Date of Award

2019

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Heather Boger

Second Advisor

Kristi Helke

Third Advisor

Jacqueline McGinty

Fourth Advisor

DeAnna L. Adkins

Fifth Advisor

Monika Gooz

Sixth Advisor

Vanessa Hinson

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 7-10 million people worldwide. There are currently no disease-modifying therapies for PD, and treatments targeting motor symptoms are often associated with debilitating side effects. Degeneration in PD is marked by 1) loss of noradrenergic neurons of the locus coeruleus (LC-NE neurons) followed by 2) loss of dopaminergic neurons in the substantia nigra (SN-DA neurons). Vagus nerve stimulation (VNS) is approved by the Food and Drug Administration for treatment of epilepsy, depression, and cluster headaches. It is thought to work by activating LC-NE neurons and has multi-modal effects through decreasing neurodegenerative mechanisms relevant to PD such as neuroinflammation and oxidative stress. Therefore, VNS may have therapeutic potential for PD. The first part of this dissertation assesses the potential of VNS to improve PD-like symptoms and pathology in a double lesion rat model. We found that VNS improves motor deficits and attenuates loss of LC-NE and SN-DA neurons, as well as reducing neuroinflammation in these regions and reducing oxidative stress in targets of these nuclei. In addition, VNS has been shown to increase brain-derived neurotrophic factor (BDNF), and when it binds to its receptor tropomyosin-related kinase B (TrkB), activates cellular pro-survival mechanisms. In our double lesion PD model, BDNF is increased after VNS in targets of the LC and SN. Therefore, the focus of the second part of this dissertation is to determine whether BDNF-TrkB is the mechanism of action for beneficial VNS effects in this double lesion PD model. TrkB inhibition had no effect on behavioral improvements of VNS, and only partially prevented the ability of VNS to attenuate LC-NE loss. It did, however, prevent VNS effects in the nigrostriatal system on neuroinflammation and attenuation of SN-DA loss. Thus, while data from the nigrostriatal system indicate a role of TrkB for VNS, behavioral and LC data indicate that BDNF-TrkB is not the only mechanism through which VNS exerts benefits in our PD model, thereby pointing to its multi-mechanistic target value for the treatment of PD. Overall, these data indicate that VNS has great multi-modal potential as a PD therapeutic.

Rights

All rights reserved. Copyright is held by the author.

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