Effects of cholinergic-rich neural grafts on radial maze performance of rats after excitotoxic lesions of the forebrain cholinergic projection system--I. Amelioration of cognitive deficits by transplants into cortex and hippocampus but not into basal forebrain

Abstract

After ibotenate (10.0 mg/ml) lesions to the nucleus basalis and medial septal regions, at the source of the cortical and hippocampal branches of the forebrain cholinergic projection system, rats displayed long-lasting stable impairment in reference and working memory in both spatial (place) and associative (cue) radial maze tasks. Cell suspension transplants of cholinergic-rich fetal basal forebrain tissue dissected at embryonic day 15 substantially improved all aspects of radial maze performance to a comparable degree whether sited in cortex, hippocampus, or both regions of the host brain. No additive effects were obtained with grafts in both terminal regions, but total graft volume, assessed stereologically, showed a significant negative correlation with error scores. Rats with behaviourally effective grafts, like controls, were disrupted in the place task when tested in dim light which obscured extra-maze spatial cues. Lesioned rats were not affected by change in lighting. Grafts of cholinergic-poor fetal hippocampal tissue did not improve radial maze performance; neither did grafts of cholinergic-rich tissue placed within the host basal forebrain lesion sites. In rats with cholinergic-rich terminal grafts, cortical and hippocampal choline acetyltransferase activity was restored to control level, commensurate with site of transplant, whereas it was significantly reduced in lesioned animals and those with functionally ineffective grafts. The indiscriminate error pattern and insensitivity to changes in lighting shown by lesioned rats suggested that lesioning primarily disrupted attention rather than short- or long-term spatial or associative memory processes. Since rats with cholinergic-rich grafts showed both reduced errors and recovery of stimulus control, the data indicated that grafts affected information processing, rather than changes in motor or motivational processes. Changes in choline acetyltransferase activity and the behavioural efficacy of cholinergic-rich grafts are consistent with the involvement of acetylcholine in the behavioural deficits and recovery displayed by lesioned and grafted groups, but do not rule out contributions from other factors. The equipotency of grafts within each terminal region suggests also that there may be a considerable degree of functional cooperation between the two branches of the forebrain cholinergic projection system. Functional recovery may involve local, nonspecific synaptic or paracrine mechanisms within the target regions, since grafts were efficacious only when placed in the terminal areas, but not when sited homotopically in the basal forebrain, indicating that they did not achieve any functionally significant structural repair to the host brain at that site.