Clinical and neurochemical studies have provided compelling evidence that cortical cholinergic pathways are consistently and severely affected in Alzheimer's type dementia (AD). We have demonstrated in the rat that the primary source of cortical cholinergic innervation is the nucleus basalis (nBM) and that these neurons atrophy and/or degenerate in patients dying with AD. In studies supported by this grant, we have characterized the organization of the cortical/hippocampal cholinergic projections in the rat and have demonstrated that they regulate cortical muscarinic receptors. We have also demonstrated that rats with lesions either in the nBM, medical septal area or both sites exhibit selective impairments in working memory but not reference memory, analogous to the cognitive defects observed early in AD. However, we have found that the lesioned rats exhibit behavioral and neurochemical recovery unlike AD. In the proposed studies, we will focus on the issues of selective vulnerability of cholinergic neurons and mechanisms involved in behavioral and neurochemical recovery after lesions of the basal forebrain cholinergic complex. 1. We will use a combination of neurochemical and neuroanatomic techniques to determine the source of recovering cholinergic markers in the prefrontal cortex following nBM lesions. 2. We will characterize the mechanism of cytotoxicity of ethylcholine aziridinium ion against cholinergic neurons. We will use this drug to characterize the choline carrier. 3. We will determine the factors that account for behavioral recovery following lesions of the basal forebrain cholinergic complex and we will characterize the differential behavioral impairments associated with either the nBM or medial septal lesions that result in a similar defect in working memory. These basic studies in the rat may clarify the role of the nBM cholinergic deficit in the pathophysiology of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS018414-05
Application #
3398461
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1982-06-01
Project End
1992-05-31
Budget Start
1986-06-01
Budget End
1987-05-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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