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Background: Psychological and physical stress can either enhance or suppress immune functions depending on a variety of factors such as duration and severity of stressful situation. Chronic stress exerts a significantly suppressive effect on immune functions. However, the mechanisms responsible for this phenomenon remain to be elucidated. Autophagy plays an essential role in modulating cellular homeostasis and immune responses. However, it is not known yet whether autophagy contributes to chronic stress-induced immunosuppression. T cell immunoglobulin and mucin domain 3 (Tim-3) has shown immune-suppressive effects and obviously positive regulation on cell apoptosis. Tim-3 combines with Tim-3 ligand galectin-9 to modulate apoptosis. However, its impact on autophagy and chronic stress-induced immunosuppression is not yet identified. Results: We found remarkably higher autophagy level in the spleens of mice that were subjected to chronic restraint stress compared with the control group. We also found that inhibition of autophagy by the autophagy inhibitor 3-methyladenine (3-MA) significantly attenuated chronic stress-induced alterations of pro-inflammatory and anti-inflammatory cytokine levels. We further elucidated that 3-MA dramatically inhibited the reduction of lymphocyte numbers. Moreover, chronic stress dramatically enhanced the expression of Tim-3 and galectin-9. Inhibition of Tim-3 by small interfering RNA against Tim-3 significantly decreased the level of autophagy and immune suppression in isolated primary splenocytes from stressed mice. In addition, α-lactose, a blocker for the interaction of Tim-3 and galectin-9, also decreased the autophagy level and immune suppression. Conclusion: Chronic stress induces autophagy, resulting with suppression of immune system. Tim-3 and galectin-9 play a crucial regulatory role in chronic stress-induced autophagy. These studies suggest that Tim-3 mediated autophagy may offer a novel therapeutic strategy against the deleterious effects of chronic stress on the immune system.

Objectives: Mental and physical stress can suppress the immune system in both humans and animals. The mechanism by which stress affects immune responses, however, remains poorly defined. Toll-like receptors (TLRs) play a key role in modulating immune responses and cell survival. The mechanisms by which TLRs modulate chronic stress are largely unexplored. Methods: Six- to 8-week-old male mice were subjected to chronic 12-hour daily physical restraint stress. Apoptotic cells were determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. We examined cytokine levels by enzyme-linked immunosorbent Assay (ELISA). The expression of CYP11A1 was determined by quantitative real-time RT-PCR. Results: TLR9-deficient mice were resistant to chronic stress-induced lymphocyte apoptosis. In addition, in TLR9 knockout (KO) mice, chronic stress-induced upregulation of corticosterone levels was significantly decreased. Notably, lymphocytes from both TLR9 KO and wild-type mice were similarly sensitive to corticosteroid-induced cell apoptosis. Moreover, TLR9 deficiency blocked the chronic stress-induced imbalance in T helper (Th) 1 and Th2 cytokine levels. Conclusion: Taken together, our findings reveal that TLR9 plays an essential role in chronic stress-induced immune suppression.

Objectives: Mental and physical stress can suppress the immune system in both humans and animals. The mechanism by which stress affects immune responses, however, remains poorly defined. Toll-like receptors (TLRs) play a key role in modulating immune responses and cell survival. The mechanisms by which TLRs modulate chronic stress are largely unexplored. Methods: Six- to 8-week-old male mice were subjected to chronic 12-hour daily physical restraint stress. Apoptotic cells were determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. We examined cytokine levels by enzyme-linked immunosorbent Assay (ELISA). The expression of CYP11A1 was determined by quantitative real-time RT-PCR. Results: TLR9-deficient mice were resistant to chronic stress-induced lymphocyte apoptosis. In addition, in TLR9 knockout (KO) mice, chronic stress-induced upregulation of corticosterone levels was significantly decreased. Notably, lymphocytes from both TLR9 KO and wild-type mice were similarly sensitive to corticosteroid-induced cell apoptosis. Moreover, TLR9 deficiency blocked the chronic stress-induced imbalance in T helper (Th) 1 and Th2 cytokine levels. Conclusion: Taken together, our findings reveal that TLR9 plays an essential role in chronic stress-induced immune suppression.

