Pathogens (bacteria, viruses, etc.) that invade a host are recognized and responded to by cells of the immune system. Proinflammatory cytokines such as interleukin-1beta (IL-1beta) are released as a natural part of this response. These cytokines act peripherally in the generation of the immune response, but are also critically involved in immune-to-brain communication. Indeed, cytokines such as IL-1beta alter brain function, thereby producing a variety of """"""""illness"""""""" responses including fever, activation of the hypothalamo-pituitary-adrenal axis, development of conditioned taste aversions to novel foods, activation of specific brain monoamine pathways, increased sleep, decreased social interaction, activation of the acute phase response, etc. These changes are adaptive in that they facilitate the survival of the host. As such, immune-to- brain communication is of central importance in an organism's ability to respond to and survive immunological challenges. Alterations in neural function produced by cytokines such as IL-1B may also be important for understanding stress and stress-related disorders such as depression. However, there is considerable uncertainty concerning how cytokine signals can enter the brain. Intriguingly, (a) IL-1 binding sites have now been identified on paraganglia which form afferent synapses with subdiaphragmatic vagal afferents, and (b) cutting the subdiaphragmatic vagus blocks are variety of IL-1beta mediated responses. These data suggest that vagal afferents may provide a neural pathway for signalling the brain. The present proposal develops an integrated exploration of the role of the vagus in cytokine-to-brain communication. Dose-response studies will systematically characterize the effect of vagotomy on illness responses and pattern of brain activation induced by various routes of administration. Potential physiological relevance will be addressed by examining the effect of vagotomy on brain activation produced during in vivo antibody response to antigen. Peripheral mechanisms underlying vagal-to-brain communication will be explored by examining the generality of IL-1 binding to paraganglia in viscera, by testing whether paraganglia are required for illness responses to be observed, by determining expression of mRNA for IL-1 receptors in these structures, and by neurophysiological recordings of vagal activity in response to cytokine exposure. Central mechanisms will be explored by examining the role of the nucleus tractus solitarius and of central induction of cytokines in illness responses.
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