Biomedical subjects

D Gaffan

Publications and source records attributed to D Gaffan.

At least 55 records · Page 3Linked to original sources

PubMed1996

Systemic NMDA receptor antagonist CGP-40116 does not impair memory acquisition but protects against NMDA neurotoxicity in rhesus monkeys.

A widely accepted hypothesis is that long-term potentiation (LTP) is a synaptic mechanism of memory. NMDA receptors are critically involved in induction but not maintenance of LTP; therefore, their blockade should impair memory acquisition but not retrieval. In Experiment 1, we investigated the effect of a systemic NMDA receptor antagonist, CGP-40116 [D-isomer of CGP-37849: (E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (6 mg/kg, i.m.) 60 min before the testing session] on memory acquisition and retrieval by monkeys in the "object-in-place" visual memory task, an analog of human episodic memory. Only a small increase in error rate was produced (< 3%), and this increase was observed in both retention and acquisition tests. This deficit is substantially smaller than the previously reported deficit after fornix transection in the same task, and is not specific to memory acquisition. In Experiment 2, we investigated the neuroprotective effect of CGP-40116. NMDA (68 nmol) was injected into the right hippocampus, then CGP-40116 (6 mg/kg) was given intramuscularly, and then NMDA was injected into the left hippocampus. The area of cell loss in CA1 and CA3 fields was smaller in both hemispheres compared with unprotected monkeys (without CGP-40116). Thus, CGP-40116 provides both retrograde and anterograde protection against NMDA neurotoxicity. These data (1) demonstrate that acquisition of episodic memories remains almost intact when an NMDA receptor antagonist is given in a dose sufficient to block NMDA receptors in the hippocampus, and (2) indirectly oppose the hypothesis that NMDA receptor-dependent LTP plays the key role in memory.

2-Amino-5-phosphonovalerate↗

PubMed1996

Associative and perceptual learning and the concept of memory systems.

An introductory review is followed by some new experimental data and a final discussion. The primate temporal lobe contains multiple qualitatively distinct memory systems. The functional properties of these memory systems can be explained by reference to the nature of the afferent information which they process, rather than by reference to any putative specialization in memory processing. In this way, the plasticity of 'memory systems' in associative memory is probably similar in principle to the plasticity of 'perceptual systems' in perceptual learning. Therefore, it is important to consider the relationship between perceptual and associative learning. Two experiments investigated perceptual learning in the Rhesus monkey (Macaca mulatta). Substantial perceptual learning was observed both with complex scenes and with simple colours. Two hypotheses as to the basis of perceptual learning are discussed. A physiological hypothesis is that training with a particular set of stimuli expands the cortical representation of those stimuli. This can explain the effects in both experiments. A psychological hypothesis is that perceptual learning is produced by learned associations among multiple features of complex stimuli. This can explain the effects in Expt. 1 but not in Expt. 2. The psychological associative hypothesis is therefore redundant. Furthermore, associative learning can itself be viewed as an expansion of the cortical representation of a complex event. Thus, the distinction between perceptual and memory systems will need to be abandoned as deeper understanding of cortical plasticity is achieved.

Animals↗

PubMed1995

Visual learning for an auditory secondary reinforcer by macaques is intact after uncinate fascicle section: indirect evidence for the involvement of the corpus striatum.

Three cynomolgus monkeys (Macaca fascicularis) were trained preoperatively in visual discrimination learning for an auditory secondary reinforcer. Each new discrimination problem was solved on the basis of the secondary reinforcer, and primary reinforcement (food reward) was given only after a new problem had been solved. The animals learned 50 new problems in each daily session and it was therefore possible to assess accurately their average rate of learning new discrimination problems in this procedure. After the learning rate had stabilized preoperatively the animals were operated upon to transect the uncinate fascicle, the cortico-cortical pathway from visual association cortex in the temporal lobe to prefrontal cortex. The animals' learning rate was unchanged after uncinate fascicle section. A previous experiment has shown that visual learning for an auditory secondary reinforcer is unaffected by disconnection of visual association cortex from the amygdala and the fornix. Taken together, this negative evidence points strongly to the conclusion that visual learning for an auditory secondary reinforcer depends upon interaction of temporal lobe visual association cortex with the corpus striatum, since other possibilities have been excluded.

Acoustic Stimulation↗

PubMed1995

Cerebral achromatopsia in monkeys.

