Very little is known about chronic, long-term actions of endogenous proinflammatory cytokines on basic biobehavioral processes, particularly neuroimmune-mediated sickness behavior, motor function, fatigue and memory. We and others have documented a significant rise in the proinflammatory cytokines IL-6, IL-1 and TNF in both the periphery and brain of healthy aging mice. We hypothesize that this chronic elevation in proinflammatory cytokines is responsible for performance deficits in multiple biobehavioral processes in aged animals. We have established that IL-6 increases and IL-10 decreases significantly in the brain and plasma of healthy aging mice. These changes are associated with reduced hippocampal-dependent spatial memory and motor function (as assessed by locomotor activity and treadmill running). We have also shown that two important aspects of sickness behavior, immobility and social investigation following i.c.v, injections of either LPS or IL-1, are ameliorated in IL-6 knockout mice. We postulate that the normal, chronic, age-associated rise in IL-6, IL-1 and TNF impacts numerous biobehavioral processes, as assessed by an increase in sickness-related behaviors (diminished social investigation, spatial memory loss) and a reduction in motor function (fatigue on a treadmill, alternations in a 4-arm plus maze, stationery rod). In Objective 1, we will test the hypothesis that all of these age-associated biobehavioral variables are attenuated in Toll-like receptor-4 and NF-KappaB p50 knockout mice but are exacerbated in mice deficient in IL-10. Objective 2 will use IL-6- deficient mice and cytokine-specific antibodies to define intracellular substrates that lead to age-associated reductions in these biobehavioral events. Objective 3 will expand our exciting findings that IGF-I, a growth factor that behaves as an anti-inflammatory cytokine and declines during aging, counteracts age-associated biobehavioral deficits. Finally, Objective 4 will utilize a well-defined model that is very likely to explain the molecular events that are directly responsible for biobehavioral performance deficits in both muscle and brain. These experiments will use both in vitro and in vivo approaches and are needed to understand how chronic, long-term elevations in proinflammatory cytokines impair important biobehavioral processes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG023580-03
Application #
7173371
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Monjan, Andrew A
Project Start
2005-01-01
Project End
2009-12-31
Budget Start
2007-03-01
Budget End
2007-12-31
Support Year
3
Fiscal Year
2007
Total Cost
$295,066
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Jurgens, Heidi A; Johnson, Rodney W (2012) Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation. Exp Neurol 233:40-8
Jang, Saebyeol; Johnson, Rodney W (2010) Can consuming flavonoids restore old microglia to their youthful state? Nutr Rev 68:719-28
Buchanan, J B; Sparkman, N L; Johnson, R W (2010) Methamphetamine sensitization attenuates the febrile and neuroinflammatory response to a subsequent peripheral immune stimulus. Brain Behav Immun 24:502-11
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Richwine, Amy F; Sparkman, Nathan L; Dilger, Ryan N et al. (2009) Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide. Brain Behav Immun 23:794-802
Strle, Klemen; McCusker, Robert H; Johnson, Rodney W et al. (2008) Prototypical anti-inflammatory cytokine IL-10 prevents loss of IGF-I-induced myogenin protein expression caused by IL-1beta. Am J Physiol Endocrinol Metab 294:E709-18
Huey, Kimberly A; McCusker, Robert H; Kelley, Keith W (2008) Exaggerated expression of skeletal muscle-derived interleukin-6, but not TNFalpha, in mice lacking interleukin-10. J Neuroimmunol 199:56-62
O'Connor, Jason C; McCusker, Robert H; Strle, Klemen et al. (2008) Regulation of IGF-I function by proinflammatory cytokines: at the interface of immunology and endocrinology. Cell Immunol 252:91-110
Rosczyk, H A; Sparkman, N L; Johnson, R W (2008) Neuroinflammation and cognitive function in aged mice following minor surgery. Exp Gerontol 43:840-6
Sparkman, Nathan L; Johnson, Rodney W (2008) Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation 15:323-30

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