Abstract

Cognitive deficits were produced in rats by different methods of damaging the brain: chronic ingestion of alcohol, causing widespread damage to diffuse cholinergic and aminergic projection systems; lesions (by local injection of the excitotoxins, ibotenate, quisqualate, and AMPA) of the nuclei of origin of the forebrain cholinergic projection system (FCPS), which innervates the neocortex and hippocampal formation; transient cerebral ischaemia, producing focal damage especially in the CA1 pyramidal cells of the dorsal hippocampus; and lesions (by local injection of the neurotoxin, colchicine) of the granule cells of the dentate gyrus. Following chronic alcohol or lesions of the FCPS, transplants of cholinergically rich fetal brain tissue into the terminal areas (neocortex and/or hippocampus) restored performance almost to control levels, with a time course consistent with growth of the transplants and integration with host tissue; transplants of cholinergically poor fetal tissue (hippocampus) were without effect, as were transplants of cholinergically rich tissue into the region containing the nuclei of origin of the FCPS. Grafts of primary cells enriched in glia and cultured neuroblastoma cells into the terminal areas of the FCPS were equally effective, suggesting that there are multiple mechanisms by which neural transplants can restore cognitive function following diffuse cholinergic damage. In contrast, after ischaemia- or neurotoxin-induced damage to CA1 or dentate granule cells respectively, cholinergically rich fetal transplants into the damaged hippocampal formation were ineffective in restoring performance. After ischaemic damage, however, performance was restored by suspension grafts of CA1 cells but not by transplants containing CA3 pyramidal cells or granule cells; and after colchicine damage it was restored by solid grafts containing granule but not CA1 pyramidal cells. Furthermore, electrophysiological evidence has demonstrated functional, graft type-specific host-graft functional neuronal connectivity. Thus, restoration of cognitive function by neural transplants is possible after damage to either diffuse (cholinergic) or point-to-point (intrahippocampal) forebrain systems, but the transplant must be appropriate to the damage to be repaired. Because the different types of brain damage studied provide analogues of human alcoholic dementia, Alzheimer's disease, and heart attack, these results are encouraging with regard to the eventual application of neural transplant surgery to the treatment of cognitive deficits in humans