Hypoxia: an activator of neuroimmunity

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DESCRIPTION (provided by applicant): Sickness behavior has been defined classically as a coordinated set of nonspecific behavioral modifications including loss of appetite, libido, motor activity and interest in the physical and social environment that occur in response to infection. New research from our laboratory shows that acute hypoxia induces loss of social exploration in mice, demonstrating that non-infectious stimuli can activate the neuroimmune system and stimulate sickness behavior. Acute hypoxia occurs in many types of accidents and in a host of disease states, yet little is known about immunobehavioral activation and recovery from acute hypoxia. Our exciting new data demonstrate that acute hypoxia elicits loss of social exploration and rapid up-regulation of brain IL-12. Importantly, this acute hypoxia-induced sickness behavior is dramatically shortened in mice deficient in IL-1 receptor/Toll-like receptor superfamily signaling. In leptin receptor defective mice, we have shown that acute hypoxia-induced sickness is longer lasting and ameliorated by subcutaneous administration of IL-1 receptor antagonist (IL-1RA). Together, these data indicate that acute hypoxia triggers activation of the brain-based innate immune system. The objective of this application is to examine the hypothesis that acute hypoxia activates the IL-1 arm of the neuroimmune system causing sickness behavior during hypoxia recovery. The long-term goal of this project is to understand the mechanisms of immunobehavioral recovery from acute hypoxia and to develop strategies that prevent and/or speed recovery from the immunobehavioral consequences of acute hypoxia. In Objective #1, we will define the acute hypoxia-induced sickness behaviors experienced during hypoxia recovery and determine if they are mediated by the pro-inflammatory cytokine IL-12. In Objective #2, we will ascertain if leptin is essential to rapidly resolving loss of social exploration due to acute hypoxia and discover the impact of obesity on recovery from acute hypoxia-induced sickness behaviors. In Objective #3, we will use a pharmacologic approach featuring IL-1RA to speed recovery from acute hypoxia-induced sickness behaviors, determine the importance of the IL-1 decoy receptor (IL-1R2) to acute hypoxia recovery and ascertain if vanadium-dependent up-regulation of brain IL-1RA and/or IL- 1R2 can provide protection from acute hypoxia. These studies are needed to define new targets in order to alleviate suffering in those afflicted by acute hypoxia.