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R M Ridley

Publications and source records attributed to R M Ridley.

At least 19 recordsLinked to original sources
PubMed2002

Contralesional neglect in monkeys with small unilateral parietal cortical ablations.

Transient contralesional spatial neglect, in addition to motor impairment in the contralesional arm, is sometimes seen in patients following cerebral infarction in the right hemisphere and is seen following experimental occlusion of the right middle cerebral artery in primates. To test whether contralesional visuospatial neglect arises from a disruption of the forward flow of information from the striate cortex through the dorsal territory of the middle cerebral artery, we made a small strip suction ablation in the right parietal cortex from the medial edge of the dorsal cortical surface to the posterior ventral edge of the superior temporal gyrus in marmoset monkeys. These monkeys did not exhibit a motor impairment, or misreaching, with the contralesional arm. When they were unrestrained and free to use either arm, they were impaired at finding rewards in their contralesional space and in choosing the nearer of two rewards hidden in ipsilesional space (i.e. they had an ultra-ipsilesional bias in ipsilesional space). Comparison of performance under four conditions in a task in which the monkeys were constrained to reach into each hemispace with each arm separately indicated that they were impaired at reaching into contralesional, but not ipsilesional, space with either arm but they did not exhibit any impairment confined to the contralesional arm. These impairments in contralesional space were transient suggesting that the monkeys were able to re-align their egocentric spatial coordinates to obviate these deficits.

Animals↗
PubMed2002

Crossed unilateral lesions of temporal lobe structures and cholinergic cell bodies impair visual conditional and object discrimination learning in monkeys.

Monkeys with excitotoxic lesions of the CA1/subiculum region in the right hemisphere and with immunotoxic lesions of the cholinergic cells of the diagonal band in the left hemisphere were impaired on a visual conditional task. In this task, correct choice of one of two objects depends on which of two background fields both objects are presented against, irrespective of the spatial positions of the objects. They were not impaired on simple object or shape discrimination tasks. The pattern of impairments is the same as that seen after bilateral excitotoxic lesions of CA1/subiculum, implying that the diagonal band lesion disables the ipsilateral CA1/subiculum. It also argues that CA1/subiculum, sustained by its cholinergic input, is necessary for some forms of nonspatial conditional learning. Addition of an inferotemporal (IT) cortical ablation to the left hemisphere did not affect simple visual discrimination learning, although all the monkeys then failed to learn a new visual conditional task. This demonstrates that intact IT cortex in only one hemisphere is sufficient to sustain simple visual discrimination learning but implies that the cholinergic input and the inferotemporal cortical input to the hippocampus both contribute to visual conditional learning. The subsequent addition of an immunotoxic lesion of the basal nucleus of Meynert in the right hemisphere resulted in an additional impairment on a difficult shape discrimination. This argues that it is the cholinergic projection to the inferotemporal cortex, rather than to the rest of the cortex, which contributes to visual discrimination learning and memory.

Animals↗
PubMed2002

Unilateral lesions of the cholinergic basal forebrain and fornix in one hemisphere and inferior temporal cortex in the opposite hemisphere produce severe learning impairments in rhesus monkeys.

It has been proposed that isolation of the inferior temporal cortex and medial temporal lobe from their cholinergic afferents results in a severe anterograde amnesia. To test this hypothesis directly, seven rhesus monkeys received a unilateral immunotoxic lesion of the cholinergic cells of the basal forebrain with an ipsilesional section of the fornix. In a second surgery, inferior temporal cortex was ablated in the opposite hemisphere. All animals were severely impaired at learning visual scenes and object-reward associations. The impairment in learning scenes was correlated with cholinergic cell loss in the basal forebrain, but not with generalized tissue damage. Two monkeys served as surgical controls with saline injection in place of the immunotoxin, but all other procedures the same, and were not as severely impaired as those with immunotoxic lesions. Previous work has shown that monkeys with bilateral section of the anterior temporal stem (white matter of the temporal lobe), amygdala and fornix show a severe new learning impairment, and provide a model of human medial temporal lobe amnesia. One effect of this combined ablation is to isolate inferior temporal cortex and medial temporal lobe from their cholinergic afferents, possibly in addition to a direct disruption of the hippocampal system. The results of the present study, then, provide a novel link between the mechanisms of medial temporal lobe amnesia and Alzheimer's disease in which the cholinergic basal forebrain shows pathology. We propose that in both cases the mnemonic impairments result from isolating inferior temporal cortex and medial temporal lobe from their cholinergic afferents, possibly in addition to a direct disruption of the hippocampal system.

