This is a competitive renewal application for a project that focuses on the systems-level organization of cholinergic innervation in the cerebral cortex of the monkey and human brain. The experiments proposed in this investigation have immediate implications for understanding the neurochemical substrate of memory and arousal, the pathogenesis of Alzheimer's disease and the cognitive potential of normal aging. We will continue to investigate the regional variations of cortical cholinergic innervation in the human cerebral neocortex, the comparative cytochemical signature of cholinergic neurons and their cortical projection patterns. Our recent studies showed that the human brain contains a vast network of acetylcholinesterases (AChE)-rich intra-cortical cholinoceptive neurons with an unusual and perhaps uniquely human developmental profile. The AChE-rich staining pattern of these neurons is not detectable until mid-to-late childhood, becomes established during early adulthood and maintains a remarkable stability into advanced senescence in non-demented individuals. Homologous neurons are not conspicuous in other animals species. These neurons may provide an anatomical substrate for development and plasticity during adulthood and perhaps even during healthy old age. These AChE-rich neocortical neurons appear to be depleted in Alzheimer's disease and may contribute to the genesis of cognitive deficits in patients with this condition. While these neurons represent a subset of cortical cholinoceptive cells, there are reasons for suggesting that their intense AChE activity is also associated with a host of non-cholinergic mechanisms that range from proteolysis to neural plasticity. One focus of this proposal aims to elucidate the cytochemical signature and developmental regulation of these neurons and their fate in the course of Alzheimer's disease. In a special sample of cognitively evaluated, non-demented senescent subjects we will determine if cognitive performance in old age is correlated with the density of these neurons and with the density of cortical cholinergic afferents. The methods to be employed include enzyme histochemistry, immunocytochemistry, in situ hybridization, electron microscopic histochemistry and axonal tracing (with horseradish peroxidase and fluorescent tracers) in the monkey brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS020285-08
Application #
3400569
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1984-09-01
Project End
1995-11-30
Budget Start
1991-12-23
Budget End
1992-11-30
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Mesulam, M-Marsel (2013) Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer's disease. J Comp Neurol 521:4124-44
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Mapstone, Mark; Weintraub, Sandra; Nowinski, Caralynn et al. (2003) Cerebral hemispheric specialization for spatial attention: spatial distribution of search-related eye fixations in the absence of neglect. Neuropsychologia 41:1396-409
Mesulam, Marsel; Guillozet, Angela; Shaw, Pamela et al. (2002) Widely spread butyrylcholinesterase can hydrolyze acetylcholine in the normal and Alzheimer brain. Neurobiol Dis 9:88-93
Mesulam, M-M; Guillozet, A; Shaw, P et al. (2002) Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience 110:627-39
Mesulam, M M (2000) A plasticity-based theory of the pathogenesis of Alzheimer's disease. Ann N Y Acad Sci 924:42-52
Mesulam, M M (1999) Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron 24:521-9
Mesulam, M M (1998) Some cholinergic themes related to Alzheimer's disease: synaptology of the nucleus basalis, location of m2 receptors, interactions with amyloid metabolism, and perturbations of cortical plasticity. J Physiol Paris 92:293-8
Selden, N R; Gitelman, D R; Salamon-Murayama, N et al. (1998) Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain 121 ( Pt 12):2249-57

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