Older individuals often experience precipitous declines in cognitive function after events (Ex. surgery, infection, or injury) that trigger activaion of the peripheral immune system. Even in cases where this decline is temporary, its occurrence is associated with a greatly increased risk of ultimately developing dementia. Although clinically important, this phenomenon is much less studied than gradual senescence and aging-associated neurodegenerative disorders. This proposal seeks to examine possible mechanisms, and identify potential therapeutic targets. It uses a rodent model of aging-associated cognitive vulnerability to infection to continue testing the hypothesis that aging and infection interact to significantly decrease the capacity of the hippocampus to provide the brain derived neurotrophic factor (BDNF) needed for some forms of synaptic plasticity. Aging sensitizes the hippocampal inflammatory response to peripheral infection, increasing the size and duration of the resulting spike in interleukin-1beta (IL-1?). This exaggerated elevation in IL-1? gives rise to profound and specific deficits in hippocampus-dependent long-term memory tasks. As part of an earlier R21, we demonstrated that these memory deficits are paralleled by specific deficits in late phase LTP (L-LTP) in the hippocampus, and are associated with reductions in BDNF in hippocampal synapses. The reductions in memory, plasticity and BDNF can all be blocked with an IL-1 receptor antagonist. The current project extends these observations, with goals that include: (1) Examining the duration of the reductions in BDNF and L-LTP. The deficits in formation of long-term memory last as long as the excessive elevation of IL-1?. Will this also be true of the reductions in L-LTP, and BDNF? Can the effects of the exaggerated inflammatory response be potentiated or prolonged by additional insults, or by preexisting cofactors? (2) Identifying mechanisms involved in the reductions in BDNF and BDNF-related plasticity processes. Is the combination of aging and infection associated with selective alterations in molecules needed for BDNF production, processing or signaling (Ex. BDNF mRNAs, and molecules that cleave and sort BDNF)? [Are other key plasticity proteins modulated by BDNF (Ex. Arc) affected?] (3) Testing the hypothesis that reduced synaptic availability of BDNF may contribute to the observed deficits in synaptic plasticity. Ex. Can theta burst L-LTP be rescued with exogenous BDNF isoforms? Does inflammation differentially affect BDNF and the capacity for plasticity in different portions of the neurons (i.e. somatic vs. dendritic compartments)? BDNF also regulates long-term depression (LTD) - how is it affected by age and infection? These experiments examine the interactions of aging, inflammation, and BDNF biology, and should provide insights into mechanisms that may contribute to aging-associated cognitive vulnerability and decline. They may ultimately suggest strategies for improving cognitive resiliency and treating cognitive decline in its earliest stages.
This project seeks to examine the origins of an important, but comparatively understudied, clinical problem - previously high functioning older people often experience precipitous declines in cognitive function after an acute infection, injury or surgery, and even if they recover they are at greatly increased risk of eventually developing dementia. The proposed experiments use a rodent model of this phenomenon to test the hypothesis that the combination of age and a secondary stressor may give rise to an exaggerated inflammatory state in the brain, which in turn, disrupts molecular systems critical for memory. These studies may ultimately suggest strategies for improving cognitive resiliency, and for early treatment of some forms of cognitive decline.