Acetylcholine↗
PubMed2001

Visual agnosia and Klüver-Bucy syndrome in marmosets (Callithrix jacchus) following ablation of inferotemporal cortex, with additional mnemonic effects of immunotoxic lesions of cholinergic projections to medial temporal areas.

Inferotemporal ablations in the New World monkey, the common marmoset (Callithrix jacchus), produced a persistent impairment on visual discrimination learning and a florid, but transient, Klüver-Bucy syndrome. Monkeys with these ablations were impaired on acquisition of object discriminations to a high criterion and on concurrent discrimination learning, to a single high criterion across all trials. Neither the control monkeys nor the monkeys with inferotemporal ablations found acquisition more difficult when the component discriminations of a set were presented concurrently compared to consecutively, although the monkeys with inferotemporal ablations found acquisition under both these conditions somewhat more difficult than did control monkeys. This suggests that the severe impairment caused by inferotemporal ablations on concurrent learning measured across all trials is due to the need for sustained performance across a concurrent set rather than to the extra mnemonic demands of concurrent presentation. When immunotoxic lesions of the cholinergic projection to the hippocampal formation were added to the inferotemporal ablations, a further impairment on retention, and a differential impairment on concurrent, compared to consecutive, learning was observed. Previous studies have shown that lesions of the cholinergic projection to the hippocampus alone, or excitotoxic hippocampal lesions, do not affect simple visual discrimination learning. It is suggested that large inferotemporal ablations in monkeys produce a visual agnosia which causes severe 'psychic blindness' in the first instance, and a persistent impairment on visual discrimination learning. The hippocampus makes a contribution, which may be mnemonic, to discrimination performance after inferotemporal ablations.

Acetylcholinesterase↗
PubMed2001

Visual discrimination learning impairments produced by combined transections of the anterior temporal stem, amygdala and fornix in marmoset monkeys.

Marmoset monkeys (Callithrix jacchus) with bilateral transections of the anterior temporal stem, amygdala and fornix were unable to relearn a 2-choice object discrimination first learnt prior to surgery, and were very severely impaired at relearning a concurrent object discrimination task which they had learnt and relearnt prior to surgery, indicating that they had a dense retrograde amnesia. They also had difficulty learning new visual object discriminations but were only mildly impaired on spatial learning. When tested on new learning of concurrent discriminations 8 to 10 weeks after surgery, three operated monkeys were unable to reach criterion in 400 trials while the remaining two operated monkeys performed within the normal range. The operated monkeys were subsequently shown to be impaired on acquisition of shape discriminations using black objects. These anterograde effects suggest that the impairment runs mainly in the domain of visual analysis. The monkeys also exhibited many of the features of the Klüver-Bucy syndrome. Histological analysis indicated that in addition to cutting some of the subcortical temporal lobe efferent pathways, the surgical procedures had cut the cholinergic afferents to the temporal neocortex, entorhinal cortex, and hippocampus. In a second experiment we found that treatment with the cholinergic agonist pilocarpine, which is effective in monkeys with specific cholinergic lesions, was unable to remediate the lesion-induced impairments. This suggests that transection of the non-cholinergic afferents, or the temporal lobe subcortical efferents, contributed to the behavioural syndrome and the learning and retention deficits seen in these monkeys.

