The purpose of this research program is to study the behavioral and neurochemical responses to experimentally-induced neurodegeneration in the basal forebrain cholinergic system of young and aged rats. Neurodegeneration in this area is associated with the cognitive deficits observed in aging and Alzheimer's disease. Lesions were made using the neurotoxicant colchicine, which binds to tubulin and blocks mitosis and axoplasmic transport. Initial studies examined the neurobiological effects of the colchicine in the nucleus basalis. Stereotaxic infusion of colchicine resulted in damage limited to the site of injection, and decreased the number of cholinergic cells in the nucleus basalis. Histochemical and neurochemical analysis showed that colchicine lesions reduced presynaptic cholinergic markers including acetylcholinesterase, choline acetyltransferase and muscarinic receptor binding in the cortex. nucleus basalis lesions had no effect on cholinergic markers in the hippocampus or striatum. At long post-lesion time points, recovery of cholinergic function in the cortex was observed. Behaviorally, colchicine lesions of the nucleus basalis resulted in impaired acquisition of both short-term and long-term memory tasks. Further studies characterized the effects of colchicine lesions of the medial septum. Intracerebroventricular administration of colchicine produced selective destruction of cholinergic cells in the medial septum, resulting in a decrease in cholinergic markers restricted to the hippocampus and an impairment of long-term memory. Future studies are planned to study the compensatory changes which occur after basal forebrain lesions including recovery of function and cholinergic activity, changes in cholinergic receptor mediated phosphoinositide turnover, and synaptic sprouting in response to neurotrophic factors. An important factor in all of these studies will be the comparison of young and aged animals, since compensation may be comprised with age.
