EFFECT OF THE IMMUNE STRESS RESPONSE ON HYALURONIC ACID METABOLISM IN THE BRAIN UNDER CHRONIC STRESS CONDITIONS

Abstract

Hyaluronic acid (HA) is a glycosaminoglycan present in the extracellular matrix of the brain that has been shown to exhibit a wide range of cell signaling functions based on differing molecular weights metabolized by cells. For my thesis, I evaluated how HA metabolism of the brain is altered by and involved in the immune stress response under conditions of chronic stress in the presence of latent viral infection. Characterization of how HA is involved in the stress response has become an ever-increasing area of research associated with anxiety, depression, and even suicide. However, little has been revealed as to how HA metabolism is affected by stress and whether these changes are associated with pathological manifestation. Our murine model of chronic stress included four main groups with an additional baseline (N=6) control collected prior to experimentation. The remaining mice were divided in half comprising virally infected and non-virally infected groups. Virally infected mice were intranasally inoculated with murine herpes virus (MHV4) strain 68. The infected and non-infected mice groups were further divided into two more groups where animals were subjected to a 30-day period of chronic unpredictable mild stressors (CUMS model). The 4 groups in the study were designated Non-stressed/Non-Viral (S-V-; N=7), Stressed/Non-Viral (S+V-; N=8), Non-stressed/Viral (S-V+; N=8), and Stressed/Viral (S+V+; N=8). Following the 30-day period of stress the mice were sacrificed and key organs/tissues (brain, spleen, and blood plasma) were collected. During the stress period, animal weights were measured at regular intervals along with performing marble tests to gauge how the stressors were affecting behavioral reactivity of the mice. Statistically significant differences in food consumption and mice weights based on the presence of stress and viral infection were found. As well, lymphocyte subset distribution, systemic cytokine, and corticosterone levels were altered significantly enough to suggest active immune stress response in the animals. Gene expression of all hyaluronic acid synthase isoforms (HAS) were affected with the most changes (16-fold increase) in HAS-3, which produces pro-inflammatory low molecular weight HA (LMW-HA). An increased presence of LMW-HA could lead to an increased inflammatory state in the brain and contribute to psychological pathologies.