A growing body of evidence suggests that social stress contributes to the pathogenesis of neurodegenerative diseases, such as multiple sclerosis (MS). For example, prior research has shown that social disruption (SDR) stress behaviorally and immunologically exacerbates Theiler’s murine encephalomyelitis virus (TMEV) infection. TMEV infection results in acute infection of the central nervous system (CNS) followed by a chronic demyelinating autoimmune disease, similar to that seen in MS. Research suggests that social stress exerts these effects by altering the immune response to infection. More specifically, it is hypothesized that SDR sensitizes the acute inflammatory response to infection and suppresses T cell effector function in the acute phase of disease. It was demonstrated that SDR is sufficient to alter inflammation. Exposure to a single session of SDR increases IL-­‐1β mRNA expression; however, IL-­‐6 mRNA expression, but not IL-­‐1β, is up regulated in response to chronic SDR. Furthermore, chronic SDR prior to infection resulted in increased infection related central IL-­‐6 and IL-­‐1β mRNA expression, and central administration of IL-­‐6 neutralizing antibody during SDR reverses this increase in neuroinflammation. This suggests that SDR sensitizes infection related CNS inflammation through an up-­‐regulation of IL-­‐6. Chronic SDR prior to infection also resulted in enhanced CNS viral titers and suppression of virus-­‐induced CD4 and CD8 T cell IFN-­‐γ release within the CNS. As a whole, this research indicates that SDR exacerbates the disease course of TMEV infection by altering the central innate and adaptive immune response to infection. This research enhances our understanding of the mechanisms by which social stress exacerbates neurodegenerative disease pathogenesis.

Stress is known to alter immune function, both in positive and negative ways. The disparate effects of stress on immune function remains an active area of investigation. This thesis investigates how the application of social disruption stress either prior to or concurrent with infection alters the neuropathogenesis of Theiler's murine encephalitis virus. Experiment 1 verified that social disruption prior to infection exacerbated the course of infection. Experiment 2 examined application of social disruption concurrent with infection, and found that this may produce a delay in symptom onset, and possibly a protective effect. Experiment 3 directly compared the two schedules to each other. The previous findings were replicated and expanded with additional measures (both behavioral and physiological) that further verified the earlier findings. Social disruption applied prior to infection resulted in greater behavioral and physiological exacerbation of the disease. Concurrently applied stress remained protective or inhibitory in the disease progression. Timing of stress is one of several quantitative aspects of stress that has been found to impact the stress-immune interaction and should be further investigated.