Henry Skelton
BME PhD Defense Presentation

Date: 2024-03-26
Time: 4PM
Location / Meeting Link: ENTICe Conference room, 6th floor, Woodruff Memorial Research Building, Emory/https://emory.zoom.us/j/92052421037

Committee Members:
Robert E. Gross, MD/PhD (Advisor); Nicholas Au Yong, MD/PhD; Nassir Mokarram, PhD; Machelle Pardue, PhD; Thomas Wichmann, MD;


Title: Reverse Engineering Exercise in Parkinson’s Disease Models

Abstract:
Parkinson’s Disease (PD) is a neurodegenerative condition affecting millions of people, involving the deterioration of the dopaminergic (DA) nigrostriatal tract with associated characteristic motor deficits. While existing treatments can alleviate those symptoms, they do not protect or restore the vulnerable cell population, and therapeutic gaps remain. Physical exercise is known to have unique therapeutic properties in PD, and may even be neuroprotective. Here, we hypothesized that the benefits of exercise were driven by the neurophysiological changes that it evokes, with the specific hypothesis that it promotes direct excitoprotection of the nigrostriatal DA cells. With this in mind, we aimed to identify the neurophysiology of exercise and replicate it as a neuroprotective, neuromodulatory intervention. To do so, we developed an adaptive wheel platform that provided for running exercise in the 6-hydroxydopamine mouse model of PD, as well as bioluminescent-optogenetic and ablative approaches to excite the nigral DA cell population. However, we did not observe neuroprotection with either intervention, though our ablative treatment did suppress behavioral hemiparkinsonism. Unexpectedly, we also found that running performance was not measurably impaired by the intractable motor lesion. Our exercise platform allowed us to test the mechanisms and physiology of exercise in the DA depleted state, showing that it provoked characteristic activity in the basal ganglia that could be suppressed, along with running itself, by further perturbing DA signalling. Overall, we believe that the paradigm of reverse engineering exercise holds promise, even in the absence of neuroprotection, as a way to investigate the mechanisms of retained motor performance in order to guide neuromodulatory therapies.