This proposal is directed at understanding some of the factors that contribute to cognitive decline during aging. It is motivated by the novel hypothesis that aging is a vulnerability factor that sensitizes or primes glial cells, thereby resulting in an age-related exaggerated brain proinflammatory cytokine (PIC) response to certain challenges. It is this sensitized PIC response, and its """"""""downstream"""""""" products that are hypothesized to be at the core of the aged humans'(&animals') vulnerability to cognitive dysfunctions often associated with bacterial infection, surgery, and stress. The hypothesis rests on the following findings: 1) In response to infection or injury, immune cells in the periphery release PICs such as interleukin-1beta. 2) PICs can signal the brain and induce the synthesis and release of PICs in the brain, primarily by glial cells. 3) PICs in the brain, particularly ILI beta in the hippocampus, can interfere with memory consolidation, and perhaps other cognitive processes Thus, if aging sensitizes glial cells, then there should be exaggerated brain PIC responses to challenge in the aged, and a resultant impairment in memory formation.
The first Aim asks whether the aged rat is more vulnerable to memory impairments associated with immune system activation and other events that induce hippocampal PICs (peripheral infection, surgery, and social stress).
The second Aim asks whether glial activation, brain PICs, and downstream products of PICs, particularly reductions in brain derived neurotrophic factor (BDNF) are responsible for the age-related memory impairments produced by these challenges.
The third Aim i nvestigates whether a manipulation that is known prevent age-related glial priming, namely dietary restriction (DR), will prevent age-related exaggeration of brain PIC responses and challenge-induced memory impairments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028271-04
Application #
7651101
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M1))
Program Officer
Mackiewicz, Miroslaw
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$355,264
Indirect Cost
Name
University of Colorado at Boulder
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
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Spencer, Sarah J; D'Angelo, Heather; Soch, Alita et al. (2017) High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory. Neurobiol Aging 58:88-101
Fonken, Laura K; Kitt, Meagan M; Gaudet, Andrew D et al. (2016) Diminished circadian rhythms in hippocampal microglia may contribute to age-related neuroinflammatory sensitization. Neurobiol Aging 47:102-112
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Barrientos, R M; Kitt, M M; Watkins, L R et al. (2015) Neuroinflammation in the normal aging hippocampus. Neuroscience 309:84-99
Barrientos, Ruth M; Thompson, Vanessa M; Kitt, Meagan M et al. (2015) Greater glucocorticoid receptor activation in hippocampus of aged rats sensitizes microglia. Neurobiol Aging 36:1483-95
Barrientos, Ruth M; Hein, Amy M; Frank, Matthew G et al. (2012) Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats. J Neurosci 32:14641-8
Chapman, Timothy R; Barrientos, Ruth M; Ahrendsen, Jared T et al. (2012) Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus. Neurobiol Aging 33:832.e1-14

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