In human cerebral achromatopsia, extrastriate cortical damage produces a severe or complete loss of colour vision, with relative sparing of non-chromatic vision. The critical lesion appears to be in a medial occipito-temporal area, occupying the lingual and caudal fusiform gyri; positron emission tomography has shown that this cortical region is one of several activated in normal human observers during colour vision tasks. Attempts to find an analogous 'colour centre' in the cortex of monkeys have not been successful. In particular, ablation of cortical area V4, sometimes thought on physiological grounds to be more involved in wavelength and colour coding than any other visual cortical area, produces only mild impairments in colour discrimination. In the present study we tested the colour vision of monkeys after cortical ablations that mainly or entirely spared area V4. One group of monkeys (group AT) received ablations in the temporal lobe anterior to area V4, and a second group (group MOT) received ablations in a medial occipito-temporal area roughly corresponding in cranial location to the lesion that produces human cerebral achromatopsia. The animals in group MOT showed no impairment of their colour vision. Group AT, in contrast, had a severe impairment in chromatic vision, with a relative sparing of non-chromatic vision. Their behaviour was indistinguishable from that of a human patient with total cerebral achromatopsia who had been tested on the same tasks. These results show that area V4 in macaque monkeys is not analogous, and probably not homologous, to the human colour centre. Instead, they suggest that the area of the monkey's brain corresponding to the colour area in the human brain is in the temporal cortex, anterior to area V4.

Animals↗

PubMed1995

Uncinate fascicle section leaves delayed matching-to-sample intact, with both large and small stimulus sets.

An earlier study found that rhinal cortex ablations in the monkey (Macaca fascicularis) impaired delayed matching-to-sample only when the stimuli in the experiment came from a large population of possible stimuli, not when the stimulus population was small. The present experiment tested the idea that delayed matching-to-sample with a small stimulus population selectively engages the direct projection from visual association cortex to the prefrontal cortex, bypassing the rhinal cortex. This selective involvement could explain the preservation, after rhinal cortex ablations, of memory for items drawn from a small stimulus population. We trained monkeys preoperatively in delayed matching-to-sample with large and small stimulus populations, exactly as in the earlier study, then examined the effect of sectioning the cortico-cortical pathway between visual association cortex and prefrontal cortex, the uncinate fascicle. Uncinate fascicle section had no effect on postoperative performance of delayed matching-to-sample, with either large or small stimulus populations. These data give no support to the idea that preserved matching with a small stimulus population after rhinal lesions reflects the selective involvement in this task of the direct projection from visual association cortex to prefrontal cortex. Further, they strengthen the idea (derived from earlier studies of uncinate fascicle section) that the uncinate fascicle does not play a general role in visual memory or perception, but instead has a specialized function in the processing of conditional instruction cues.

Animals↗

PubMed1995

Correlation of fornix damage with memory impairment in six cases of colloid cyst removal.

We studied six patients in whom colloid cysts had been removed surgically from the third ventricle. The patients were selected simply by availability for the study, not on grounds of clinically diagnosed amnesia or its absence. The outcomes of operation ranged from one patient who had postoperatively resumed a normal life without complaint of memory disorder at any stage, through four who complained of memory disorder since operation, to one who was so severely amnesic as to require constant supervision. Each patient was given psychometric tests of memory, and was also scanned by magnetic-resonance imaging. One of us examined the six scans and assessed the extent of damage to the fornix, and any other brain damage, in ignorance of the outcomes of the psychometric tests. The fornix in the right hemisphere had been destroyed in all six cases, and all showed evidence of moderate or severe impairment in nonverbal memory. The fornix in the left hemisphere was intact in only one patient; this was the patient who had resumed a normal life without complaint of memory disorder. The left fornix was damaged with some sparing in one further patient, and the remaining four patients showed destruction of the fornix in the left as well as in the right hemisphere. The severity of impairment in verbal memory in these six cases was related to the severity of the damage to the left fornix. No other evidence of brain damage appeared to be systematically related to memory ability. These results add to the evidence that bilateral fornix damage produces amnesia, and that sparing of the left fornix alone is sufficient to ensure a more favourable outcome.

Adult↗

PubMed1995

Olfactory-visual associative learning in monkeys depends on intrahemispheric olfactory-visual interaction.

Three Cynomolgus monkeys (Macaca fasicularis) learned a series of food-visual conditional discrimination problems. In each problem, 1 of 2 possible food items was presented at the beginning of each trial and acted as an instruction cue as to which of 2 visually distinct stimulus objects the monkey must displace on that trial to obtain a further food reward. Following surgical disconnection of olfactory-visual intrahemispheric interaction, the monkeys were unable to use olfactory properties of the food items to guide visual choices. These results show both that olfactory differences between foodstuffs are a powerful olfactory stimulus, which can enter into cross-modal association with visual stimuli, and that this association depends on an intrahemispheric pathway of olfactory-visual interaction.

