Date of Award

Fall 2023

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Lawrence Reagan

Abstract

Gulf War Illness (GWI) is a multi-symptom illness that presents with cognitive disturbances and immune dysregulation and continues to affect over 25% of Gulf War veterans. While soldiers were exposed to several hazards in the Gulf, the prophylactic use of the acetylcholinesterase inhibitor, pyridostigmine bromide (PB) and war-related stress have been identified as chief factors in GWI pathology. As both PB and stress alter acetylcholine (ACh), a critical mediator of cognition and inflammation, the focus of my dissertation work was investigating the lasting effects of PB and stress on peripheral and central cholinergic signaling. Specifically, I assessed hippocampal-dependent learning and memory, inflammatory markers, and cholinergic neurochemistry in a previously established rat model of GWI consisting of PB treatment and repeated restraint stress (RRS). Interestingly, many clinical studies have found that GWI patients exhibit exaggerated cognitive deficits following a stressful stimulus such as an exercise challenge. Thus, I also investigated how an innate immune or stress challenge may alter cholinergic responses and behavior. Results indicate that a history of PB treatment elicits 24-hour hippocampal-dependent memory deficits when challenged with low-dose lipopolysaccharide (LPS, 30 µg/kg) or the stress of swimming. However, PB-treated rats did not exhibit any impairments in memory acquisition. By assessing peripheral and central inflammatory responses to LPS, I report that PB treatment produces exaggerated inflammatory responses that emerge long-after treatment cessation and likely contribute to the observed 24-hour memory impairments. Lastly, using in vivo microdialysis, I found that within the hippocampus, PB-treated rats exhibited potentiated cholinergic response to both immune and stress challenges over three months after treatment cessation. Conversely, this potentiated cholinergic response was only observed in the PFC of rats previously subjected to PB and RRS and challenged with LPS. These findings suggest that PB has lasting effects on hippocampal-dependent memory and dysregulates the cholinergic anti-inflammatory pathway in this region, but not the PFC. My studies also illustrate the latent phenotype of GWI and how deficits are best observed following a physiological stressor. Lastly, my results identify the cholinergic anti-inflammatory pathway as a potential site of therapeutic intervention to alleviate the progressive cognitive affecting GWI patients.

Rights

© 2024, Hannah Elizabeth Burzynski

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