Acetylcholinesterase↗
PubMed2001

Chronic elevation of amyloid precursor protein in the neocortex or hippocampus of marmosets with selective cholinergic lesions.

In vitro studies have consistently demonstrated a link between cholinergic neurotransmission and amyloid precursor protein metabolism, although few studies have examined such a relationship in vivo and none have been conducted in primate species. The purpose of this study was to test the hypothesis that a reduction in cholinergic activity in neocortical and hippocampal areas consequent upon destruction of ascending cholinergic projections may lead to long-term changes in levels of amyloid precursor protein in these target areas in a primate species. The status of three synaptic proteins associated with neurotransmitter release, synaptophysin, syntaxin and SNAP-25, was also been examined. Selective immunolesions of the basal forebrain cholinergic projections led to increases in amyloid precursor protein-like immunoreactivity in hippocampus and cortex, measured 8 months postlesion. Furthermore, reductions in cortical and hippocampal SNAP-25, but not syntaxin or synaptophysin, immunoreactivity were observed. These results imply that the reduced cholinergic activity characteristic of Alzheimer's disease may contribute to the continuing emergence of neuropathology in addition to the well-known association with cognitive dysfunction.

Amyloid beta-Protein Precursor↗
PubMed2001

Non-spatial acquisition and retention deficits following small excitotoxic lesions within the hippocampus in monkeys.

Marmoset monkeys with excitotoxic lesions confined to cornu ammonis subfields 1-3, subiculum and pre-subiculum, but sparing the entorhinal cortex, were impaired on retention and learning of conditional object-choice discriminations. For each of these discriminations, the monkeys were required to choose one of two objects depending on which of two patterned backgrounds was used on each trial. Two styles of order of trial presentation were used: 'random' presentation which maximised the degree of interference between trials, and 'runs' presentation which was intended to encourage the monkeys to learn each component of the discrimination separately. Before surgery monkeys found the discriminations more difficult to learn when the trials were presented in the 'runs' style than when presented in the 'random' style suggesting that the task is best learnt by applying a conditional rule. After surgery a significant 'group x style' interaction indicated that the 'runs' style was especially difficult for the lesioned monkeys. From these results we suggest that the hippocampus is involved in learning about and remembering non-spatial, conditional relations between objects.

Animals↗
PubMed2001

NXY-059, a free radical--trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species.

BACKGROUND AND PURPOSE: NXY-059 is a novel nitrone with free radical-trapping properties that has a considerable neuroprotective effect in rats. We have now examined the efficacy of this drug at reducing long-term functional disability in a primate model of stroke. METHODS: Twelve monkeys were trained and tested on a variety of behavioral tasks used to dissociate and quantify motor and spatial deficits. Five minutes after permanent occlusion of the right middle cerebral artery, monkeys received a 1-mL intravenous infusion of either saline or NXY-059 (28 mg x kg(-1)), and osmotic minipumps, model 2001D, were implanted subcutaneously to provide continuous drug or saline infusion for 48 hours. Drug-filled pumps released NXY-059 at 16 mg x kg(-1) x h(-1). The monkeys were retested 3 and 10 weeks after surgery to assess functional disability. Surgery, behavioral testing, and histology were all done blinded to treatment condition. RESULTS: NXY-059-treated monkeys were significantly better at reaching with their hemiparetic arm than were saline-treated monkeys when retested 3 weeks (P:<0.01) and 10 weeks (P:<0.01) after surgery. Drug treatment also significantly lessened the degree of spatial perceptual neglect (P:<0.01), a debilitating though ameliorating consequence of this infarct. NXY-059 treatment reduced the overall amount of brain damage by >50% of saline-treatment values, with similar levels of protection afforded to both white and gray matter. CONCLUSIONS: This novel drug has a substantial protective effect, lessening the disability caused by an experimentally induced stroke in a primate species. These findings provide considerable encouragement for the clinical development of NXY-059.

Analysis of Variance↗
PubMed2000

Clomethiazole protects against hemineglect in a primate model of stroke.

