It has been long recognized that the relationship between psychosocial stress and somatic health is bi-directional: psychosocial stress affects general health status and somatic disease influences coping responses to stress. However, the mechanisms of this relationship remain poorly understood. Research from our laboratories and others has shown that the immune system is a nexus, interfacing between the central nervous systems and peripheral organ systems. Recent studies in mice indicate that T lymphocytes are protective against the development of maladaptive behavioral responses to stress. These studies are in agreement with our preliminary results suggesting that the T cell deficient RAG2-/- mice is more susceptible to the development of maladaptive behavioral responses to stress after acute or chronic stress exposure, and that reconstitution with CD4+ T cells from wild type mice restore adaptive responses to stress. Furthermore, our previous studies also indicates that miss-directed CD4+ T cell function, such as those seen in chronic inflammatory diseases, results in maladaptive behavioral stress responses. The objective of the present application is to further establish the bi-directional role played by CD4+ T cells in stress responsiveness and to enhance knowledge regarding mechanisms conferring resilience or susceptibility to psychosocial and other stress related disorders. The central hypothesis is that T cells will transiently traffic to the brain after stress exposure where they will stimulate the production of neurotrophic factors and cytokines, ultimately resulting in protection or aggravation of behavioral coping responses to stress. We further hypothesize that the mechanism of CD4+ T cell activation will determine the pattern of neurotrophic factor or cytokine expression. We will employ the RAG2-/- deficient mouse model, which lack functional T and B cells. We will reconstitute these mice with T cells by adoptive transfer and assess their behavior in models of acute and chronic stress. In vitro activation of T cells against environmental antigens will be applied to test differential mechanisms of activation. BALB/c wild type, RAG2-/-, and RAG2-/- mice reconstituted with T cells will be evaluated in the learned helplessness paradigm or in the social isolation model of stress. Immunohistochemistry and in situ hybridization histochemistry will be employed to analyze the presence of CD4+ T cells in the brain and the expression of neurotrophic factors. Real-time RT-PCR will be used to compare cytokine mRNA expression in the brain to evaluate brain inflammatory responses and the effects of T cell treatment. Lastly, blockade of glucocorticoid receptor function after stress exposure by administration of RU486 will be employed to evaluate the role of hormonal responses to stress known to mediate either homeostatic or deleterious effects of stress. These studies will provide insight into cellular mechanisms of resilience to psychogenic stress that when stimulated may provide regenerative and repair functions in the brain and restore normal stress responses and behaviors.
Mechanisms underlying the bi-directional relationship between psychological stress and organ systems are poorly understood. The present application will employ a genetically engineered mice model to study the role played by the CD4+ T lymphocyte subtype as key cellular entities conferring susceptibility or resilience to psychogenic stress and emotional behaviors. This information will significantly advance our understanding of the mind-body connection, and its role in mediating susceptibility to somatic disease.
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|Clark, Sarah M; Pocivavsek, Ana; Nicholson, James D et al. (2016) Reduced kynurenine pathway metabolism andÂ cytokine expression in the prefrontal cortex ofÂ depressed individuals. J Psychiatry Neurosci 41:386-394|
|Clark, Sarah M; Soroka, Jennifer A; Song, Chang et al. (2016) CD4(+) T cells confer anxiolytic and antidepressant-like effects, but enhance fear memory processes in Rag2(-/-) mice. Stress 19:303-11|
|Clark, Sarah M; Michael, Kerry C; Klaus, Joseph et al. (2015) Dissociation between sickness behavior and emotionality during lipopolysaccharide challenge in lymphocyte deficient Rag2(-/-) mice. Behav Brain Res 278:74-82|
|Clark, Sarah M; Sand, Joseph; Francis, T Chase et al. (2014) Immune status influences fear and anxiety responses in mice after acute stress exposure. Brain Behav Immun 38:192-201|