Severe deterioration in the ability to learn and remember is a hallmark of patients with Alzheimer's disease. Foremost among the neuropathological changes that occur in the brains of the victims of Alzheimer's disease is a loss of basal forebrain cholinergic neurons. The loss of cholinergic innervation to the hippocampal formation, a brain region known to be necessary for the formation of new long-term memories, is thought to be major contributor to memory loss. The objective of the experiments described in this proposal is to understand the contributions of muscarinic and nicotinic cholinergic function in the hippocampus to hippocampus-dependent learning and memory. A rodent model will be used to determine the relationship between age-related alterations in cholinergic neurotransmission in the hippocampus and the mnemonic deficits with aging. Experimental measures of cholinergic function will be assessed in rats of different ages after their learning ability has been evaluated using the Morris water maze, a place learning task known to depend upon intact cholinergic input to the hippocampus, and for which age-related decrements have been well documented. Subsequently, several measures of cholinergic function will be evaluated: 1) the responsiveness of hippocampal neurons to local application of muscarine and nicotine; 2) the capacity of intrinsic hippocampal connections to demonstrate long-lasting synaptic plasticity, and the ability of muscarinic and nicotinic drugs to modulate this phenomenon; and 3) biochemical measures of the status of the cholinergic projection to the hippocampus, including measures of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity, the status of pre- and post-synaptic nicotinic receptors. A key element of the experimental design is that ages of the rats to be tested will be selected so that the influences of aging and cholinergic system function upon learning ability can be independently evaluated. Thus, in addition to using young (3 months old; learning unimpaired) and aged (24 months old; learning impaired) rats in the experiments, a third group (20 months old) be used. In this latter population, some animals will have intact learning ability, while others will be learning impaired. Within-subject comparisons of learning ability and measures of hippocampal cholinergic function can be made in this group independent of age, and will provide the strongest test of correlations between physiological/biochemical parameters and learning ability. Finally, the effect of chronic infusion of nerve growth factor (NGF), a trophic substance which is necessary for the survival of central cholinergic neurons, upon the above described behavioral and electrophysiological/biochemical measures will be evaluated.
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