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.
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