Decline in cognitive function is a critical concern during normal aging. The proposed research will study? synaptic changes that accompany cognitve decline as well as the functional consequences of those? changes. In addition, studies will determine the relationship between these measures and variations in the? GH/IGF-1 axis. The proposed studies will utilize two rodent models, the Fisher 344 X Brown Norway? (F344XBN) rat and a dwarf rat model of adult onset growth hormone deficiency. F344XBN rats demonstrate? an aging-related decline in learning and memory accompanied by changes in subunit levels of AMPA and? NMDA types of the glutamate receptor in the hippocampus, a brain region closely linked to memory? consolidation. Infusion of IGF-1not only ameliorates the aging-related decline in learning and memory, it also? increases the incidence of multiple spine bouton synapses that have been associated with an increased? presence of glutamate receptors as well as enhanced long term potentiation (LTP), thought to be a? physiological correlate of learning and memory. Proposed studies will address raise the issue of what role? IGF-1 plays in the maintaining synapses across life span. In addition, studies will use the dwarf rat model of? adult onset growth hormone deficiency to study the impact of variation in GH/IGF-1 levels on synapse? structure and function in rats of the same age. The overall hypothesis is that aging-related changes in the? GH/IGF-1 axis mediate alterations in the composition and function of synapses in the hippocampus across? life span.
Specific Aim 1 evaluates whether aging-related declines in NMDA and AMPA receptor subunit? levels in hippocampus are accompanied by synaptic redistributions of glutamate receptor subunits and lower? levels of brain IGF-1.
Specific Aim 2 evaluates whether rats deficient in GH/IGF-1 have lower levels of? NMDA and AMPA receptor subunits, a redistribution of those subunits, and lower levels of brain IGF-1 than? age-matched rats with higher GH/IGF-1 levels.
Specific Aim 3 evaluates whether low GH/IGF-1 levels are? associated with functional changes in NMDA and/or AMPA receptors and with deficits in LTP expression.? The goal of the proposed studies is to provide insight into the role of IGF-1 in the maintenance of neural? function during normal aging and to suggest strategies for the prevention or amelioration of aging-related? cognitive decline.
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