Biomedical subjects

J L Muir

Publications and source records attributed to J L Muir.

At least 37 records · Page 2Linked to original sources

PubMed1998

Neural systems underlying arousal and attention. Implications for drug abuse.

The monoaminergic and cholinergic systems are implicated in different forms of behavioral arousal that can be dissected in terms of their forebrain targets and the nature of the behavioral processes they modulate in distinct regions. Thus, evidence in rats with selective neurochemical manipulations tested behaviorally using an analog of an attentional task developed for human subjects indicates that the coeruleo-cortical noradrenergic system is implicated in divided and selective attention, the basal forebrain cholinergic system in stimulus detection, the mesostriatal and mesolimbic dopaminergic systems in response speed and vigor, and the mesencephalic serotoninergic or 5-HT systems in response inhibition. Our recent studies have focused on fractionating, in the same task, the differential contributions of the dorsal and median raphé 5-HT systems as well as elucidating the functions of the mesocortical dopaminergic system, each of which may be relevant to understanding the behavioral and cognitive sequelae of cocaine administration in human subjects as well as in experimental animals.

Animals↗

PubMed1998

Fornix lesions can facilitate acquisition of the transverse patterning task: a challenge for "configural" theories of hippocampal function.

Configural theories of hippocampal function predict that hippocampal dysfunction should impair acquisition of the transverse patterning task, which involves the concurrent solution of three discrimination problems: A+ versus B-; B+ versus C-; and C+ versus A-. The present study tested this prediction in rats using computer-graphic stimuli presented on a touchscreen. Experiment 1 assessed the effects of fornix lesions when the three problems were introduced sequentially (phase 1: A+ vs B-; phase 2: A+ vs B-, B+ vs C-; phase 3: A+ vs B-, B+ vs C-, C+ vs A-). Fornix lesions significantly facilitated acquisition of the complete transverse patterning task (phase 3) but had no effect on the number of sessions or errors required to attain criterion during phase 1 or phase 2. In experiment 2, in which all three problems were presented concurrently from the outset of training, fornix-lesioned animals outperformed control animals during the seventh block of acquisition trials and were not impaired during any stage of acquisition. Importantly, these same animals were significantly impaired on two allocentric spatial tasks: T-maze alternation (experiments 1 and 2) and the Morris Swim Task (experiment 1). These results contradict the predictions of configural theories of hippocampal function and cast doubt on the popular notion that spatial learning is a special case of configural learning.

Animals↗

PubMed1998

Comparing the effects of selective cingulate cortex lesions and cingulum bundle lesions on water maze performance by rats.

The ability of rats to learn the location of a hidden platform in a swim maze was compared in animals with excitotoxic lesions of the anterior or posterior (retrosplenial) cingulate cortex or radiofrequency lesions of the cingulum bundle or fimbria-fornix. Performance of this allocentric spatial task was unaffected by the posterior cingulate cortex lesions, while anterior cingulate cortex damage produced only a mild acquisition deficit. Transection of the fornix and lesions of the cingulum bundle produced similar patterns of impairment on initial acquisition, but the cingulum bundle lesions had less effect on reversal of the task. The results from the water maze, and from a subsequent T-maze alternation task, indicate that cingulum bundle lesions can produce a spatial deficit that is similar, but milder, to that observed after fornix transection. The results of the excitotoxic lesions suggest that previous studies examining conventional cingulate lesions may have been influenced by damage to adjacent fibre tracts, such as the cingulum bundle.

Animals↗

PubMed1998

The cerebral metabolic effects of manipulating glutamatergic systems within the basal forebrain in conscious rats.

