AMPA-INDUCED EXCITOTOXIC LESIONS OF THE BASAL FOREBRAIN - A SIGNIFICANT ROLE FOR THE CORTICAL CHOLINERGIC SYSTEM IN ATTENTIONAL FUNCTION

The aim of the present study was to clarify the role of the basal fore brain (BF)-cortical cholinergic system in visual attentional function by investigating the effect of alpha-amino-3-hydroxy-5-methyl-4-isoxaz ole propionic acid (AMPA)-induced lesions of the basal forebrain on pe rformance of a five-choice serial reaction time task. AMPA lesions in the present study produced a profound effect on performance of the tas k, as measured by choice accuracy and correct response latency. This d eficit was significantly greater than that observed in earlier studies following ibotenate- or quisqualate-induced lesions of the BF. Howeve r, detailed histological and biochemical analysis revealed three rathe r different BF lesions depending upon the batch of AMPA supplied. In o ne group of animals (BF/1) the deficits in task performance were subst antially greater and longer lasting compared to another group of lesio ned animals (BF/2), which showed behavioral recovery several months fo llowing the lesion. The former sustained severe pallidal damage in add ition to marked reductions in cortical ChAT activity. Support for the attentional nature of these deficits was obtained by the ability to im prove task performance in BF/1 lesioned animals by increasing the dura tion of the visual stimulus and thus reducing the attentional load pla ced on these animals. In contrast, performance deficits could be reins tated in those animals showing behavioral recovery (BF/2) by reducing the duration of the visual stimulus and thus increasing attentional lo ad. In the second experiment more discrete lesions of the magnocellula r cholinergic neurons were made, resulting in extensive reduction of c ortical ChAT activity with considerably less neuronal loss from the do rsal pallidum compared to the BF/1 lesion group. Once again, deficits on the task were substantially greater than observed previously follow ing either quisqualate- or ibotenate-induced BF lesions. Furthermore, the cholinergic specificity of these deficits was supported by the att enuation of behavioral impairments following administration of the ant i-cholinesterase physostigmine. Taken together with our earlier work, which has failed to demonstrate mnemonic deficits following lesions to the magnocellular neurons of the nucleus basalis of Meynert, these re sults suggest that the most consistent deficit produced following lesi ons of the BF-cortical cholinergic system is attentional dysfunction. Analogous deficits in visual attention are also seen in patients with Alzheimer's disease, which can also be improved by anti-cholinesterase treatment.