In the initial submission of this program project, we hypothesized that the decline in high amplitude growth hormone secretion and the concomitant decrease in plasma IGF-1 levels (one of the most well-characterized endocrine changes to occur in animals and man) contribute to the decrease in brain function and cognitive abilities of aged animals via two mechanisms 1) by altering vascular density and CNS blood flow and 2) by withdrawing IGF-1 related trophic support from the aged brain. Since the initial funding of this project in April 1995, data obtained through projects 1 and 2 of the original program have confirmed the decline in IGF-1 levels in aged animals, reported that cortical surface arterioles, venules and anastomoses decreases with age, established a high correlation between plasma IGF-1 and vascular density, found that systemic injections of growth hormone increase vascular density in aged animals, and reported that cerebrovasculature expresses IGF-1 mRNA. In addition, decreases in cortical synapses, type 1 IGF receptors as well as alterations in NMDA and GABA receptor subtypes are evident in aged animals and regulated by IGF-1. Administration of IGF-1 icv for 28 days to older animals was also found to increase cognitive ability (Object Recognition and performance in the Morris Water Maze) and increase some aspects of neuronal function. Finally, chronic treatment with D[Ala/2]GHRH increased growth hormone secretion and prevented the age-related decline in cognitive ability. Due to the pending retirement of Dr. Hutchins, projects 1 and 2 of the original project have been combined and Dr. Sonntag has assumed leadership of this project. Based on the previous studies of this project, the original hypothesis has been retained and we plan to: 1) Assess whether modifications in vascular architecture and/or blood flow are necessary for the increase in cognitive ability induced by icv IGF-1. 2) Determine whether a decline in growth hormone in early adulthood is sufficient to modify cerebrovascular architecture and blood flow in specific brain regions and assess the relationship of these changes to cognitive deficits. 3) Determine whether a decline in growth hormone or vascular response to growth hormone contributes to a decrease in vascular-derived IGF-1 with age. The results of these studies will further elucidate the relationship between the decline in growth hormone and IGF-1, the rarefaction of cerebrovasculature and the significance of the trophic effects of brain vasculature on cognitive ability. These studies will provide valuable information on factors contributing to the etiology of dementia and disease commonly observed in the elderly.
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