Subpopulations of rats show a significant decline in learning and memory during the aging process which is not attributable to sensory, motor or motivational deficits. The basal forebrain cholinergic system is also impaired in these behaviorally impaired aged rats. In addition, evidence supports a decline in Nerve Growth Factor (NGF) and NGF receptors and their respective mRNAs in aged animals. Further, high voltage EEG spindles (HVS) in the neocortex which can disrupt cognitive function are increased dramatically with aging and are controlled in part through cholinergic neurons in the basal forebrain. Finally, the inserted form of the amyloid precursor protein (APP-751) which is regulated in part by NGF is abnormally expressed in the aged, behaviorally impaired rats. We wish to determine whether and/or which of these physiological markers of aging are causally linked to the age related learning and memory deficits. To test the generalizability of these results we will repeat the experiments in several rat strains, and will expand the learning test repertoire. We have shown that chronic infusions of the NGF can have a positive influence of retention in the learning task of the aged impaired animals, and that grafts of fetal basal forebrain tissue to the brains of the aged impaired animals have an ameliorative effect on acquisition in the same learning task. In the present set of experiments we propose to test the influence of NGF infusions, intracerebral rafts of fetal basal forebrain and a combination of NGF and intracerebral grafting on the physiological parameters described above in an attempt to determine whether any of these parameters are influenced by the treatments which have ameliorative influences on aspects of aged related behavioral impairments. These experiments are designed to test experimental therapeutic protocols in behaviorally impaired aged animals, and to determine the functional relationship between cholinergic activity, NGF function, and expression of the APP.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Neurology B Subcommittee 2 (NEUB)
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Salk Institute for Biological Studies
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