Date of Award

Spring 4-25-2025

Embargo Period

4-28-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Wei Jiang

Second Advisor

Rachel Penrod-Martin

Third Advisor

Melinda Engevik

Fourth Advisor

Michael Scofield

Fifth Advisor

Steven Tomlinson

Abstract

Cocaine use disorder remains a significant public health challenge. However, the mechanisms by which chronic cocaine use contributes to neuroinflammation and cognitive decline are still not fully understood. Chronic non-intravenous cocaine use is associated with oral microbial dysbiosis. Although the gut-brain axis has been widely studied, the impact of cocaine-mediated shifts on the oral microbiome on systemic and neuroinflammation remains a significant yet largely unexplored gap. This dissertation investigates the hypothesis that cocaine-specifically enriched oral Streptococcus parasanguinis triggers neuroinflammation, neuropathology, and cognitive deficits. In a human study, the saliva microbiomes from chronic cocaine users exhibited reduced α-diversity, enriched Streptococcus genus, specifically S. parasanguinis at the species level, alongside decreased genera such as Neisseria, compared to non-drug users. In an in vitro study, cocaine explicitly promoted the growth of S. parasanguinis but not S. australis, S. thermophilus, or S. anginous. In a wild-type B6 mouse study with four groups (S. parasanguinis, S. salivarius, Neisseria flavescens, and vehicle control (carboxymethylcellulose), 3 months of oral inoculation with S. parasanguinis led to neuroinflammation (IL-1β), Aβ42 production in the brain, and impaired spatial memory using the Barnes Maze assay. The increased IL-1β levels were not determined in the oral swabs, gut, or serum samples from S. parasanguinis group compared to the three controls. Notably, increased Aβ42 production in the brain was also found in the two control microbiome groups but neuroinflammation and memory decline were not determined. RNAscope analysis of mouse brain tissue revealed increased resident microglial activation based on Iba1 and TMEM119 expression, and no bacterial DNA was detected. Metabolomic profiling of mouse oral swab samples identified the presence of a neurotoxic metabolite cysteine-S-sulfate in the S. parasanguinis-treated group only, which enhanced Aβ42 production in a HEK-293-APP cell line. Together, these findings suggest a synergistic effect of neuroinflammation and Aβ42 production on memory decline. Moreover, this work offers new insight into the intersection of substance use, host-oral microbiome interactions, and brain health, with implications for developing microbiome-informed approaches to address neuropathology in CUD.

Rights

Copyright is held by the author. All rights reserved.

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