N-methyl-D-aspartate (NMDA) and non-NMDA receptor-mediated manipulations of the cortical cholinergic input arising from the basal forebrain differentially affect cognitive function. We used [14C]-2-deoxyglucose autoradiography in conscious rats to map the effects of excitatory amino acid agonist infusions into the nucleus basalis magnocellularis (NBM) on cerebral functional activity, as reflected by local rates of glucose utilization. Acute stimulation of NBM neurones by local infusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 15 min before glucose use measurement, resulted in glucose use reductions in nine cortical regions innervated by NBM efferents including prefrontal, frontal, sensorimotor and cingulate cortices. NMDA infusions altered glucose use in two cortical areas. Both AMPA and NMDA markedly increased glucose use in the striatum and globus pallidus, with concomitant perturbations in striato-pallidal projection targets including the substantia nigra, entopeduncular nucleus, subthalamic nucleus and lateral habenular nucleus. In contrast, the GABAA agonist muscimol did not affect glucose use in the NBM or neocortical regions, but induced glucose use increases in several subcortical nuclei including the substantia nigra and entopeduncular nucleus. The delayed effects of excitotoxic lesions were assessed 3 weeks after basal forebrain infusions of AMPA, NMDA, ibotenate or quisqualate. Statistically significant glucose use changes only occurred in the hypothalamus after NMDA, and the NBM after ibotenate infusions, although reduced cortical metabolism was apparent following AMPA-induced lesions of the NBM. Results support a dissociation between the functional sequelae of NMDA and non-NMDA receptor-mediated events in the basal forebrain, and long-term compensatory functional adaptation following cortical denervation.

Animals↗

PubMed1998

Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist.

Ciproxifan, i.e., cyclopropyl-(4-(3-1H-imidazol-4-yl)propyloxy) phenyl) ketone, belongs to a novel chemical series of histamine H3-receptor antagonists. In vitro, it behaved as a competitive antagonist at the H3 autoreceptor controlling [3H]histamine release from synaptosomes and displayed similar Ki values (0.5-1.9 nM) at the H3 receptor controlling the electrically-induced contraction of guinea pig ileum or at the brain H3 receptor labeled with [125I]iodoproxyfan. Ciproxifan displayed at least 3-orders of magnitude lower potency at various aminergic receptors studied in functional or binding tests. In vivo, measurement of drug plasma levels, using a novel radioreceptor assay in mice receiving ciproxifan p.o. or i.v., led to an oral bioavailability ratio of 62%. Oral administration of ciproxifan to mice enhanced by approximately 100% histamine turnover rate and steady state level of tele-methylhistamine with an ED50 of 0.14 mg/kg. Ciproxifan reversed the H3-receptor agonist induced enhancement of water consumption in rats with and ID50 of 0.09 +/- 0.04 mg/kg, i.p. In cats, ciproxifan (0.15-2 mg/kg, p.o.) induced marked signs of neocortical electroencephalogram activation manifested by enhanced fast-rhythms density and an almost total waking state. In rats, ciproxifan enhanced attention as evaluated in the five-choice task performed using a short stimulus duration. Ciproxifan appears to be an orally bioavailable, extremely potent and selective H3-receptor antagonist whose vigilance- and attention-promoting effects are promising for therapeutic applications in aging disorders.

Animals↗

PubMed1997

A behavioural analysis of the delayed non-matching to position task: the effects of scopolamine, lesions of the fornix and of the prelimbic region on mediating behaviours by rats.

The delayed non-matching to position task (DNMP) is a widely used automated test of spatial memory, yet its validity has been challenged by suggestions that animals use motor mediating behaviours which facilitate correct responding. This possibility was systematically studied by analysing video recordings of rats displaying delay-dependent and delay-independent deficits following lesions or drug manipulations. Rats were first trained to perform the DNMP task and whilst untreated, a number of potential mediating behaviours were identified from the video recorded behaviour. Two independent raters recorded any apparent motor strategies and attempted to predict the response the animals made during the choice phase of the task by viewing only behaviour during the delay periods. Subsequently, the behaviour of the same animals was examined following scopolamine treatment and following lesions of the prelimbic cortex or of the fornix. The experiment confirmed previous reports of delay-dependent and delay-independent deficits under the varying conditions (drug, lesions), but also revealed that rats use clearly identifiable mediating behaviours that appear to facilitate correct responding in the DNMP task. Consequently, apparent "memory" impairments in the DNMP task, may reflect a disruption of behavioural strategies used by the animal to assist in performing the task.

Animals↗

PubMed1997

Acetylcholine, aging, and Alzheimer's disease.

