novel Dopamine Depletion Paradigm: Investigation of Progressive Circuit Dysfunction in Parkinson’s Disease

2018-10-11T18:26:12Z (GMT) by Amanda Willard
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. Here, 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.<br>First, we developed a gradual dopamine depletion mouse model by injecting multiple low doses of the neurotoxin 6-OHDA over months to better recapitulate the slow progression of dopamine loss seen in PD. Behavioral assessment of these animals throughout the progression of dopamine loss 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 depletion models.<br>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 provided the first quantitative analysis of the trajectory with which the basal ganglia output physiology breaks down over the course of progressive dopamine depletion.<br>In the final chapter, we discuss the evolving field of animal models of PD and potential physiological correlates of motor function based on current treatments effects on physiology and other studies of pathophysiology leading up to motor symptom onset. 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.<br>