Neuropsychiatric problems can result from cytokine immunotherapy. This may reflect differences in the way the brain responds to exogenous cytokines as opposed to endogenous cytokines elicited by antigens as part of a dynamic cytokine network. Therefore, the current project addresses how the brain reacts to endogenous cytokine production induced by T cell bacterial superantigens (SAgs), and in particular Staphyloccocal Enterotoxin A (SEA). This model involves activation of a natural repertoire of immunological events that regulate immune responses, but also influence adaptive neurobehavioral adjustments (e.g., during sickness). Administration of SAgs (e.g., SEA and SEE) in vivo stimulates T cells to produce high levels of tumor necrosis factor-a (TNFa). This has been associated with increased transcription of central corticotropin releasing hormone (CRH) and the reputed """"""""anti-stress"""""""" peptide, nociceptin/orphanin FQ (N/OFQ) in the amygdala, and paraventricular nucleus of the hypothalamus, with behavioral changes showing increased neophobic reactivity (i.e. fear of novelty). Animals deficient in TNFa display reduced neuroendocrine responses to SEA, and CRH antagonism in the brain attenuates gustatory neophobia. These data implicate TNFa and CRH in the neural and behavioral effects of T cell superantigens. Based on these observations, this proposal will address the following aims in C57BIV6J mice challenged with SEA.
Specific Aim 1 will characterize further the role of endogenous TNFa in the neural and behavioral effects of SEA, through the use of TNFa deficient and TNFa receptor I and/or II deficient mice. These studies will also address the potential role of TNFa actions within the brain after T cell activation with SEA.
In Specific Aim 2 the role of CRH in promoting the behavioral effects of SEA will be tested by site-specific administration of CRH receptor antagonist, antalarmin, into the bed nucleus of the stria terminalis, amygdala and PVN, regions known to mediate anxiogenic and anti-appetitive effects of CRH. Finally, Specific Aim 3 will address the modulatory role of the hypothesized anxiolytic peptide, N/OFQ, in regulating the behavioral effects of SEA challenge. These studies will utilize mice deficient for N/OFQ or its receptor, ORL-1. It is hypothesized that the induction of N/OFQ in limbic brain regions serves to modulate anxiogenic processes (perhaps driven by CRH) that are induced after challenge with SEA. These studies will confirm if immunological activation modifies CNS reactivity to psychological stressors, which in turn may promote efforts to understand how endogenous cytokines (such as TNFa) support and/or influence behavioral adaptation to stress. In view of the increasing emphasis on the role of the immune system in affecting motivational systems altered in clinical depression, this research will contribute to understanding the aetiology and strategies for treatment of affective illness.
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