A substantial body of literature has suggested that the memory and learning deficits associated with Alzheimer's disease and aging are attributable to degeneration of the cholinergic magnocellular neurons of the nucleus basalis of Meynert (nbM). Subsequently, lesion-induced damage to the cholinergic projections from the nbM to the neocortex has been utilized extensively as an animal model of dementia. In addition, the effect of the normal aging process on deterioration of these neurons and on cognitive function has also been examined. Such studies have revealed, for example, that many of the learning and memory impairments traditionally attributed to the cholinergic corticopetal system are not due to degeneration of the cholinergic neurons of the nbM, but instead may be due to damage of more rostral elements of the cholinergic basal forebrain system. This review will examine the contribution of behavioural animal and human studies to out understanding of the role of the basal forebrain cholinergic neurons in age-related cognitive impairments.

Acetylcholine↗

PubMed1997

Cognitive enhancers in theory and practice: studies of the cholinergic hypothesis of cognitive deficits in Alzheimer's disease.

The current status of the cholinergic hypothesis of cognitive dysfunction in Alzheimer's disease is reviewed in the context of recent attempts to alleviate specific cognitive impairments produced in rats by excitotoxic lesions of basal forebrain neurons by treatment with cholinergic agents. AMPA-induced lesions of the nucleus basalis region in rats produce profound and relatively specific reductions in neocortical markers of cholinergic function but fail to affect performance in many tests of memory and learning in rats. However, such lesions produce specific deficits in responding accurately in a test of visual attentional performance, which are reversed dose-dependently by treatment with systemic physostigmine or nicotine. Analogous improvements have been reported in a clinical trial of the anticholinesterase tacrine in patients with Alzheimer's disease. By contrast, AMPA-induced lesions of the medial septum produce profound reductions in hippocampal acetylcholine and accompanying delay-dependent deficits in a delayed non-matching-to-position procedure which measures spatial working memory in rats. This impairment is shown to be reversed to some extent by treatment with low doses of physostigmine. The results are discussed in terms of the multivariate nature of the neurochemical pathology of Alzheimer's disease and attendant limitations in the use of the cholinergic strategy. The cognitive costs, as well as benefits, of cognitive enhancers are discussed, as well as the need to broaden our therapeutic approach to other neurotransmitter systems and other neurodegenerative disorders.

Alzheimer Disease↗

PubMed1997

Triple dissociation of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat.

Four experiments examined effects of quinolinic acid-induced lesions of the anterior cingulate, posterior cingulate, and medial frontal cortices on tests of visual discrimination learning, using a new "touchscreen" testing method for rats. Anterior cingulate cortex lesions impaired acquisition of an 8-pair concurrent discrimination task, whereas posterior cingulate cortex lesions facilitated learning but selectively impaired the late stages of acquisition of a visuospatial conditional discrimination. Medial frontal cortex lesions selectively impaired reversal learning when stimuli were difficult to discriminate; lesions of anterior and posterior cingulate cortex had no effect. These results suggest roles for the anterior cingulate, posterior cingulate, and medial frontal cortex in stimulus-reward learning, stimulus-response learning or response generation, and attention during learning, respectively.

Animals↗

PubMed1996

Attention and stimulus processing in the rat.

There is little doubt that rats are an essential species in laboratory testing. Given the substantial amount of anatomical and pharmacological information which is available for this species, rats are the animal of choice for many initial neurobiological investigations of the basic mechanisms of learning and memory as well as for pharmacological screening. Indeed, the study of brain-behaviour interactions is greatly facilitated in the rat given the ease with which brain transmitter systems and structures can be selectively manipulated, in contrast to the technical difficulties involved in undertaking such techniques in non-human primates. However, when considering the processing of information that occurs during cognitive processes such as learning and memory it is important to remember that fundamental to such processes are mechanisms of attention. When considering the concept of attentional functioning, it is important to keep in mind that attention is not a unitary construct but consists of several distinct mechanisms: vigilance, divided attention and selective attention, not all of which have been adequately modelled in the rat. Furthermore, attentional processes are also involved in learning operant discrimination tasks and appear to be quite different from those involved in maintaining high levels of trained performance. Consideration of discrimination learning is important given that firstly, during such learning the animal must select from the environment those stimuli which are relevant and secondly, that this type of learning is obviously inherent in many other tests used to assess cognitive function, such as delayed matching-to-sample procedures. Such issues will therefore form the basis of the following discussion.

Animals↗

PubMed1996

Measurement of cognitive function: relating rodent performance with human minds.

