The neurological manifestations of aging in mammals include slowing of reflexes, decreased motor coordination and a decline in cognitive function. A number of reports have indicated that age-related changes in central cholinergic neuronal systems play an important role in many of these changes. The hypothesis of a relationship between altered cholinergic function and many of the manifestations of aging has prompted considerable interest in pharmacologically improving cholinergic neuronal function to restore performance. However, little is known regarding the effects of these treatments on the processes that regulate cholinergic neuronal activity and function in the aged animal. The proposed project is designed to examine the effects of various drug treatments thought to improve cholinergic neuronal function on behavioral performance, cholinergic neurochemical markers, and the relation between performance and neurochemistry in mice of several ages. Mice will be implanted with an indwelling intraperitoneal cannula attached through an infusion swivel that allows unrestricted movement for the continuous infusion of several drug regimens for 30 days. Before and after the 30-day infusion period, mice will be assessed in a seven procedure psychomotor test battery to obtain measurements of activity, and strength and coordination. After the last evaluation in the psychomotor test battery, the mice will be tested for memory retention using a one-trial passive avoidance procedure. Shortly thereafter, mice will be decapitated and their brains dissected into frontal-parietal cortex, striatum, cerebellum, and hippocampus. Using homogenates of each of these regions, measures of sodium-dependent high affinity choline uptake, choline acetyltransferase activity, and [3H]quinuclidinyl benzilate binding will be made. Considered together, these three markers provide insight into the processes that regulate central cholinergic neuronal activity. The information obtained from this project should provide considerable insight into the potential usefulness of this simple approach to evaluating potential pharmacotherapies directed at improving cholinergic deficits of aging. This project also will greatly expand our understanding of the responsiveness of cholinergic systems to both aging and directed drug treatments as well as provide valuable information regarding the effects of aging and drug treatments on relations between behavioral performance and cholinergic neurochemistry.
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