Degenerative Changes in Forebrain Cholinergic Nuclei Correlate with Cognitive Impairments in Aged Rats

Abstract

Degenerative changes in the forebrain cholinergic nuclei have been studied morphometrically in behaviourally characterized aged female Sprague-Dawley rats. In all regions analysed (medial septum, diagonal band of Broca, nucleus basalis, and striatum) the acetylcholinesterase-positive neurons were reduced in both size and number in the aged (24-months-old) rats as compared to the young (3-months-old) controls. The overall reduction in cell size amounted to between 20 and 30% and the overall reduction in cell number to between 27 and 45%. Impairment in learning and/or memory performance in the aged rats, as assessed in the Morris' water-maze task, was significantly correlated with both cholinergic cell size and cell number in the medial septum, and with cholinergic cell number in the diagonal band of Broca and in the striatum. In the nucleus basalis there was a trend in the same direction but it did not reach significance. In contrast to these degenerative changes in the cell body regions, no significant differences in cortical or hippocampal choline acetyltransferase activity were detected biochemically between the young and the aged rats, and the enzyme activity levels did not correlate with the degree of behavioural impairment in the aged rats. The present results provide evidence that all major forebrain cholinergic cell groups undergo degenerative changes with age in the rat, and that the most severe changes are found in those rats which display the most profound spatial learning impairments. Despite the severe changes at the cell body level, however, the choline acetyltransferase activity in the cortical projection areas are affected only to a minor degree, perhaps as a result of functional compensatory changes at the terminal level.

Selective Antibody-Induced Cholinergic Cell and Synapse Loss Produce Sustained Hippocampal and Cortical Hypometabolism with Correlated Cognitive Deficits

“…Many animal studies have shown that acetylcholine neurotransmission in both neo-and allocortex can, if disrupted, create severe deficits in cognitive function (20,21). Deficits in memory tasks have been found after loss of cholinergic input to the hippocampus, based on extensive studies of fimbria-fornix lesions (also creating some extracholinergic damage) (38,48,54,59) or cholinergic degeneration associated with aging (21,25,76).…”

“…Deficits in memory tasks have been found after loss of cholinergic input to the hippocampus, based on extensive studies of fimbria-fornix lesions (also creating some extracholinergic damage) (38,48,54,59) or cholinergic degeneration associated with aging (21,25,76). NBM lesions, causing loss of neocortical cholinergic input, have suggested an important role for acetylcholine in cortical neurotransmission for attention to stimuli, and therefore indirectly to learning and memory formation (18,68,77).…”

Neurocognitive aging: prior memories hinder new hippocampal encoding

“…The decrease in ACh-mediated modulation is reflected in reductions in the levels of ACh-processing enzymes in the medial septum, which provides the major cholinergic innervation to all three subregions of the hippocampus (see Figure 1 for modulation details) [42][43][44][45][46]. Furthermore, there is a blunted response in aged animals in all three hippocampal subregions to electrophysiological stimulation of cholinergic input fibers [47].…”

The role of nerve growth factor in Alzheimer's disease

“…However, this conflicted with Larkfors et al (1987) who, using rats known for age dependent changes, noted significant falls in the levels of both NGF and NGF mRNA in aged rats. Cognitive impairments in aged rats, as assessed by maze test performance, are due to degenerative changes in the forebrain cholinergic neurons (Fischer et al 1989). These cognitive impairments are reversed with cerebral intraventricular infusion of NGF (Fischer et al 1987).…”