Rodents are the most commonly employed animals to model human cognitive dysfunction, but many of the behavioural paradigms employed for evaluation of rodent cognitive abilities measure functions rather different from those generally assessed in humans. This may be one reason for the failure of these models to allow valid predictions about drug effects in demented patients. One solution to this may be the use of a more comparative approach. Careful experimental designs indicate that comparative attentional as well as mnemonic processes can be assessed in rat and human subjects. This could be an essential step towards the successful development of drugs with therapeutic potential in cognitive disorders.

Animals↗

PubMed1996

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.

The aim of the present study was to investigate the role of the cholinergic innervation of the cingulate cortex in visual attentional function and acquisition of a visual conditional discrimination task. Following AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) lesions of the vertical limb diagonal band of Broca (VDB) which provides the main cholinergic projection to cingulate cortex, animals were not significantly impaired on the 5-choice serial reaction time task. This task, which provides a continuous performance test of visual attention, has previously been shown to be sensitive to AMPA lesions of the nucleus basalis magnocellularis (nbM). In contrast to the results obtained for visual attentional function, lesions of the VDB did significantly affect the acquisition of a visual conditional discrimination. While showing a significant facilitation in the early learning stage of acquiring this task animals with lesions of the VDB were significantly impaired during the late stages of learning this task. This late learning deficit was not the result of the animals being unable to learn the task due to the presence of the lesion throughout task acquisition as the results of a second experiment revealed that when animals were pre-trained to 70% accuracy on the task and then lesioned, the impairment in late learning was still apparent. In light of the results presented in the accompanying paper (Bussey et al., Behav. Brain Res., 1996), these results suggest that the early learning effects may be due to cholinergic denervation of the anterior cingulate cortex while the late learning effects may be due to denervation of the posterior cingulate cortex. Taken together with previous work indicating a role for the nbM cholinergic system in visual attentional function, these results suggest a role for the cholinergic innervation of the cingulate cortex in conditional learning but not for continuous attentional performance.

Animals↗

PubMed1996

Dissociable effects of anterior and posterior cingulate cortex lesions on the acquisition of a conditional visual discrimination: facilitation of early learning vs. impairment of late learning.

Two experiments investigated the effects of quinolinic acid induced lesions of the anterior and posterior cingulate cortices on the acquisition and performance of a conditional visual discrimination (CVD) task, in which rats were required to learn a rule of the type: "If lights are flashing FAST, press the right lever; if SLOW press left". In Experiment 1, animals with lesions of the anterior cingulate cortex (ANT group) demonstrated a significant enhancement in learning during the early stages of task acquisition. Conversely, animals with lesions of the posterior cingulate cortex (POS group) were impaired in learning during the later stages of acquisition. There were no significant differences between the ANT and POS groups on the performance of the task when either variable inter-trial intervals or reduced stimulus durations were imposed. In Experiment 2, the specificity of the lesion effects for processes operative during the early and late stages of learning was tested. Animals were trained to a criterion of 70% correct choices on two consecutive sessions prior to lesioning, and subsequently allowed to continue to acquire the task to the mean asymptotic performance level of 85% correct choices on two consecutive sessions. Animals of the POS group were impaired in learning during this later stage of task acquisition, thus replicating the pattern of results obtained in Experiment 1. The animals in Experiment 2 were then tested following a 30-day retention interval and during extinction (removal of sucrose from the magazine). The extinction test revealed an impairment in the ability of animals in the ANT group to omit lever responses in the absence of reinforcement. These results indicate that the anterior and posterior cingulate cortices are functionally dissociable, and suggest that they may form part of complementary, but competing, learning and memory systems.

Animals↗

PubMed1995

Reversal of visual attentional dysfunction following lesions of the cholinergic basal forebrain by physostigmine and nicotine but not by the 5-HT3 receptor antagonist, ondansetron.

