Acute cognitive impairment is common in elderly emergency department patients and frequently results from infections that are unrelated to the CNS. Cognitive impairment leads to a failure in self-care and is associated with increased hospitalization and delayed recovery. Preliminary data presented in this application indicate that normal aging is associated with increased neuroinflammation and that an exaggerated inflammatory response occurs in the brain of healthy aged mice when lipopolysaccharide (LPS) activates the peripheral innate immune system. We believe that this phenomenon may underlie the cognitive deficits that are highly prevalent in elderly patients and explain why infection is a risk factor for development of neurodegenerative diseases. In this application, we will directly test the hypothesis that activation of the peripheral innate immune system produces an exaggerated inflammatory response in the aged brain that causes severe and prolonged deficits in cognitive function and changes in hippocampal pyramidal neuron morphology. We propose four specific aims in an aged mouse model to address the hypothesis. To determine if inflammation in the brain of older adults with a systemic infection is exacerbated, in the first aim adult and aged mice will be given LPS i.p. and inflammatory cytokines will be measured in hippocampal tissue obtained using laser capture microdissection techniques, and cytokine-positive microglia will be localized by immunohistochemical staining. Special attention will be paid to the hippocampus because it is sensitive to aging and involved in cognitive disorders that are evident in elderly patients with systemic infections.
The second aim will determine the behavioral consequences of the exaggerated inflammatory response in aged mice by assessing their performance in several hippocampal-dependent tests;
and aim three will explore the root of the behavioral changes by determining the effects of LPS and recombinant cytokines on hippocampal pyramidal neuron morphology. Finally in the fourth aim we will inhibit inflammatory cytokines in the brain of aged mice that are challenged with LPS to determine if this inhibits the age-associated exacerbation of neurobehavioral deficits and indications of diminished neuronal circuitry. One of the major conundrums in the current literature is that behavioral deficits persist in the elderly long after the infection has been resolved and cytokines returned to normal. Therefore, we contend that understanding the effects of inflammatory cytokines on morphology of neurons in brain areas that mediate cognitive behavior is critical. A better understanding of how aging influences the neurobehavioral complications associated with systemic infections is needed to improve the likelihood for """"""""successful"""""""" aging. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016710-07
Application #
7282393
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (03))
Program Officer
Wagster, Molly V
Project Start
2000-04-01
Project End
2011-06-30
Budget Start
2007-07-15
Budget End
2008-06-30
Support Year
7
Fiscal Year
2007
Total Cost
$300,331
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
Matt, Stephanie M; Zimmerman, Jalisa D; Lawson, Marcus A et al. (2018) Inhibition of DNA Methylation With Zebularine Alters Lipopolysaccharide-Induced Sickness Behavior and Neuroinflammation in Mice. Front Neurosci 12:636
Matt, Stephanie M; Allen, Jacob M; Lawson, Marcus A et al. (2018) Butyrate and Dietary Soluble Fiber Improve Neuroinflammation Associated With Aging in Mice. Front Immunol 9:1832
Townsend, Brigitte E; Johnson, Rodney W (2017) Sulforaphane reduces lipopolysaccharide-induced proinflammatory markers in hippocampus and liver but does not improve sickness behavior. Nutr Neurosci 20:195-202
Matt, Stephanie M; Lawson, Marcus A; Johnson, Rodney W (2016) Aging and peripheral lipopolysaccharide can modulate epigenetic regulators and decrease IL-1? promoter DNA methylation in microglia. Neurobiol Aging 47:1-9
Townsend, Brigitte E; Johnson, Rodney W (2016) Sulforaphane induces Nrf2 target genes and attenuates inflammatory gene expression in microglia from brain of young adult and aged mice. Exp Gerontol 73:42-8
Matt, Stephanie M; Johnson, Rodney W (2016) Neuro-immune dysfunction during brain aging: new insights in microglial cell regulation. Curr Opin Pharmacol 26:96-101
Johnson, Rodney W (2015) Feeding the beast: can microglia in the senescent brain be regulated by diet? Brain Behav Immun 43:1-8
Bhattacharya, Tushar K; Pence, Brandt D; Ossyra, Jessica M et al. (2015) Exercise but not (-)-epigallocatechin-3-gallate or ?-alanine enhances physical fitness, brain plasticity, and behavioral performance in mice. Physiol Behav 145:29-37
Gibbons, Trisha E; Pence, Brandt D; Petr, Geraldine et al. (2014) Voluntary wheel running, but not a diet containing (-)-epigallocatechin-3-gallate and ?-alanine, improves learning, memory and hippocampal neurogenesis in aged mice. Behav Brain Res 272:131-40
Townsend, Brigitte E; Chen, Yung-Ju; Jeffery, Elizabeth H et al. (2014) Dietary broccoli mildly improves neuroinflammation in aged mice but does not reduce lipopolysaccharide-induced sickness behavior. Nutr Res 34:990-9

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