Central cholinergic neurons of the basal forebrain and possibly cerebral cortex contribute the cognitive processes. Dysfunctions of this system, as in Alzheimer's Disease, result in cognitive deficits. The long term goals of this project are to better understand the anatomical and functional organization of this system, and the abnormalities that can result in disease. In the present proposal, monoclonal antibodies previously developed against the cholinergic marker choline acetyltransferase (ChAT) will be employed to study the synaptic organization and development of cholinergic pathways in the basal forebrain and cerebral cortex. The topography and neurochemical identity of basal forebrain cortical projections will be studied by combination horseradish peroxidase retrograde transport and ChAT immunohistochemistry. The neuronal targets and synaptic organization of cholinergic cortical innervation will be studied at the light/electron microscopic levels by combinations of ChAT immunohistochemistry, Golgi impregnation, lesioning, and retrograde transport. The development of the cholinergic basal forebrain system and its projections to cortex will be studied by [3H]-thymidine autoradiography to determine neuronal birth dates and possible migration patterns; ChAT-immunohistochemistry for determination of neuronal phenotype expression; and retrograde tracing to determine the developmental time course of cortical projections. In order to gain greater resolution of cholinergic synapses and targets, monoclonal antidodies will be developed against the high affinity choline transport system and against muscarinic receptors, which are preferentially localized in cholinergic terminal fields. In addition, reagents and techniques will be developed to allow for immunocytochemical studies of cholinergic systems in ordinary post-mortem human tissues. The information provided from these studies will offer a better understanding of cholinergic function in health and in disease.
