Dysfunction of the cholinergic septo-hippocampal system is thought to be a major factor underlying the memory loss and cognitive deficits associated with aging. The objective of this proposal is to clarify the relationship between age-dependent loss or atrophy of cholinergic neurons in the basal forebrain and the progression of age-related impairments in hippocainpal information processing. This objective will be pursued in mature, middle-aged, and aged rats using neuroanatomical, neurobehavioral, and neurophysiological techniques. This proposal is unique in correlating these multidisciplinary measures in individual animals. These studies will characterize in detail the changes which occur with normal aging in cholinergic neurons of the basal forebrain. Progress along this line of research will provide the basis for developing pharmacological strategies for the prevention and treatment of age-related neurodegenerative disorders, such as Alzheimer's disease. The specific aims of the research plan are: 1) To characterize age-dependent changes in the distribution and morphology of cholinergic projection neurons in the brains of mature, middle-aged, and aged rats. This aim will be addressed by constructing detailed cell maps of choline acetyltransferase (ChAT) immunoreactive cells in the basal forebrain. 2) To relate the age-dependent changes in cholinergic projection neurons determined in Specific Aim #1 to corresponding functional deficits in behavioral tasks which require an intact septo-hippocampal cholinergic system. Animals which show age-dependent dysfunction will be examined for specific patterns of atrophy in the basal forebrain cholinergic system as determined in Specific Aim #1. 3) To utilize electrophysiological assessments of hippocampal cell activity during continual tracking of delayed match-to-sample (DMTS) and delayed nonmatch-to-sample (DNMTS) performance in aged rats as signatures of age-dependent dysfunction of the septo-hippocampal cholinergic projection system. 4) To retard or reverse age-dependent changes in functional, anatomical, and electrophysiological indices of cholinergic system deterioration through chronic administration of nerve growth factor (NGF). This aim will provide a critical test of the putative cholinergic mechanism of NGF-induced facilitation of memory in aged rats.