Several lines of evidence suggest that large cholinergic neurons of the forebrain cholinergic (Ch) system, which project to amygdala, hippocampus, and neocortex, play a role in the neural mechanisms of electroencephalogram (EEG) activation, learning, and memory. Moreover, it has been suggested that impairments in the Ch system may be responsible for some of the memory dysfunctions in aging and that severe cholinergic deficiencies may be important in the pathogenesis of the dementia of Alzheimer's disease (AD) and senile dementia of the Alzheimer's type (SDAT). If we are to understand the roles of this system in the geriatric memory dysfunction and dementia of AD, knowledge of the organization and functional properties of the Ch system is essential. To clarify the roles of the Ch system in health, aging, and disease, we will use immunocytochemical and histochemical methods, computer-assisted morphometric studies, retrograde and anterograde transport techniques, [3H] ligand receptor autoradiography, assays of transmitter-specific enzymes, unit recordings, microstimulation, EEG, and a variety of behavioral tests to assess the Ch system in: normal rats and nonhuman primates; animals with selective lesions of the Ch system; and nonhuman primates showing age-associated functional and structural abnormalities, including memory dysfunction and neuritic plaques. Lesioned animals and aged animals will be assessed as potential models for evaluating pharmacological strategies to improve the functions of the Ch system. These multidisciplinary approaches, which are designed to clarify the structure and functions of the Ch system, are essential if we are to understand the contributions of cholinergic and other transmitter-specific abnormalities in the clinical manifestations of aging and AD/SDAT. Only by understanding the normal and abnormal biology of these processes can we expect to design rational approaches to deal with these neurological disorders that affect so many individuals in our society.
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