2008 — 2009 |
Patterson, Susan |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Effects of Aging and Inflammatory Challenge On Bdnf-Dependent Synaptic Plasticity @ University of Colorado At Boulder
[unreadable] DESCRIPTION (provided by applicant): Age is a significant risk factor in vulnerability to cognitive decline associated with infection, surgery, heart attack and psychological stress. The cognitive function of previously normal older people is more likely to be seriously impaired if they experience one of these physiological or psychological stressors. The mechanisms that mediate this vulnerability are largely unknown. In this exploratory project, we will use a rodent model of aging-associated cognitive vulnerability to infection to examine the hypothesis that the combined effects of aging and infection will significantly decrease BDNF and BDNF-dependent synaptic plasticity in the hippocampus. We hypothesize that aging sensitizes the hippocampal inflammatory response to peripheral infection, increasing the magnitude and the duration of the increase in brain IL-1, thus prolonging its suppression of BDNF-dependent processes. In this proposal, we outline experiments (Specific Aim 1) to examine basal synaptic transmission and short-lasting forms of synaptic plasticity in hippocampal slices taken from young and aged rats, with and without recent exposure to an immune challenge. In Specific Aim 2, we will examine several forms of long-lasting synaptic plasticity in the hippocampal slices. In doing so, we will test the hypothesis that the memory deficits observed in the aged animals following infection, which are specific to long-lasting forms of memory, will be mirrored by specific deficits in long-lasting synaptic plasticity. We will also be able to test the hypothesis that forms of long-lasting synaptic plasticity that are BDNF-dependent will be particularly compromised by the combined effects of aging and infection. These proposed experiments will provide the basis for further investigation of the cellular and molecular processes giving rise to aging-associated increases in vulnerability to cognitive decline, and may ultimately provide strategies for improving cognitive resiliency. PUBLIC HEALTH RELEVANCE The cognitive abilities of older people are more vulnerable to the deleterious effects of challenging life events including surgery, infection and psychological stress than those of younger people, but very little is known about the mechanisms that mediate this vulnerability. The experiments proposed here are designed to explore the brain mechanisms involved, using a rodent model that closely mimics the age-associated increases in cognitive vulnerability to infection. Specifically, we plan to determine if infection-evoked deficits in memory in aged animals are associated with specific deficits in synaptic function/plasticity. [unreadable] [unreadable] [unreadable]
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0.915 |
2012 — 2018 |
Patterson, Susan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Aging, Inflammatory Challenge, and Bdnf-Dependent Synaptic Plasticity Processes
DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.
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0.915 |