Stress can either enhance or suppress immune functions depending on a variety of factors such as duration of stressful condition. Chronic stress has been demonstrated to exert a significant suppressive effect on immune function. However, the mechanisms responsible for this phenomenon remain to be elucidated. Here, male C57BL/6 mice were placed in a 50-ml conical centrifuge tube with multiple punctures to establish a chronic restraint stress model. Serum IL-10 levels, IL-10 production by the splenocytes, and activation of STAT3 in the mouse spleen were assessed. We demonstrate that IL-10/STAT3 axis was remarkably activated following chronic stress. Moreover, TLR4 and p38 MAPK play a pivotal role in the activation of IL-10/STAT3 signaling cascade. Interestingly, blocking antibody against IL-10 receptor and inhibition of STAT3 by STAT3 inhibitor S3I-201 attenuates stress-induced lymphocyte apoptosis. Inhibition of IL-10/STAT3 dramatically inhibits stress-induced reduction in IL-12 production. Furthermore, disequilibrium of Th1/Th2 cytokine balance caused by chronic stress was also rescued by blocking IL-10/STAT3 axis. These results yield insight into a new mechanism by which chronic stress regulates immune functions. IL-10/STAT3 pathway provides a novel relevant target for the manipulation of chronic stress-induced immune suppression.

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This experiment explored whether a long-term aerobic exercise program may induce significant structural and functional changes in the hippocampus, an area of the brain that is important for spatial navigation and memory formation. Based on existing rodent studies, we hypothesize that exercise will cause a shift to allocentric processing, away from a less robust egocentric learning strategy. It is possible that exercise-induced relief of chronic stress, which contributes to improved hippocampal function, will increase reliance on allocentric spatial navigation. Neurogenesis, which occurs in the dentate gyrus region of the hippocampus, is another indicator of hippocampal function that may influence this shift to allocentric learning. The current study examines whether six weeks of aerobic exercise enhances allocentric processing in healthy young adults. Forty-nine young adults (35 female; age range 18-29 years) were randomly assigned to one of three groups: 1) High intensity interval training group, 2) Moderate intensity training group, or 3) Non-exercising control group. Hippocampus-dependent memory was assessed before and after the intervention on a Virtual Reality Water Maze task, and a high interference memory task, the Mnemonic Similarity Task (MST) which may be dependent on hippocampal neurogenesis. Levels of chronic stress and depression were measured using the Beck Depression Inventory II. It was expected that exercise would improve spatial memory performance on the water maze task, and that performance would improve in proportion to enhanced fitness levels. This improvement in spatial memory performance was expected to correlate with the two indicators of hippocampal function that were assessed in the current study—chronic stress and performance on the high interference memory task. Six weeks of regular aerobic exercise resulted in a 21.5% improvement in spatial memory performance on the water maze task, indicating improved hippocampus-mediated spatial memory function. Improvements displayed by high intensity exercisers were greater than those observed in the moderate intensity exercisers, suggesting that higher intensity exercise may be more effective in enhancing hippocampal function. Importantly, low responders to exercise exhibited a 30% improvement in water maze performance, suggesting that even minor fitness improvements can lead to significant cognitive gains. Chronic stress and depression, and performance on the MST were not significantly associated with changes in spatial memory performance; however trends observed may offer some explanation to the aforementioned changes in spatial memory. Findings from the current study have important implications for treatment options in populations that are currently, or at risk of suffering from impaired hippocampal function. / Thesis / Master of Science (MSc)

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ABSTRACT The Implications of Chronic Stress on Obesity: Allostatic Load on Body Mass Index (BMI) Classification in the United States, NHANES 2005-2006 INTRODUCTION: In this modern environment, our world is reflecting an exponential increase in not only population, but in body size. Obesity is an overwhelming public health concern among the United States population. Research has shown there is a positive correlation between adiposity and stress. Allostatic load (AL) has been presented to be a consistent measure of chronic stress damage on the body. Yet, there is few studies exemplifying the presence AL on classification of body mass index (BMI). AIM: The aim of this study is to find a relationship between allostatic load (AL) and body mass index (BMI) classification in the United States adult population on a large national scale. This complex interaction can predetermine who among the US population will be at greater risk for excess adiposity following this psychoneuroendocrinology. METHODS: A representative sample size of n=3826 was gathered using NHANES data (2005-2006). Criteria for sample included all United States adults that had numerical values for 10 biomarkers chosen to represent chronic stress damage (allostatic load) along with individual body mass index (BMI). Allostatic load (low, high) and BMI classification (underweight to class III obese) were further categorized on severity and computed in SPSS to find significance between gradients of each variable (α=.05). Cross-sectional analysis and logistical regression (multivariate) were used to further decipher an association between allostatic load and BMI category. RESULTS: A strong positive correlation between allostatic load risk and BMI category was found (p<.001). Also among the variables in the study, significance was found within the strata of age, gender, race, smoking status and poverty income ratio (PIR). Findings show a strong statistically significant relationship between allostatic load and BMI. DISCUSSION: It is imperative to decipher the directional relationship between stress and obesity to provide effective treatment. Understanding the pathology of how stress affects adiposity could open the door for many clinical and public health interventions to eradicate a very preventable outcome. By addressing the effect of chronic stress, a new avenue of prevention can be developed to combat the growing obesity rates in the United States.