Exercise and TLR: Mechanisms underlying resilience to chronic stress

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Stress is an inevitable and normal part of daily life, and activation of the stress response is vital for survival. However, chronic stress can have a negative impact on mental health and wellbeing, and lead to mental illness in susceptible individuals. We do not fully understand how chronic stress impacts behavior, but one way of investigating this issue is to determine mechanisms that promote protection from chronic-stress induced behaviors. In recent years, inflammation from chronic stress has been associated with the development of mental disorders. Inflammatory factors are elevated in individuals suffering from Major Depressive Disorder, Anxiety, and Neurodegenerative Disorders, which could underly the progression of these diseases. Similar inflammatory mediators are also upregulated in mouse models of inflammatory and chronic stress. We found that TLR1, a toll- like receptor involved in downstream inflammatory response, was upregulated in the hippocampus of stressed mice, however, voluntary exercise during the chronic stress paradigm protected mice from upregulated TLR1, and behavioral changes associated with chronic stress. In this proposal, we will determine if TLR1 modulation has a role in resilience to the behavioral and inflammatory response to chronic stress. Exercise has long been known to induce positive effects on physical and mental health, and it is also associated with reduced inflammatory factors. Our preliminary data indicates that voluntary exercise during chronic stress promotes a protective phenotype in behavioral tests of hyponeophagia, avoidance, spatial memory recognition, and weight loss in both male and female mice. In this proposal, we will enhance our knowledge of the mechanisms underlying resilience to chronic stress. We hypothesize that hippocampal TLR1 activation is a central mechanism for this effect. Our aims are to (1) determine if voluntary exercise protects from the effects of chronic stress and prevents the stress-induced increase in hippocampal TLR1, (2) identify downstream inflammatory factors affected by chronic stress +/- voluntary exercise and determine if micro-RNA regulators of TLR1 are disrupted due to chronic stress, (3) and determine if TLR1 deficiency is a mechanism underlying resilience to chronic stress. To pursue these aims, we will conduct a mechanistic molecular and behavioral study with a primary focus on training undergraduate researchers. In accordance with the goals of the R15 mechanism, undergraduate students will be central to all aspects of the study design, data collection, analysis, interpretation, and presentation of data. Conducting these types of preclinical studies is essential for training the next generation of researchers and progression of the field.