This application is a competing continuation of the Program Project entitled 'Growth Hormone & IGF-1 in CNS and Cerebrovascular Aging' originally funded in April 1995. The projects and studies described in this application build on the results of the previous two years work. The original hypothesis proposed in this application was that the decrease in growth hormone and the subsequent decrease in plasma IGF-1 with age result in a rarefaction of cerebral vasculature, a decline in vascular IGF-1, and contribute to brain aging. during the initial funding period, we have demonstrated that administration of growth hormone secretagogues, growth hormone and/or IGF-1 enhance working memory in old animals, increase vascular density on the surface of brain, and regulate NMDA receptor subtypes. In addition, age-related changes in growth hormone are associated with synaptic loss in several brain regions. The focus of the current proposal is designed to assess 1) whether modification in brain architecture (vascular dendritic, or synaptic) are necessary for the increase in cognitive ability, 2) whether a decline in plasma growth hormone and IGF-1 in adulthood is sufficient to modify brain architecture and induce cognitive deficits, and 3) whether effects of growth hormone and IGF-1 are mediated by direct actions on brain vascular tissue. Three projects and one Administrative/Animal Core are proposed to continue our research into the effects of growth hormone and IGF-1 deficiency in aged animals. Project 1 (W.E. Sonntag) is designed to assess the effects of growth hormone and/or IGF-1 administration on cerebral vascular density, dynamics, blood flow and cognitive ability. In addition, this project will assess the regulation of vascular-derived IGF-1 and growth hormone signal transduction in cerebral vasculature. Project 2 (D. Riddle/O. Delbono) will assess the effect of age on the size and complexity of dendritic arbors and markers of neuronal metabolism in brain regions associated with performance in the Morris Water Maze. In addition, mechanisms of action of IGF-1 in the regulation of dendritic arborization will be pursued. Project 3 (J. Brunso-Bechtold) will determine the effects of growth hormone and IGF-1 on synaptic contacts in cerebral cortex and its regulation by growth hormone and IGF-1. A unique aspect of this application is that the projects will use a transgenic animal model for adult-onset growth hormone deficiency from other biological changes associated with age. The Core will be responsible for program administration, ordering aged animals, raising transgenic animals and coordinating the use of tissues between the projects. This program project will provide valuable information on the interactions between endocrine, cerebral vasculature and the central nervous system which may contribute to vascular dementia and increased susceptibility to disease commonly observed in the elderly.
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