08 Jun 1999

The "cholinergic hypothesis" of cognition places emphasis on the role of cholinergic neurons in the basal forebrain and their projections to cortical areas. This hypothesis is based to a large extent on findings that this system is compromised in normal human aging as well as in dementia. There is further support from animal studies that correlate basal forebrain lesions or cholinergic antagonists with adverse cognitive effects. A recent report, published in Neuroscience, by John Bruno, Martin Sarter, and James Fadel describes an attempt to distinguish deficits in the cholinergic system caused by aging versus those caused by specific lesions.

Bruno and colleagues used microdialysis to study the efflux of ACh in the frontoparietal cortex of young and old rats with lesions in the ventral pallidum/substantia inominata region of the basal forebrain. As expected, the lesions reduced baseline cortical ACh efflux in both young and old animals. However, an environmental stimulus that signaled food (in combination with the benzodiazepine receptor weak inverse agonist ZK 93 426), was still capable of increasing ACh efflux in the young rats with lesions (as well as in the old rats without lesions). On the other hand, in the old rats with basal forebrain lesions, the cholinergic system was not capable of responding to the stimuli with increased ACh efflux.

The authors suggest that these results support the idea that aging can act as an "intervening variable" that by itself does not diminish the responses of the cholinergic system, but may work in concert with underlying pathologies to give rise to aging-related neurodegenerative disorders such as Alzheimer's disease.—Hakon Heimer

For a theoretical discussion of these issues, see Sarter and Bruno.