Afferent Pathways↗

PubMed1994

Preserved recognition memory for small sets, and impaired stimulus identification for large sets, following rhinal cortex ablations in monkeys.

Seven cynomolgus monkeys (Macaca fascicularis) performed a series of tasks designed to assess their visual memory and their ability to identify visual stimuli. Preoperatively they were trained and tested in delayed and simultaneous matching-to-sample, both with a large stimulus set and with a small stimulus set; there were approximately 500 million possible stimuli in the large set, which effectively means that stimuli were trial-unique with this set, while in the small set there were only four stimuli, which appeared repeatedly in every session of training with the small set. Three of the monkeys then had the cortex within and adjacent to the rhinal sulcus removed bilaterally, while the other four served as an unoperated control group. Postoperatively, the animals with ablation of the rhinal cortex showed severe impairment in delayed matching-to-sample with the large set. With the large set they were also impaired, however, in matching-to-sample with no delay between sample and test (0 s delay) and in simultaneous matching-to-sample, in which the sample and the two choice patterns were simultaneously present for inspection. The impairment in simultaneous matching-to-sample was particularly clear when the task was made more difficult by reducing the physical discriminability of the trial-unique stimuli. With the small set of four stimuli, the animals with rhinal cortex ablation were not significantly impaired in overall performance level in delayed matching-to-sample, though their level was on average below that of the normal control animals. The stimulus set was then further restricted, so that there were now only two stimuli used throughout; in this condition, the animals with rhinal cortex ablation performed delayed matching-to-sample without any suggestion of impairment, showing indistinguishable performance levels from those of the control animals over a range of forgetting intervals. Subsequently, the animals were trained in trial-unique non-matching-to-sample with 0 s delay, which required reversal of the matching-to-sample rule they had previously learned; animals with rhinal cortex ablation showed a clear impairment in this rule-reversal learning. The final experimental task was a concurrent discrimination learning task in which 20 pairs of stimuli were presented once per session; the animals with rhinal cortex ablation learned more slowly than the control animals on average, but the difference between the groups did not attain statistical significance.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Dissociated effects of perirhinal cortex ablation, fornix transection and amygdalectomy: evidence for multiple memory systems in the primate temporal lobe.

Four experiments were performed with macaque monkeys (rhesus, Macaca mulatta, and cynomolgus, M. fascicularis). In experiment 1 six rhesus monkeys learned pre-operatively to perform delayed matching-to-sample, with complex naturalistic scenes as the stimulus material. Three of these monkeys then received bilateral ablations of the perirhinal cortex, while the other three received fornix transection. Both groups showed an impairment postoperatively, but the effect of perirhinal cortex ablation was significantly more severe than the effect of fornix transection. In experiment 2 the same animals, together with three normal, control rhesus monkeys, which had a similar training history, performed simple, spatial discrimination learning in a Wisconsin General Test Apparatus. The animals with fornix transection were impaired, but the animals with ablations of perirhinal cortex were not. In experiment 3 the nine animals from experiment 2 were tested for the acquisition of systematic preferences among four novel foods (apple, lemon, olive, meat). Their results were compared with those from a previously published experiment with normal and amygdalectomized cynomolgus monkeys which had been given the same food preference test. Amygdalectomy produced a significant disruption of food preference learning but the other two lesions (fornix transection and perirhinal cortex ablation) did not. In experiment 4, 16 rhesus monkeys (9 normal controls, 4 with perirhinal cortex ablation, and 3 with fornix transection) learned to discriminate among complex naturalistic scenes, in a task in which each scene was presented only once per day in the main part of the experiment. The two operated groups were impaired, and there was no significant difference between the severity of the impairments. Thus, the effects of perirhinal cortex ablation can be doubly dissociated from the effects of fornix transection (experiments 1 and 2) and both can be dissociated from the effects of amygdalectomy (experiment 3). Furthermore, the results of experiment 4 show that the effects of perirhinal cortex ablation are not limited to tasks of memory over short retention intervals. On the basis of the presently reported data and other known effects of perirhinal cortex ablation, it is suggested that this ablation produces an impairment in knowledge (semantic memory) about objects.

Amygdala↗

PubMed1994

Role of the amygdala in picture discrimination learning with 24-h intertrial intervals.

Six monkeys (Macaca mulatta) learned to discriminate visually between pictures of objects. Each pair of pictures was presented only once per day (24-h intervals between successive trials with the same pair). Choice of the correct picture of a pair produced immediate food reward. One set of 20 pairs was learned before operation and a second set of 20 different pairs was learned after the amygdala had been removed bilaterally in three of the monkeys. The amygdalectomized animals were severely retarded in learning the second set. These results confirm earlier results indicating that amygdalectomy impairs visual discrimination learning in tasks where the discriminanda are directly associated with the incentive value of a primary reward, and they show that, contrary to the indication of some previous results, this impairment extends to the case where each picture is seen only once per day.

