What factors regulate neuronal plasticity in the mature brain and spinal cord? This question is at the center of research that seeks to promote the ability of the central nervous system (CNS) to recover from injury resulting from stroke, trauma or degenerative disease. Axonal growth and synapse formation can occur in the mature CNS. The mechanisms underlying such growth, however, are not clear. Damage to the basal forebrain of the rat (brain regions that are known to be affected in Alzheimer's disease) results in the growth of vascular autonomic fibers (sympathetic axons) into the hippocampal formation, a response that is significantly reduced in the aged animal. This example of axonal growth within the young rat is preceded by an increase in the amount of Nerve Growth Factor (NGF) in the region where growth occurs. However, we have demonstrated that global infusion of exogenous NGF is not sufficient to induce sympathetic ingrowth in the presence of septal fibers suggesting that local elevation of NGF may be required to elicit sprouting. Two of the goals over the next five years are to determine whether local availability of NGF within the hippocampal formation determines the topography of sympathetic ingrowth and whether septal lesions alter the growth-promoting ability of hippocampal tissue sections when used as a substrate in culture. A third goal is to determine whether the age-related decline in sympathetic sprouting is due to reduced trophic factor induction following septal denervation and/or alterations in tissue substrate properties. This arises from our finding that there is no age-related decline in total NGF activity in the rat hippocampal formation. The fourth goal is to determine the responsivity of aged sympathetic neurons to exogenous NGF to test the hypothesis that reduced sprouting is partly due to reduced responsiveness of aged sympathetic neurons to NGF. All of the experiments are designed to reveal information regarding the factors that regulate axonal growth within the mature and aging nervous system.
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