Permanent occlusion of the M1 segment of the middle cerebral artery (pMCAO) in the marmoset, a New World species of monkey, produces unilateral functional deficits, including motor neglect with the contralesional arm and contralesional spatial hemineglect. In this study we examined whether clomethiazole, a drug which modulates the gamma-aminobutyric acid(A) receptor, reduced the severity of the hemineglect and other deficits in this primate model of stroke. Nine monkeys received pMCAO; 1 h later four of the nine were administered clomethiazole by intraperitoneal injection and subcutaneous implantation of osmotic mini-pumps, which released clomethiazole for 48 h. The monkeys had been trained and tested on a number of behavioral tasks prior to surgery and were re-tested 3 and 10 weeks later. Three weeks after pMCAO, monkeys treated with clomethiazole had a significantly reduced degree of spatial neglect compared to untreated controls. Clomethiazole was not effective against the severe contralesional motor impairment in the current study, although it ameliorated a somewhat less severe motor deficit in a previous study in which the more distal, M2 segment of the middle cerebral artery had been occluded. Postmortem analysis of the brains showed that clomethiazole treatment had significantly reduced the area of damage in part of the parietal cortex. These data suggest that clomethiazole may reduce the neglect that can be a debilitating consequence of right-sided stroke in man.

Animals↗
PubMed2000

The 5-HT1A antagonist, WAY 100 635, alleviates cognitive impairments induced by dizocilpine (MK-801) in monkeys.

Central glutamate neurotransmission is modulated by an upregulatory cholinergic influence and an inhibitory serotonergic influence. In Alzheimer's disease, cognitive decline is associated with loss of both glutamatergic and cholinergic neurones (Francis et al., 1992, Progress in Neurobiology 39, 517-545). While therapeutic strategies for alleviating this cognitive decline have concentrated on restoring cholinergic tone, we suggest that 5-HT1A antagonists also have the potential to alleviate the cognitive symptoms of Alzheimer's disease. Previous studies have shown that dizocilpine (MK-801), a glutamatergic antagonist acting at the NMDA receptor, produces learning impairments in the common marmoset, a non-human primate. Specifically, it impairs the acquisition of shape discrimination and visuospatial conditional tasks, at doses that do not affect locomotor behaviour or coordination (Harder et al., 1998, Society for Neuroscience Abstracts 23(1), 219). In the present study we investigated the effects of WAY 100 635, a 5-HT1A antagonist, on the cognitive deficits induced by dizocilpine. The number of trials required to learn each type of task under combined treatment with dizocilpine and WAY 100 635 was significantly lower than under dizocilpine treatment alone, and did not differ significantly from the number of trials required under saline, demonstrating that the cognitive effects of glutamatergic blockade can be overcome by treatment with a 5-HT1A antagonist.

Animals↗
PubMed2000

Naturally occurring and experimentally induced beta-amyloid deposits in the brains of marmosets (Callithrix jacchus).

Cerebral beta-amyloid occurs in elderly animals of some species and in Alzheimer's disease. Previously, we injected 3 young marmosets intracerebrally with brain tissue from a patient with Alzheimer's disease. Six years later, when the monkeys were middle aged, we found moderate numbers of intracerebral plaques and cerebrovascular deposits containing beta-amyloid. We have re-examined these brains and those of 10 other marmosets injected with brain homogenate containing beta-amyloid, and have found some beta-amyloid in animals injected more than 4 years previously. We have found beta-amyloid in 4 of 26 elderly control marmosets, but not in 9 young to middle-aged control marmosets. The beta-amyloid found in middle aged marmosets injected with Alzheimer brain tissue was, therefore, not a consequence of their age. Deposits in large cerebral vessels in elderly marmosets, and in marmosets previously injected with brain tissue containing beta-amyloid, reacted with antibodies to Abeta and Abeta1-40; plaques and microvessel deposits reacted with antibodies to Abeta and Abeta1-42.

