ArticlesThe Role of the Central Cholinergic Projections in Cognition: Implications of the Effects of Scopolamine on Discrimination Learning by Monkeys
Introduction
Despite the early view that central cholinergic projection systems are critically involved in learning and memory, doubt has been cast on this by studies of the effects on learning of lesions of the site of origin of these projection systems [20]. In rodents, stereotaxic injections of quisqualic acid or α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) into the basal nucleus of Meynert (NBM), which produced relatively large lesions of the cholinergic projection to the neocortex, were found to be less disruptive of task performance than were lesions produced by less specific excitotoxins, such as ibotenic or kainic acid [18]. This suggested that some of the impairments observed in studies using ibotenic or kainic acid may have been due to damage to noncholinergic cells. Although some of the tasks reviewed by Dunnett et al. [18]involved postlesion acquisition, i.e., learning, and others involved postlesion measurement of delay-dependent performance of preoperatively acquired delayed-matching type tasks (where such performance is assumed to measure memory across the delay period), some tests were concerned with more general aspects of behaviour. Where performance of a task is not affected but acquisition is impaired, then it is unlikely that the learning difficulty is a result of some more general dysfunction. For example, Dunnett et al. [19]found that while rats with quisqualic acid lesions of the NBM were not impaired on performance of delayed matching and delayed nonmatching to position tasks, they were impaired on postoperative acquisition of, or postoperative reversal to, delayed nonmatching to position but not delayed matching to position. These results suggest that the lesion does not impair memory in general across the delay, nor does it impair learning in general, but rather that it impairs the acquisition of information in some particular way that is specific for learning nonmatching tasks. Several studies in rats using the excitotoxins ibotenic acid, quisqualic acid, or AMPA have indicated that the NBM may have a role in the performance of serial reaction-time tasks which are thought to measure attention rather than learning or memory 40, 59. Quisqualic acid or AMPA lesions of the cholinergic projections from the medial septum and vertical limb of the diagonal band (MS/VDB) in rats did, however, produce substantial impairments in learning certain conditional tasks [34], even though rats with this lesion were unimpaired in the performance of an attentional task [39]. These results indicate that it is inappropriate to attempt to ascribe a unitary function to the role of the basal forebrain cholinergic system.
Combined excitotoxic lesions of the MS/VDB and NBM, using quisqualic acid, produce impairments in performance of the preoperatively acquired reference-memory component and of the working-memory component of completing the eight-arm radial maze [70]. These wide-ranging impairments suggest that combined lesions may be very effective, possibly because many tasks can be solved by using cognitive strategies served by either the NBM or MS/VDB. This experiment does not, however, address the issue of task acquisition. Here we consider the evidence, mainly in monkeys, for and against a role for the cholinergic systems in learning, by which we mean the acquisition of information into long-term memory.
Section snippets
Immunotoxic Lesions of the NBM and MS/VDB in Rodents
Highly specific cholinergic lesions of the NBM, MS/VDB, or both, have been produced in rats using the immunotoxin 192 IgG-saporin. Many of these studies have used behavioural tests that do not measure acquisition into long-term memory and are not considered further. Berger-Sweeney et al. [11]found impairment in acquisition and performance of place location in the water maze following immunotoxic lesion of the NBM, but the possibility that the impairment was related to collateral damage in the
Monkey Studies
In monkeys, excitotoxic lesions of the NBM result in modest, or short-lasting, impairments in the learning, retention, and reversal of visual discrimination tasks 47, 49, 55, 60, 61. Irle and Markowitsch [28]found more enduring effects of ibotenic acid lesions of the NBM on visual discrimination learning, reversal, and concurrent discrimination learning. A large and persistent impairment in learning certain conditional tasks (including a visuospatial task described below) is seen following
Effects of Scopolamine on Visual Discrimination Learning and Visuospatial Conditional Learning in Monkeys
Six young adult marmosets (Callithrix jacchus) with previous experience of visual discrimination learning and visuospatial conditional learning in the Wisconsin General Test Apparatus were used. Monkeys were trained on each task to a criterion of 27 correct responses in 30 consecutive trials and were presented with ∼ 40 trials per day.
In Experiment 1, each monkey was tested on acquisition of four simple visual discriminations using small, coloured plastic junk objects as stimuli. In Experiment
Results
Fig. 1 shows learning scores on the three types of tasks under scopolamine or saline. Two-way ANOVA with repeated measures showed a highly significant drug × task interaction (F 2, 20= 61.5, p < 0.001). Matched pairs t-tests showed that scopolamine produced a significant learning impairment in the perceptually difficult task using black objects (t = 2.84, 5 df, p < 0.05) and in the visuospatial conditional task (t = 9.85, 5 df, p < 0.001). The effect of scopolamine on perceptually easy tasks
Effects of Scopolamine on Visuospatial Learning in Monkeys
The present experiments indicate that scopolamine produces a significant impairment of the learning of visuospatial conditional tasks (as well as of the learning of visual discrimination tasks using perceptually similar stimuli, exemplified by black objects).
Excitotoxic lesion of the CA1 field of the hippocampus [58], fornix transection 54, 57, or excitotoxic 44, 56or immunotoxic (Ridley et al. 1997, in preparation) lesion of the MS/VDB results in a learning impairment that is specific to the
Acknowledgements
The authors would like to thank Wyeth-Ayerst for their support of J.A.H.
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