Considerable neuropsychiatric problems result from cytokine immunotherapy (eg., interleukin-2: IL-2), which 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 aims to understand how the brain reacts to endogenous cytokine production induced by Staphyloccocal enterotoxin B (SEB). This model involves activation of a natural repertoire of immunological events that serves to regulate not only immune responses, but how the organism should perform adaptive behavioral adjustments (eg., during sickness). Administration of SEB in vivo stimulates T cells to produce high levels of IL-2 and tumor necrosis factor-alpha (TNF-a), and this has been associated with increased transcription of central corticotropin releasing hormone (CRH) in the central nucleus of the amygdala, (ceA) and paraventricular nucleus (PVN) of the hypothalamus, which was associated with increased neophobic reactivity. Immunoneutralization of systemic IL-2 significantly attenuated the impact of SEB challenge on neuronal activation in the central nucleus of the amygdala and adjacent limbic regions of the brain. Therefore, in Specific Aim 1 we will test whether SEB challenge promotes enhanced reactivity to anxiety-provoking stimuli. These will include ethological tests of anxiety and/or fear (viz., open field and elevated plus maze) under familiar and novel contextual conditions. In addition, SEB challenged animals will be tested for learned fear responses, such as fear potentiated startle reactivity, a behavior that is strongly linked to the amygdala.
Specific Aim 2 will determine the role of IL-2 and TNF-a in the behavioral effects of SEB. Studies will involve anti-immune cytokine monoclonal antibody treatment, and in the case of studying IL-2, SEB challenge of mice possessing IL-2 gene mutations.
Specific Aim 2 will also test whether the SEB-induced CRH mRNA increases in the amygdala and other brain regions are mediated by the aforementioned cytokine manipulations. Finally, in Specific Aim 3 the role of CRH in promoting the behavioral effects of SEB will be tested by site-specific administration of CRH receptor antagonists into the ceA and locus coeruleus, regions known to mediate some of the anxiogenic effects of CRH. These studies will confirm if immunological activation modifies CNS reactivity to psychological stressors, which in turn may promote efforts to understand how T cell derived cytokines (such as IL-2 and TNF-a) 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 typically altered in clinical depression, this research will contribute to understanding the aetiology and strategies for treatment of affective illness.
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