Age Factors↗
PubMed2000

Synergistic effects of unilateral immunolesions of the cholinergic projections from the basal forebrain and contralateral ablations of the inferotemporal cortex and hippocampus in monkeys.

Monkeys, with unilateral immunotoxic lesions of the basal nucleus of Meynert that remove cholinergic innervation of the ipsilesional neocortex, and ablations of the contralateral inferotemporal neocortex, were impaired on retention of visual discriminations learnt before surgery and on acquisition of new discriminations. This demonstrates that the cholinergic projection from the basal nucleus supports the functions of its cortical target area. Our previous studies have shown that the impairment on discrimination performance following bilateral lesions of the basal nucleus is transient and that bilateral lesions of the diagonal band of Broca, that remove cholinergic innervation of the hippocampus, are without effect on these tasks. However, the impairment resulting from bilateral lesions of the basal nucleus plus the diagonal band, or from bilateral inferotemporal cortex ablations, is severe and persistent. Bilateral inferotemporal ablations deprive the hippocampus of much of its visual input by producing a discontinuity in cortico-cortical transmission, whereas basal nucleus lesions may merely prevent the modification of visually-derived information in the inferotemporal cortex without depriving the hippocampus of visual input. In the monkeys with crossed unilateral basal nucleus plus inferotemporal cortex lesions, the addition of a diagonal band lesion to the basal nucleus lesion produced an impairment on retention of visual discriminations and sustained the acquisition impairment. This confirms the previous finding that the basal nucleus and diagonal band act synergistically in producing a severe and permanent impairment. Further addition of an excitotoxic hippocampal lesion to the hemisphere with the inferotemporal cortex ablation did not add to the learning impairment. This supports the suggestion that the inferotemporal cortex ablation has deprived the hippocampus of its visual input.Overall, these experiments demonstrate that the cholinergic projections from the basal nucleus and diagonal band participate in the learning and memory functions of the temporal lobes.

Acetylcholinesterase↗
PubMed1999

Severe learning impairment caused by combined immunotoxic lesion of the cholinergic projections to the cortex and hippocampus in monkeys.

Monkeys with immunotoxic lesions of both the basal nucleus of Meynert and the vertical limb of the diagonal band of Broca (NBM+VDB) lost cholinergic innervation throughout the cortex and hippocampus. They were impaired at learning discriminations between objects differing in either few, or many, attributes and at learning visuospatial conditional discriminations. Monkeys with immunotoxic lesions of the NBM lost cholinergic innervation of the neocortex only. Initially, they were unable to learn a simple visual discrimination where the stimuli differed in a limited number of attributes but they were unimpaired at learning discriminations between objects that differed in more attributes. They were mildly impaired at learning a visuospatial conditional task. The impairment exhibited by monkeys with lesions of the NBM alone ameliorated with time but that following NBM+VDB lesions did not. Previous experiments have shown that monkeys with immunotoxic lesions of the VDB alone are impaired at learning visuospatial conditional discriminations but are unimpaired at learning simple visual discriminations. When monkeys with NBM lesions were given excitotoxic lesions of the CA1 field of the hippocampus the learning impairment on discriminations between objects which differed in few attributes was reinstated. Pretreatment with a cholinergic agonist improved learning ability on visual discrimination learning in all monkeys but this improvement was significantly greater in monkeys with lesions of the NBM. On conditional discrimination learning, which is particularly sensitive to hippocampal damage, pilocarpine produced a significant improvement in monkeys with NBM+VDB lesions (where the hippocampal dysfunction was cholinergic) but not in monkeys with NBM+CA1 lesions (where the hippocampal damage was structural).

Acetylcholine↗
PubMed1999

The effect of excitotoxic hippocampal lesions on simple and conditional discrimination learning in the rat.

