Targeting the inflammatory response to treat post-traumatic anxiety and depression.

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The stress of deployment and exposure to traumatic events puts soldiers at a greater risk than the general public for the development of psychological disorders, including anxiety and depression, as well as post-traumatic stress disorder. These mental disorders occur with high comorbidity, and the prevalence of these conditions in Veterans of the recent Iraq and Afghanistan wars (OEF/OIF) is a concern of high significance for the VA. While a number of therapeutic options are available for the treatment of these conditions, they are marginally responsive to classical anxiolytic and antidepressant treatment when they develop as a consequence of traumatic stress exposure. Extensive research in the field of psychoneuroimmunology has indicated that these conditions are associated with dysregulated immune function, manifested as increased systemic inflammation and altered cellular and humoral immunity; which is believed to be a mechanism underlying the pathophysiology of these disorders. Our previous studies and others in the literature have shown that T cells are responsive to traumatic stress exposure and can influence behavioral responses of mice, conferring either resilience or susceptibility to stress depending upon the type of T cell and the cytokine milieu. Our preliminary results strongly indicate that CD8+ cytotoxic T cells are a major source of systemic and brain inflammation and promote susceptibility to develop maladaptive behavioral responses to stress. On the other side, our recently published study indicates that CD4+ T cells improve behavioral responses to stress, perhaps by reducing inflammation, in line with the work of others in the field. Thus, the overall objective of this application is to test, in a pre-clinical mouse model, the therapeutic efficacy of treating anxiety and depression by reducing inflammatory processes triggered by traumatic stress exposure. We propose to specifically manipulate CD4+ and CD8+ T cell mediated immunity to reduce systemic and brain inflammation, and improve behavioral outcomes. We propose 3 specific aims: Specific Aim 1 will identify mechanisms by which traumatic stress alters T cell functions by examining homing properties of CD4+ and CD8+ T cells in response to stress, and whether they develop alterations in glucocorticoid receptor sensitivity. To accomplish this we will reconstitute T cell deficient Rag2-/- mice with T cell subsets derived from green fluorescent protein (GFP) expressing mice, allowing for the tracking and identification of T cells in multiple tissues- including the brain. Additionally, we will conduct transcriptome analysis of T cells of stressed vs non-stressed wild type mice using RNA-sequencing (RNAseq) to identify pathways of T cell activation induced by traumatic stress. Specific Aim 2 is designed to determine the effects on behavior of manipulating CD4+ and CD8+ T cells in stressed mice. The approach will involve a) reconstitution in Rag2-/- mice with CD4+ or CD8+ T cells from stressed wild type mice, and b) the use of neutralizing antibodies against CD4+ or CD8+ T cells in stressed wild type mice. Following treatment, mice will be assessed for anxiety, behavioral despair, and startle reactivity as measures of emotional behavior. Specific Aim 3 will study the effects of manipulating CD4+ and CD8+ T cells on peripheral and brain inflammation. Plasma and tissue cytokine levels will be evaluated in peripheral tissue and brain; neuroinflammation will be further assessed using microglial cultures and flow cytometry. Finally, to determine if CD8+ T cells confer their effects through the actions of the cytokines TNF-α and IL-6. We will also block these cytokines in the presence of CD8+ T cells and determine if there is a reduction in neuroinflammation. The studies in this application are expected to provide proof of concept that CD8+ T cells are the main source of inflammatory processes triggered by traumatic stress exposure and it is possible to improve emotional regulation by targeting these cells. Furthermore, they may help identify unique mechanisms of stress induced T cell activation and novel targets of therapeutic intervention to treat stress related mental disorders.