Biological aging has been associated with a decline in tissue function. The brain, in particular, demonstrates a decline in neuronal function ranging from molecular changes such as a decrease in protein synthesis to systemic changes such a general reduction in cognitive ability. They hypothesis of the Program Project has been that the age-related decrease in pulsatile growth hormone (GH) secretion and the concomitant decrease in plasma levels of insulin-like growth factor 1 (IGF-1) lead to a loss of cerebral vasculature with resulting changes in brain structure and function. Along with other findings, we have reported that there is an age-related rarefaction of surface cerebral arterioles that can be reversed by GH/IGF-1, that intracerebroventricular (icv) administration of IGF-1 improves behavioral performance in old rats, and that there is a significant age-related decrease in synaptic density, particularly in presumptive inhibitory terminals. The cognitive decline and decrease in synaptic density in old animals suggest a diminished ability to form new and/or maintain old synapses. The amelioration of age-related vascular and behavioral changes in the presence of elevated levels of GH and IGF-1 support the notion that these factors may be involved in the establishment and/or maintenance of synaptic density as well. Accordingly, in the present proposal, we will test they hypothesis that the age-related decrease in synaptic density will be reversed by acute icv delivery of IGF-1 and that synaptic density in the brain will be controlled by plasma IGF-1 levels independent of age. In order to address this hypothesis, three specific aims are proposed: 1) to test the hypothesis that a 28 day icv infusion of IGF-1 in aged animals will prevent the age-related decrease in density of presumptive excitatory and inhibitory synaptic contacts, using the techniques of quantitative electron microscopy (EM) and EM immunocytochemistry, 2) to test the hypothesis that density of presumptive excitatory and inhibitory synaptic contacts will be determined by plasma levels of IGF-1, independent of the age of the animal, using a transgenic model of adult onset growth hormone deficiency that can be reversed by D[Ala/2]GHRH injections, and 3) to test the hypothesis that synapse formation and/or maintenance is dependent on IGF-1, using organotypic slice preparation and EM, immunocytochemistry, and western blot analysis following IGF-1 receptor blockade. The results of the proposed experiments will provide the first direct evidence for the involvement of IGF-1 in synaptic plasticity and/or maintenance. This evidence is essential if trophic factors are to be used to ameliorate functional declines accompanying brain aging. Moreover, results of the proposed studies will begin to address the mechanism(s) of IGF-1 dependent regulation of synapses in the brain.
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