To investigate further the cholinergic specificity of the effects of basal forebrain lesion-induced disruption of attentional performance, the present study examined the efficacy of various pharmacological agents in improving performance of a five-choice serial reaction time task in rats that had received lesions of the cholinergic basal forebrain. Specifically, the effects of the novel 5-HT3 receptor antagonist, ondansetron (0.3, 1, 10 ng/kg), and of nicotine (0.03, 0.06, 0.1, 0.3 mg/kg) and the anticholinesterase, physostigmine (0.05, 0.1 mg/kg), on attentional function were examined in animals which had received AMPA-induced lesions of the nucleus basalis magnocellularis (nbM). The behavioural impairments observed immediately following the lesion were a reduction were choice accuracy and an increase in correct response latency. Although these impairments showed recovery over the course of the following weeks, the deficit in choice accuracy could be reinstated by reducing the duration of the visual stimulus and thus increasing the attentional load placed on the animals. This reduction in choice accuracy could be dose dependently improved by systemic administration of either physostigmine or nicotine, suggesting that this impairment in attentional function may be attributed to disruption of cholinergic function. The pharmacological specificity of these improvements was supported by the inability of d-amphetamine to improve task performance (0.2, 0.4, 0.8 mg/kg). Ondansetron was also unable to improve accuracy of performance in lesioned animals, but was effective in reducing the anticipatory or premature responding observed in both control and lesioned animals, even when elevated (in the case of controls) by treatment with systemic d-amphetamine. The results of the present study therefore suggest that cholinergic dysfunction can lead to attentional impairments which can be ameliorated by cholinergic treatments such as physostigmine and nicotine, but that ondansetron, despite its proposed ability to release cortical acetylcholine, was unable to restore choice accuracy at the doses employed. The results further suggest a double dissociation of effects on accuracy and the disinhibition of responding.

Amphetamine↗

PubMed1994

AMPA-induced excitotoxic lesions of the basal forebrain: a significant role for the cortical cholinergic system in attentional function.

The aim of the present study was to clarify the role of the basal forebrain (BF)-cortical cholinergic system in visual attentional function by investigating the effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-induced lesions of the basal forebrain on performance of a five-choice serial reaction time task. AMPA lesions in the present study produced a profound effect on performance of the task, as measured by choice accuracy and correct response latency. This deficit was significantly greater than that observed in earlier studies following ibotenate- or quisqualate-induced lesions of the BF. However, detailed histological and biochemical analysis revealed three rather different BF lesions depending upon the batch of AMPA supplied. In one group of animals (BF/1) the deficits in task performance were substantially greater and longer lasting compared to another group of lesioned animals (BF/2), which showed behavioral recovery several months following the lesion. The former sustained severe pallidal damage in addition to marked reductions in cortical ChAT activity. Support for the attentional nature of these deficits was obtained by the ability to improve task performance in BF/1 lesioned animals by increasing the duration of the visual stimulus and thus reducing the attentional load placed on these animals. In contrast, performance deficits could be reinstated in those animals showing behavioral recovery (BF/2) by reducing the duration of the visual stimulus and thus increasing attentional load. In the second experiment more discrete lesions of the magnocellular cholinergic neurons were made, resulting in extensive reduction of cortical ChAT activity with considerably less neuronal loss from the dorsal pallidum compared to the BF/1 lesion group. Once again, deficits on the task were substantially greater than observed previously following either quisqualate- or ibotenate-induced BF lesions. Furthermore, the cholinergic specificity of these deficits was supported by the attenuation of behavioral impairments following administration of the anti-cholinesterase physostigmine. Taken together with our earlier work, which has failed to demonstrate mnemonic deficits following lesions to the magnocellular neurons of the nucleus basalis of Meynert, these results suggest that the most consistent deficit produced following lesions of the BF-cortical cholinergic system is attentional dysfunction Analogous deficits in visual attention are also seen in patients with Alzheimer's disease, which can also be improved by anti-cholinesterase treatment.

Analysis of Variance↗

PubMed1994

6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine.

The effects of 6-hydroxydopamine lesions of the prefrontal cortex in monkeys were investigated on two cognitive tests of prefrontal function, spatial delayed response, and attentional set shifting. The latter test provided a componential analysis of the Wisconsin Card Sort Test, a commonly used clinical test of frontal lobe function in man. Acquisition of a visual compound discrimination requiring a shift of attention from one dimension to another (extradimensional shift), for example, shapes to lines, was significantly improved. This enhancement was behaviorally specific in that there were no effects on acquisition of a discrimination that required the continued maintenance of an attentional set toward one particular dimension (intradimensional shift), nor any effects on a series of visual or spatial discrimination reversals that involved the repeated shifting of responding between two exemplars from the same dimension. In contrast, spatial delayed response performance was impaired, in agreement with previous results. Neurochemical measures showed a marked depletion of dopamine limited to the prefrontal cortex and a smaller loss of prefrontal noradrenaline. This was accompanied by a long-term adaptive change in the striatum such that extracellular dopamine in the caudate nucleus, as measured by in vivo microdialysis, was elevated in response to potassium stimulation as long as 18 months postsurgery. It is proposed that attentional set shifting is mediated by a balanced interaction between prefrontal and striatal dopamine, and that elevated dopamine contributes to the improvement in attentional set-shifting ability. This interpretation is consistent with the impairment in attentional set-shifting ability observed in patients with Parkinson's disease or with damage to the frontal lobes using the same test as used here for infrahuman primates.

