Date Approved
6-9-2025
Embargo Period
6-9-2027
Document Type
Dissertation
Degree Name
Ph.D.
Department
Biological and Biomedical Sciences
College
College of Science & Mathematics
Advisor
Melissa Manners, Ph.D.
Committee Member 1
Thomas Keck, Ph.D.
Committee Member 2
Maggie Panning Pearce, Ph.D.
Committee Member 3
Stephen Artim, V.M.D./Ph.D.
Committee Member 4
Daniel Manvich, Ph.D.
Disciplines
Biology | Life Sciences
Abstract
Toll-like receptors (TLRs) modulate downstream inflammatory signaling by inducing the synthesis of a variety of pro-inflammatory cytokines. Increased TLR levels are associated with elevated incidence of chronic stress-induced neuropsychiatric disorders, while reduced TLR expression is observed with therapeutic interventions like antidepressant treatment and exercise. Exercise inhibits neuroinflammation, reduces TLR expression and offsets the impact of chronic stress. This led us to hypothesize that the reduction of TLR signaling can promote resilience to chronic stress and could be a primary mechanism through which exercise induces resilience. First, we observed that voluntary wheel running promoted resilience to the behavioral effects of unpredictable chronic mild stress in male and female mice. We then identified TLR6 as a potential target, as reduced levels were measured in the hippocampi of exercised males resilient to chronic stress. Two miRNAs, miR-124 and miR-126, predicted to target TLR6 were upregulated in the hippocampi of male exercised mice. We identified miR-124 and miR-126 as critical regulators of TLR6 that can knock down its expression in vitro. We further observed a significant TLR6 knockdown in mice subjected to AAV-mediated hippocampal injections of miR-124 or miR-126. Finally, we observed that male mice exposed to unpredictable chronic mild stress post-injection with miR-124 or miR-126 were resilient to the physiological and behavioral effects of chronic stress. Our results suggest that TLR6 could be an important therapeutic target for the treatment of chronic stress-induced disorders.
Recommended Citation
Elias, Elias, "Toll-like Receptor 6 in Chronic Stress: Exercise and miRNA-Mediated Regulation of Neuroinflammatory Mechanisms of Resilience" (2025). Theses and Dissertations. 3380.
https://rdw.rowan.edu/etd/3380
