Exploring the Role of Acetylcholine in Primate Cognition Using Me20.4 IgG-Saporin

Two factors led to the emergence of the “cholinergic hypothesis of geriatric memory dysfunction” (1): evidence that cholinergic blockade in human volunteers leads to impaired acquisition of new information (2,3) and the demonstration of loss of cortical cholinergic activity and loss of cholinergic cell bodies in the basal forebrain of patients dying with Alzheimer’s disease (4–6). It has been proposed that it is the loss of the rising cholinergic pathways from the basal forebrain to the cortex (including the hippocampus) that is responsible for the amnesia seen in dementing illnesses (6). This view has been challenged (e.g., in ref. 7). Cholinergic antagonists also block transmission at cholinergic neurons intrinsic to many subcortical areas and block transmission in the cholinergic projections to noncortical areas; this may affect memory, either directly or via an influence on arousal and attention. Furthermore, studies with rats did not produce a correlation between the magnitude of cholinergic loss in the basal forebrain across various nonimmunotoxic lesion techniques and learning or performance impairments (8).