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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058525-05
Application #
8212047
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Bosetti, Francesca
Project Start
2008-02-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$319,670
Indirect Cost
$105,295
Name
University of Illinois Urbana-Champaign
Department
Pathology
Type
Schools of Medicine
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Moon, Morgan L; Joesting, Jennifer J; Lawson, Marcus A et al. (2014) The saturated fatty acid, palmitic acid, induces anxiety-like behavior in mice. Metabolism 63:1131-40
Chiu, Gabriel S; Darmody, Patrick T; Walsh, John P et al. (2014) Adenosine through the A2A adenosine receptor increases IL-1? in the brain contributing to anxiety. Brain Behav Immun 41:218-31
Kaczmarczyk, Melissa M; Machaj, Agnieszka S; Chiu, Gabriel S et al. (2013) Methylphenidate prevents high-fat diet (HFD)-induced learning/memory impairment in juvenile mice. Psychoneuroendocrinology 38:1553-64
York, Jason M; Blevins, Neil A; Meling, Daryl D et al. (2012) The biobehavioral and neuroimmune impact of low-dose ionizing radiation. Brain Behav Immun 26:218-27
Park, Min Jung; Yoo, Samuel W; Choe, Brian S et al. (2012) Acute hypoglycemia causes depressive-like behaviors in mice. Metabolism 61:229-36
Moon, Morgan L; McNeil, Leslie K; Freund, Gregory G (2011) Macrophages make me sick: how macrophage activation states influence sickness behavior. Psychoneuroendocrinology 36:1431-40
Lavin, Desiree N; Joesting, Jennifer J; Chiu, Gabriel S et al. (2011) Fasting induces an anti-inflammatory effect on the neuroimmune system which a high-fat diet prevents. Obesity (Silver Spring) 19:1586-94
Sherry, Christina L; Kim, Stephanie S; Dilger, Ryan N et al. (2010) Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization. Brain Behav Immun 24:631-40
Sherry, Christina L; Kim, Stephanie S; Freund, Gregory G (2009) Accelerated recovery from acute hypoxia in obese mice is due to obesity-associated up-regulation of interleukin-1 receptor antagonist. Endocrinology 150:2660-7
Sherry, Christina L; Kramer, Jason M; York, Jason M et al. (2009) Behavioral recovery from acute hypoxia is reliant on leptin. Brain Behav Immun 23:169-75

Showing the most recent 10 out of 13 publications