Animals↗

PubMed1993

Excitotoxic lesions of basal forebrain cholinergic neurons: effects on learning, memory and attention.

A substantial body of literature has suggested that the memory and learning deficits associated with Alzheimer's disease are attributable to degeneration of the cholinergic magnocellular neurons of the nucleus basalis of Meynert (nbM). Subsequently, lesion-induced damage to the cholinergic projections from the nbM to the neocortex has been utilized extensively as an animal model of dementia. Ibotenic acid lesions of the basal forebrain have been found, for example, to produce deficits in a wide variety of tasks involving learning and memory. However, recently, with the availability of more potent cholinergic excitotoxins such as AMPA, it has become apparent that nbM lesions do not provide a simple animal model of the cognitive deficits in ageing and Alzheimer's disease. Further analysis suggests that many of the learning and memory impairments traditionally attributed to the cholinergic corticopetal system are due not to destruction of cholinergic neurons in the nbM, but instead result from the disruption of cortico-striatal outputs passing through the dorsal and ventral globus pallidus. Furthermore, experiments utilizing quisqualic acid and AMPA have revealed that the most convincing deficit observed as a result of such lesions is in visual attention. This role for the basal forebrain-cortical cholinergic system in attentional function is further supported by results obtained from complementary pharmacological studies. This does not exclude a role for acetylcholine in learning and memory processes. Rather, such cognitive processes appear to depend not upon the integrity of the nbM itself, but upon more rostral elements of the cholinergic basal forebrain system.

Acetylcholine↗

PubMed1992

Attentional functions of the forebrain cholinergic systems: effects of intraventricular hemicholinium, physostigmine, basal forebrain lesions and intracortical grafts on a multiple-choice serial reaction time task.

Degeneration of the cholinergic magnocellular neurons in the basal forebrain and their cortical projections is a major feature of the neuropathology of Alzheimer's disease. In the present study, two experiments examined the disruptive effects on visual attentional performance of two different manipulations that reduce central cholinergic function. In Expt. I, pharmacological manipulation of the cholinergic system was investigated using icv administration of hemicholinium (HC-3), a high affinity choline uptake blocker, administered either alone or in conjunction with the anticholinesterase, physostigmine. The results revealed impairments in the ability of the rats to localize brief visual targets in a serial reaction time task, as shown in particular by a reduction in choice accuracy and lengthening of the latency to respond correctly to the visual stimulus. Cholinergic specificity was supported by the reversal of these behavioural impairments by pre-treatment with the anticholinesterase, physostigmine. In Expt. II, quisqualate-induced lesions of the basal forebrain produced behavioural deficits at 3 weeks post-lesion surgery similar to those observed following icv infusion of HC-3. In an attempt to restore the extrinsic cortical cholinergic innervation by reinnervation of the deafferented cortex, embryonic basal forebrain cholinergic cells were transplanted into the cortex of lesioned animals. After three months recovery, impairments in performance on the baseline schedule of the task were no longer apparent in lesioned animals. However, behavioural deficits, observed predominantly as a lengthening of correct response latency, could be reinstated in the lesioned animals by interpolation of distracting bursts of white noise during each trial, and this deficit was ameliorated by the cholinergic grafts. Furthermore, a non-specific effect of both cholinergic and non-cholinergic grafts in controlling the increase in perseverative time-out responses which occurred as a result of the basal forebrain lesion was consistently observed. These results suggest that cholinergic dysfunction can produce deficits in visual attention which can be ameliorated by cholinergic treatments such as physostigmine or cholinergic-rich cortical grafts. These data provide support for a role for the basal forebrain-neocortical cholinergic projection in attentional function.

Acetylcholine↗