The effect of excitotoxic lesions of the hippocampus on acquisition and reversal of simple and conditional tasks was investigated using a Y-maze. Hippocampal-lesioned rats were severely impaired on acquisition and reversal of a conditional visuo-spatial task (where different pairs of visually distinctive choice arms indicated whether a left or right arm choice was correct on that trial) and were unable to acquire a visuo-visual conditional discrimination (where the appearance of the start arm indicated which of the visually distinctive choice arms was correct irrespective of their left/right position). They were not impaired on acquisition or reversal of a simple spatial left/right discrimination task (where all arms had the same visual appearance) nor on acquisition of a visual discrimination (where the correct, visually distinctive, choice arm varied in its left/right position). Hippocampal-lesioned rats were, however, impaired on reversal of this visual discrimination task and on acquisition and reversal of another visual discrimination task in which the visually distinctive choice arms were less different from each other than in the first version of this task. The degree of impairment in the lesioned rats was related to task difficulty for the sham-operated rats and was not specific to tasks requiring spatial choices, visual discrimination or conditional responding. The impairment on conditional tasks was greater than the impairment on those non-conditional tasks which happened to be matched for task difficulty for the sham-operated rats, suggesting that the conditional demand may target the function of the hippocampus rather closely. Statistically worse than chance performance by hippocampal-lesioned (and sham-operated) rats at the beginning of reversal testing, which was given 24 h after achieving criterion on acquisition of that task, indicated that hippocampal-lesioned rats simultaneously exhibited good memory but impaired learning for the type of information required for those tasks.

Animals↗
PubMed1999

Functional benefit from clomethiazole treatment after focal cerebral ischemia in a nonhuman primate species.

Clomethiazole (CMZ) (Zendra) is neuroprotective in rodents following focal and global ischemia. However, its neuroprotective effects in other species, particularly on functional outcome, have not been reported. We have therefore examined the ability of CMZ to ameliorate the functional deficits produced by a focal cerebral ischemic lesion in the marmoset, a New World primate. Six monkeys received permanent middle cerebral artery occlusion (pMCAO); six further monkeys received pMCAO with administration of CMZ, 5 min after the arterial occlusion, by intraperitoneal bolus injection and by subcutaneous implantation of an osmotic minipump, which released CMZ for 24 h. The monkeys were trained and tested preoperatively on a number of behavioral tasks which were repeated 3 and 9 weeks after surgery. CMZ-treated monkeys were better than non-drug-treated monkeys at using the disabled arm contralateral to the lesion and also showed a reduction in contralateral spatial hemineglect. Postmortem histopathological analysis at several stereotaxic levels showed a significant reduction in the area of ischemic damage in CMZ-treated monkeys compared to that in untreated animals. CMZ treatment reduced the overall volume of damage by 31.8% (MCA group, 370.8 +/- 37.4 mm3 of damage; CMZ group, 253.0 +/- 38.0 mm3 of damage). This study demonstrates that CMZ is neuroprotective in a nonhuman primate species and is able to ameliorate the level of functional disability and reduce the size of infarct produced by focal cerebral ischemia.

Animals↗
PubMed1999

Different effects on learning ability after injection of the cholinergic immunotoxin ME20.4IgG-saporin into the diagonal band of Broca, basal nucleus of Meynert, or both in monkeys.

Immunotoxic lesions of the diagonal band of Broca (VDB) in monkeys disrupted cholinergic input to the hippocampus, producing impaired learning of visuospatial conditional discriminations but not simple visual discriminations. Immunotoxic lesions of the basal nucleus of Meynert (NBM) deprived the cortex of most of its cholinergic input, producing impaired learning of simple visual discriminations but not visuospatial conditional discriminations. Combined lesions of the NBM + VDB resulted in impaired learning of both types of task. The impairment after NBM lesions ameliorated with time but could be reinstated by a low dose of the glutamate blocking drug MK801, which, at this dose, did not impair simple visual discrimination learning in normal monkeys. The cholinergic projections from the NBM and VDB may sustain the function of the glutamatergic pyramidal cell pathways within the cortex and hippocampus, respectively.

Analysis of Variance↗