The basal forebrain-cortical cholinergic system: interpreting the functional consequences of excitotoxic lesions

Ibotenic acid and kainic acid lesions of the basal forebrain induce profound deficits in performance on a wide variety of tasks involving discrimination learning and memory. These observations have been widely taken to reflect damage of cholinergic projections from the nucleus basalis magnocellularis (NBM) to the neocortex, and to provide an animal model of dementia. However, injections of the toxins quisqualic acid and, more recently, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) into the same site, which produce at least as extensive cholinergic cell loss, induce only marginal impairments on the same range of cognitive tasks. Further analysis suggests that the cholinergic regulation of the neocortex may influence specific aspects of discrimination learning and visual attention. Conversely, we propose that many of the functional consequences of ibotenic acid lesions on mnemonic tasks cannot be attributed to disruption of basal forebrain cholinergic systems, but may instead result from damage in the globus pallidus to corticostriatal output pathways.