Recent work has shown that administration of nerve growth factor (NGF), a neurotrophin which is critical for the survival and phenotypic maintenance of cholinergic neurons, improves cognitive performance in aged rats. The goal of the work presented in this proposal is to explore basic neurobiological mechanisms responsible for NGF-induced enhancement of cognition in aged subjects. The guiding hypotheses are that NGF acts to normalize long-term synaptic plasticity mechanisms and protein kinase C activity. In addition, a novel method for delivering peripherally administered NGF to the brain will be characterized. Young (4 month old) and aged (22 month old) male Fischer 344 rats will be evaluated in behavioral tasks which preferentially involve the hippocampus, frontal cortex, or basal forebrain cholinergic system. Hippocampal synaptic plasticity will be measured to correlate with cognitive status. After baseline evaluation, the animal will receive either NGF or appropriate control solution. Peripherally administered NGF is conjugated to a transferrin receptor antibody to allow the transport of biologically active NGF into the brain. After four weeks of treatment, the rats will be re-evaluated in the behavioral and electrophysiological tests, then sacrificed to assess the activity of protein kinase C (PKC), an enzyme which has been shown to be involved in the regulation of both learning and brain plasticity, in the hippocampus, frontal cortex and septal area. Additional experiments will be performed to directly evaluate the relationship between NGF, PKC, hippocampal plasticity and spatial learning. Taken together, this work will provide important information concerning the extent and degree of age-related learning impairments, as well as potential electrophysiological and biochemical substrates for these problems. In addition, the work will determine the extent to which age-related cognitive problems can be reduced with NGF treatment, and provide insight into the mechanism(s) by which NGF is able to achieve its effects. Finally, this work will evaluate the efficacy of a novel means of delivering NGF to the brain which has clear advantages over conventional techniques in terms of potential clinical application.
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