Amygdala↗

PubMed1994

Removal of the amygdala plus subjacent cortex disrupts the retention of both intramodal and crossmodal associative memories in monkeys.

Naive rhesus monkeys (Macaca mulatta) were trained preoperatively in an automated test apparatus on an auditory-visual (crossmodal) conditional task or on a visual-visual (intramodal) conditional task that involved learning a fixed set of stimulus-stimulus associations or paired associates. After having learned their respective tasks, each monkey received bilateral removal of the amygdala plus subjacent cortex. The 2 experimental groups showed equally poor retention of the stimulus-stimulus associations and subsequently relearned their respective crossmodal and intramodal associations at the same rate. These data argue against the idea that the amygdala is specialized for crossmodal associations. Instead, the data indicate that the amygdala or its underlying cortex, or both, play a more generalized role in stimulus-stimulus associative memory.

Amygdala↗

PubMed1994

A primacy effect in monkeys when list position is relevant.

In Experiment 1 (1a and 1b), Rhesus monkeys (Macaca mulatta) learned lists of two-choice visual discriminations in which list position was relevant to discrimination performance. For example, Stimulus A was the rewarded stimulus if it was presented at List Position 1, but was not rewarded if it was presented at any other position in the list; similarly, Stimulus B was rewarded only at List Position 2, and so on. In learning these lists, all animals showed a marked primacy effect. In Experiment 2 (2a and 2b), Rhesus monkeys and Cynomolgus monkeys (M. fascicularis) learned lists of visual discriminations in which each visual stimulus occupied a fixed position in a list, but list position was not relevant to discrimination performance. For example, Stimulus E was always rewarded, and was always presented at List Position 1. To increase the salience of list beginning as a distinctive event, successive presentations of the list were separated by 24-hr intervals. In Experiment 2 there was no primacy effect, however. These results show for the first time that a primacy effect can be obtained in visual discrimination learning by monkeys. Furthermore, they suggest that it is obtained only when list position is relevant to the discrimination learning task.

Animals↗

PubMed1993

Role of the dorsal prestriate cortex in visuospatial configural discrimination by monkeys.

Cynomolgus monkeys (Macaca fascicularis) learned a series of visuospatial configural discriminations in which particular discriminative stimulus objects were rewarded only in particular spatial locations. For example, object X was rewarded if it was on the left but not if it was on the right. After ablation of part of the dorsal prestriate cortex they were impaired in learning discriminations of this kind. The same animals were not impaired in learning visual object discriminations in which spatial position was irrelevant, nor in learning spatial discriminations in which object identity was irrelevant. The results were compared with previously reported results from fornix transection in the same tasks; the deficit following dorsal prestriate ablation in visuospatial configural discrimination learning was similar in severity to that which followed fornix transection. The results show that the dorsal prestriate area has a more general role in visuospatial processing than was known hitherto, and they suggest that it interacts with the hippocampal formation and fornix in visuospatial memory tasks.

Animals↗

PubMed1993

Interaction of the amygdala with the frontal lobe in reward memory.

Five cynomolgus monkeys (Macaca fascicularis) were assessed for their ability to associate visual stimuli with food reward. They learned a series of new two-choice visual discriminations between coloured patterns displayed on a touch-sensitive monitor screen; the feedback for correct choice was delivery of food. Normal learning in this task is known to be dependent on the amygdala. The monkeys received brain lesions which were designed to disconnect the amygdala from interaction with other brain structures thought to be involved in this memory task. All the monkeys received an amygdalectomy in one hemisphere and lesions in the other hemisphere of some of the projection targets of the amygdala, namely the ventral striatum, the mediodorsal thalamus and the ventromedial prefrontal cortex. The rate of learning new problems was assessed before and after each operation. Disconnection of the amygdala from the ventral striatum was without effect on learning rate. An earlier study had shown that disconnection of the amygdala from either the mediodorsal thalamus or the ventromedial prefrontal cortex produced only a mild impairment, significantly less severe than that produced by bilateral lesions of any of these three structures. The present results show, however, that disconnection of the amygdala from both the mediodorsal thalamus and the ventromedial prefrontal cortex in the same animal, by crossed unilateral lesions of the amygdala in one hemisphere and of both the mediodorsal thalamus and the ventromedial prefrontal cortex in the other hemisphere, produces an impairment as severe as that which follows bilateral lesions of any of these three structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗

PubMed1993

Additive effects of forgetting and fornix transfection in the temporal gradient of retrograde amnesia.

