A number of disorders characterized by selective degeneration of sets of neurons in the central nervous system are associated with both neurologic and psychiatric symptoms. These disorders, which lie at the borderlands between psychiatry and neurology including Huntington's disease and senile dementia of the Alzheimer's type (SDAT), are important in their own right as well as in terms of insights they may provide to symptom formation in """"""""functional"""""""" psychiatric disorders. A major, continuing interest of the PI concerns elucidation of the synaptic pathology of lesions placed in experimental animals similar to those found in the human neurodegenerative disorders. During the following period of support, the role of cortical cholinergic systems will be examined as they may shed light on the pathophysiology of SDAT. Several studies have demonstrated that the presynaptic markers for cholinergic neurons are profoundly and consistently reduced in the cortex of patients dying with SDAT. Using excitotoxin lesion methods, we have demonstrated that the nucleus basalis of Meynert (nBM) is a major source of cholinergic innervation to the crebral cortex and is profoundly affected in SDAT. The goal of the proposed studies is to define the neuroanatomic organization and synaptic chemistry of the cholinergic innervation of the cerebral cortex and the alterations produced by selective ablation of the nBM. 1) Through the combined application of selective excitotoxin lesions, neurochemical analysis and retrograde transport histologic methods, we shall define the topographic organization of the magnocellular cholinergic projections to cerebral cortex. 2) The role of cortical cholinergic afferents and intrinsic neurons in the regulation of cortical muscarinic receptors will be re-examined with a combination of pharmacologic and lesion techniques. 3) The adaptive effects of surviving cholinergic inputs to neocortex as well as plastic and adaptive responses of noradrenergic and serotonergic cortical afferents will be examined after excitotoxin lesion of nBM. 4) The ability of indirectly and directly cholinomimetics to correct lesion-induced cortical cholinergic deficits will be examined. 5) Factors regulating the levels of secretory acetylcholinesterase in the cerebral spinal fluid tone or integrity. 6) Choline acetyltransferase, the enzyme that synthesizes acetylcholine, will be purified to homogeneity to raise antisera for immunocytochemical visualization of cortical intrinsic and afferent cholinergic projections.
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