REGULATION OF NEURAL CONNECTIVITY IN THE AGING BRAIN

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

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