The overarching concept in this proposal is that social interactions matter to the level of gene expression. A model of repeated social defeat will be used to elucidate the pathways and mechanisms by which social stress affects peripheral physiology. The target physiological system is the immune system, and host resistance to infectious challenge is the health outcome of interest. By examining interactions among the nervous, endocrine and immune systems, ligands and receptors will be identified that are key components in modulating innate resistance during social stress. Innate immune cell activation is frequently accompanied by gene expression induced by the binding of specific cell surface receptors. Gene expression within these cells can be altered by products of the nervous and endocrine systems. Molecules released upon stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system can bind to receptors on innate immune cells and influence their activation and function. In what might be considered an environment by gene interaction, social stress shapes peripheral physiological responses as the host responds to new environmental demands imposed by social stress. The major hypothesis to be tested is that social interaction that involves repeated defeat, will activate a stress response, induce GC resistance and alter host resistance to infectious disease. The following specific aims are proposed to test this hypothesis. 1. Determine which aspects of behavior are important in social disruption (SDR) for the development of glucocorticoid (GC) resistance. 2. Examine the neuroendocrine and growth factor responses activated by SDR. 3. Examine the cellular and molecular mechanisms of GC resistance in splenic CD11b+ mononuclear cells. 4. Determine the effect of SDR on innate immunity and susceptibility to infectious disease. This study will elucidate the mechanisms of immunoregulation and host resistance to disease that are altered by social stress.
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