EFFECT OF AGE AND IGF-1 ON NEURONAL STRUCTURE AND FUNCTION

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Aging is associated with progressive declines in a variety of biological functions, often reflecting local responses to system-wide physiological changes. The overall goal of this Program Project is to investigate the effects of the age-related decline in growth hormone and resultant decline in insulin-like growth factor 1 (IGF-1) on the brain. IGF-1, like several other growth factors, influences the growth and differentiation of both neurons and the microvasculature that supports the tremendous metabolic demand within neural tissue. The large decrease in IGF-1 that occurs with senescence is likely to result in significant changes in neuronal form and function within the brain. The temporal correlation of the decrease in IGF-1 levels with a general decline in cognitive abilities, and the recent observation that administration of e exogenous IGF-1 to aged animals increases cognitive abilities, makes the factor an important candidate for further study. This project will test the hypothesis that IGF-1 influences the development and maintenance of neuronal architecture and metabolism such that the age-related decrease in IGF-1 levels significantly affects neurons structure and activity. The experiments are predicated on the idea that the cognitive deficits associated with aging must result, at least in part, from an age-associated change in neuronal architecture and/or a loss in ability to regulate and maintain neuronal connectivity and signaling. To examine the specific relationship between IGF-1 and neuronal form and function we will quantify age-related changes in the extent and complexity of dendritic processes of cortical neurons, as well as changes in metabolism and vascularization, within well-defined regions of the cerebral cortex. We will determine whether those changes are the result of the age-related decrease in IGF-1 levels by testing whether they are reversed by exogenous IGF-1 delivered to aged animals, prevented by maintaining IGF-1 levels in aging animals, and elicited by an earlier than normal decrease in IGF-1 in young adult animals. Finally, we will examine specific mechanisms by which IGF-1 may regulated neuronal structure and function by measuring the effects of IGF-1 on developing dendrites, examining the interaction of IGF-1 with other neurotropic factors that influence neuronal growth and differentiation and quantifying the effects of IGF-1 signaling on calcium homeostasis, a key regulator of the neuronal development and function. These studies will provide a greater understanding of the effects of age on the brain and of the role of one critical factor in regulating those changes.