Nine Rhesus monkeys (Macaca mulatta) learned to discriminate among 320 complex naturalistic scenes (Set A) for food reward. Six months later they learned to discriminate among a further 192 scenes (Set B). Immediately after learning Set B the animals were given a preoperative retention test of both sets, consisting of a single trial with every scene they had learned. Three monkeys were then operated upon to transect the fornix, the other six forming an unoperated control group. Two weeks after operation the scenes were presented once each in a postoperative retention test. The animals with fornix transection showed significantly poorer memory than the control animals at the postoperative retention test. Furthermore, within the fornix-transected animals' performance, postoperative amnesia for Set B was more marked than amnesia for Set A, by comparison with the animals' own preoperative retention of the two sets. However, a similar pattern of performance was also seen within the control animals' results, in that they forgot more of Set B than of Set A in the interval between the preoperative and postoperative retention tests. There was no significant difference between the groups in the gradient of forgetting, defined as the difference between forgetting of Set B and forgetting of Set A in the interval between the preoperative and postoperative retention tests. These results give no support to the idea that the severity of retrograde amnesia is graded as a function of the remoteness of the memory at the onset of amnesia, and they give some indication of possible reasons why the impression of such a gradient is frequently reported clinically.

Amnesia, Retrograde↗

PubMed1993

Normal forgetting, impaired acquisition in memory for complex naturalistic scenes by fornix-transected monkeys.

As part of an earlier experiment three rhesus monkeys (Macaca mulatta) with fornix transection and three normal control monkeys had learned to discriminate among 320 naturalistic complex scenes. The fornix-transected animals had been much slower than the controls to reach criterion in learning this task, but eventually did so. The present experiment measured long-term forgetting of these scenes. Seven weeks after reaching criterion each animal was retested. All animals showed some forgetting of the scene discriminations they had learned. The amount forgotten was equal in the two groups. These results show that the slower learning of the scenes following fornix transection was not caused by accelerated forgetting. The present findings in fornix-transected monkeys are similar to previous findings in human amnesic patients.

Animals↗

PubMed1993

Neural substrates of visual stimulus-stimulus association in rhesus monkeys.

Rhesus monkeys learned 10 visual stimulus-stimulus association, or paired associates. They then received bilateral removals of either the amygdaloid complex and underlying cortex, the hippocampal formation and underlying cortex, or both combined, or they were retained as unoperated controls. After surgery or rest, the monkeys were tested for their retention of the preoperatively learned set of paired associates, as well as for their ability to learn new associations of the same type. Both unoperated controls and hippocampectomized monkeys relearned the preoperatively trained set of paired associates almost immediately. By contrast, monkeys with amygdala removals were moderately retarded in relearning, and monkeys with combined amygdala and hippocampal ablations were severely retarded. When confronted with new sets of visual stimuli, monkeys with amygdala removals or hippocampal removals learned new sets of paired associates at the same rate as the controls, whereas monkeys with the combined ablation were again profoundly retarded. Only one monkey with the combined lesion was able to learn new stimulus-stimulus associations to criterion, and then only after extensive training, despite the ability of all three animals in this group to perform delayed matching-to-sample with the same stimuli and the same intraatrial delays as those used in the paired associate task. At the end of the main experiment, two of the unoperated controls received bilateral ablations of the rhinal cortex. These monkeys showed the same level of difficulty in learning new paired associates as the animals in the main experiment that had received the combined amygdala plus hippocampal ablations. The results implicate the medial temporal lobe, and particularly the rhinal cortex, in the formation of stimulus-stimulus associative memories.

Amygdala↗

PubMed1992

Monkeys (Macaca fascicularis) with rhinal cortex ablations succeed in object discrimination learning despite 24-hr intertrial intervals and fail at matching to sample despite double sample presentations.

Six cynomolgus monkeys (Macaca fascicularis) learned preoperatively a set of 10 concurrent object discriminations with 24-hr intertrial intervals. Three then had the rhinal cortex removed bilaterally, whereas the other 3 remained as unoperated controls. The animals with ablations were impaired in reacquiring the preoperatively acquired set but subsequently learned without any impairment a new set of 10 discriminations that was presented in the same way. The monkeys with rhinal cortex ablations then failed to learn delayed matching to sample, with double sample presentations, in 510 trials, whereas the control animals learned this task in 270 trials on average. The results add to existing evidence that rhinal cortex ablation produces a severe impairment in visual short-term recognition memory and show for the first time that this impairment is accompanied by normal long-term discrimination learning ability.

Animals↗