Elsevier

Brain Research Bulletin

Volume 45, Issue 3, February 1998, Pages 319-326
Brain Research Bulletin

Articles
The Role of the Central Cholinergic Projections in Cognition: Implications of the Effects of Scopolamine on Discrimination Learning by Monkeys

https://doi.org/10.1016/S0361-9230(97)00381-XGet rights and content

Abstract

In humans, administration of the cholinergic antagonist scopolamine impairs the encoding of information into long-term memory and has effects on other cognitive processes. It has been supposed that it is inhibition of the rising cholinergic projections from the basal forebrain, specifically from the basal nucleus of Meynert (NBM) to the neocortex and from the medial septum/vertical limb of the diagonal band of Broca (MS/VDB) to the hippocampus, that results in these cognitive impairments. In this paper, we describe the effects of scopolamine treatment in monkeys on learning different sorts of visual discrimination and visuospatial conditional tasks and compare these results to the effects of lesions of the rising cholinergic projections. Experiments in rodents in which these projections have been selectively destroyed have failed to produce a consensus view of the functions of these two areas. In particular, highly specific immunotoxic lesions of the NBM have largely failed to produce changes in task performance that can be interpreted as resulting from a cognitive impairment. In monkeys, lesions of the NBM produce modest or short-lasting, impairments in visual discrimination learning, retention, and reversal, whereas lesions of the MS/VDB produce large and permanent impairments of certain types of conditional learning. Similar impairments produced by scopolamine in monkeys and additive effects of lesions of the NBM or MS/VDB with scopolamine suggest that scopolamine has these effects by acting on the rising cholinergic pathways rather than on other cholinergic systems in the brain. It is argued that the rising cholinergic projections sustain the functions of the target areas; in the case of the hippocampus in humans, the function is usually regarded as being the analysis of information in a way that is pertinent to the formation of episodic memories and in the case of the neocortex, is the analysis of information in a manner that is relevant to the cognitive processing of on-going events and the acquisition of semantic knowledge.

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.

References (74)

  • J.A. Horel

    Local and global perception examined by reversible suppression of temporal cortex with cold

    Behav. Brain Res.

    (1994)
  • J.A. Horel

    Retrieval of color and form during suppression of temporal cortex with cold

    Behav. Brain Res.

    (1994)
  • C.A. Kitt et al.

    Fibre pathways of basal forebrain cholinergic neurons in monkeys

    Brain Res.

    (1987)
  • C.J. Maclean et al.

    The distribution of p75 neurotrophin receptor-immunoreactive cells in the forebrain of the common marmoset (Callithrix jacchus)

    Brain Res. Bull.

    (1997)
  • J.L. Muir

    Attention and stimulus processing in the rat

    Cognit. Brain Res.

    (1996)
  • J.L. Muir et al.

    Dissociable effects of AMPA-induced lesions of the vertical limb diagonal band of Broca on performance of the 5-choice serial reaction time task and on acquisition of a conditional visual discrimination

    Behav. Brain Res.

    (1996)
  • E.K. Perry et al.

    Neurotransmitter enzyme abnormalities in senile dementia

    J. Neurol. Sci.

    (1977)
  • R.M. Ridley et al.

    Learning about rules but not about reward is impaired following lesions of the cholinergic projection to the hippocampus

    Brain Res.

    (1989)
  • R.M. Ridley et al.

    A critical evaluation of monkey models of amnesia and dementia

    Brain Res. Rev.

    (1991)
  • R.M. Ridley et al.

    Restoration of cognitive abilities by cholinergic grafts in cortex of monkeys with lesions of the basal nucleus of Meynert

    Neuroscience

    (1994)
  • R.M. Ridley et al.

    An involvement of acetylcholine in object discrimination learning and memory in the marmoset

    Neuropsychologia

    (1984)
  • R.M. Ridley et al.

    Stimulus-bound perseveration after frontal ablations in marmosets

    Neuroscience

    (1993)
  • R.M. Ridley et al.

    Cognitive inflexibility after archicortical and paleocortical prefrontal lesions in marmosets

    Brain Res.

    (1993)
  • R.M. Ridley et al.

    Restoration of learning ability in fornix-transected monkeys after fetal basal forebrain but not fetal hippocampal tissue transplantation

    Neuroscience

    (1992)
  • R.M. Ridley et al.

    Learning impairment following lesion of the basal nucleus of Meynert in the marmosetModification by cholinergic drugs

    Brain Res.

    (1986)
  • R.M. Ridley et al.

    Visuospatial learning impairment following lesion of the cholinergic projection to the hippocampus

    Brain Res.

    (1988)
  • R.M. Ridley et al.

    Conditional learning and memory impairments following neurotoxic lesion of the CA1 field of the hippocampus

    Neuroscience

    (1995)
  • A.C. Roberts et al.

    The effects of excitotoxic lesions of the basal forebrain on the acquisition, retention and serial reversal of visual discriminations in marmosets

    Neuroscience

    (1990)
  • A.C. Roberts et al.

    A specific form of cognitive rigidity following excitotoxic lesions of the basal forebrain in marmosets

    Neuroscience

    (1992)
  • N.M.J. Rupniak et al.

    Direct comparison of cognitive facilitation by physostigmine and tetrahydroaminoacridine in two primate models

    Neurobiol. Aging

    (1990)
  • B.J. Spiegler et al.

    Evidence for the sequential participation of inferior temporal cortex and amygdala in the acquisition of stimulus-reward associations

    Behav. Brain Res.

    (1981)
  • J.J. Waite et al.

    192 Immunoglobulin G-saporin produces graded behavioral and biochemical changes accompanying the loss of cholinergic neurons of the basal forebrain and cerebellar Purkinje cells

    Neuroscience

    (1995)
  • T.G. Aigner et al.

    Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic-acid lesions of the nucleus basalis of Meynert

    Psychopharmacology

    (1987)
  • T.G. Aigner et al.

    Transient impairment of recognition memory following ibotenic-acid lesions of the basal forebrain in macaques

    Exp. Brain Res.

    (1991)
  • P. Alvarez et al.

    Damage limited to the hippocampal region produces long-lasting memory impairment in monkeys

    J. Neurosci.

    (1995)
  • M.G. Baxter et al.

    Selective immunotoxic lesions of basal forebrain cholinergic cellsEffects on learning and memory in rats

    Behav. Neurosci.

    (1995)
  • M.G. Baxter et al.

    Intact spatial learning following lesions of the basal forebrain cholinergic neurons

    NeuroReport

    (1996)
  • Cited by (0)

    View full text