The effect of anterior thalamic and cingulate cortex lesions on object-in-place memory in monkeys

~ ) Pergamon PII: S0028- 3932(97)00042 0

Neuropsychologia, Vol. 35, No. S, pp. 1093 1102, 1997 1997 Elsevier Science Ltd. All rights reserved

Printed in Great Britain 0028 3932/97 $17.00+0.00

The effect of anterior thalamic and cingulate cortex lesions on object-in-place memory in monkeys

A M A N D A PARKERt and DAVID G A F F A N

Department of Experimental Psychology, Oxford University, South Parks Road, Oxford OXI 3UD, U.K.

(Received 18 Not,ember 1996; accepted 16 February 1997)

Abstract---Six Macaque monkeys (Macaca mulatta) were trained in an object-in-place memory task, designed to capture the "whole scene' nature of episodic memory. In this task the correct, rewarded, response in each scene was to a particular object of a pair, which always occupied a particular position in a unique background which had been generated using randomly chosen colours and shapes. In each session, the monkey learned a new list of these unique scenes. The animals then underwent surgical ablation of either the anterior thalamic nuclei or the cingulate cortex, It was found that the animals with anterior thalamic lesions showed a substantial impairment, whereas the monkeys with cingulate cortex ablations were not significantly impaired at the task. These results confirm the importance of the anterior thalamic nuclei in episodic memory, and suggest that the cingulate gyrus is not a region which is crucial in the type of episodic memory task used in the present experiment. '.~ 1997 Elsevier Science Ltd

Key Words: non-human primate; episodic memory; cingulate cortex; anterior thalamus: amnesia.

Introduction

The proposal that the form of memory damaged in anterograde amnesia is critically dependent on the 'Papez ' circuit of cortical and subcortical structures has a long history in neuroscience, being first suggested by Benedek and Juba [9, 10]. Delay and Brion [12] expanded the theory by proposing that diencephalic and temporal lobe amnesias were caused by interrupting this circuit at different points, and evidence which supports this position has been accruing over the past half century. In a recent comprehensive review of human amnesia, Kop- elman [29] concluded that " . . . the balance of the more recent evidence appears to suggest that it is a circuit comprising the hippocampus, entorhinal and perirhinal cortex, the mamillary bodies, mamillo-thalamic tract, and the anterior (rather than the medial dorsal) nucleus of the thalamus, which is critical in memory formation." ([29], p. 159). This list of structures is almost identical to the circuit proposed by Papez [37], excepting the inclusion of the rhinal cortices and the exclusion of the cingulate gyrus.

Studies of patienls with damage to either of the two

? Address for correspondence: Department of Experimental Psychology, Oxford University, South Parks Road, Oxford OX1 3UD, U.K.; fax: 01865 310447; e-mail: amanda. parker(a psy.ox.ac.uk.

areas considered in the present paper, the anterior nuclei of the thalamus and the cingulate gyrus, can be difficult to interpret due to damage extending beyond the boundaries of either of these structures. However, there are reports of anterograde amnesia in patients with fairly circumscribed anterior thalamic lesions [11, 26, 28]. Very little mention is made of memory deficits in reports of patients with accidental or deliberate lesions of the anterior cingulate gyrus (for reviews see [13, 14]). Although amnesia has been reported as a consequence of more posterior cingulate damage [46], the problem of diffuse damage to other structures, particularly the fornix, makes a positive conclusion difficult. These structures, then, could usefully be explored in non-human primates using a test which has been developed to be an analogue of the tests used with human amnesics.

No studies of memory in monkeys after discrete anterior thalamic lesions currently exist, and there are only three experiments in the literature which have compared memory performance in monkeys before and after cingulate lesion. Murray et al. [33] used a T-maze which was modelled on the type usually used with rats and increased in size to be appropriate for use with monkeys, and an experimental procedure designed by them to be similar to that used by them with rats [30]. They found that fornix transection impaired relearning of this spatial memory task, in both monkeys and rats, whereas the cingulate-lesioned group of monkeys, although impaired,

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did not differ significantly from controls. Mishkin and Bachevalier [31] found an impairment in spatial reversal and spatial delayed response after anterior cingulate lesion, compared to a group of orbitofrontal-lesioned animals. Stern and Passingham [42] compared performance in a four-box search task before and after anterior cingulate lesion, and found a mild impairment in the use of an organized pattern of searching post- surgery. This could be interpreted as a memory deficit.

Studies of rats with discrete anterior thalamic lesions, and cingulate lesions which spared the cingulum bundle, have produced results which are largely in agreement with the patient data. A series of experiments by Aggleton and colleagues [6, 7] have shown that lesions of the anterior nuclei of the thalamus, fornix or hippocampus cause impairments of very similar severity on delayed non-matching to position. A later comparison of anterior thalamic and fornix lesions found that spatial alternation performance was impaired whilst object recognition was unimpaired in both groups [4]. Whereas lesions of the fornix and anterior thalamic nuclei consistently produce deficits on performance of tasks which require the animal to use spatial information, cingulate cortex lesions, both anterior and retrosplenial, did not produce significant impairments [5, 35]. This is in contrast to work by Suth- erland and colleagues [43, 44], who found effects of area 29 lesions on spatial memory in the rat. Studies of discrimination avoidance learning in rabbits by Gabriel and colleagues [16-19] have also suggested an important role for the anterior thalamus and cingulate cortex in this form of memory. However, as there are significant species differences in the connections between structures in the Delay-Brion circuit in primates and rodents [8, 36], infer- ence from rodent to primate may not be apposite. The present experiment should allow closer comparison between monkeys and rats on a task designed to stress the spatial aspect of episodic memory.

Recognition memory in non-human primates has traditionally been tested using delayed matching or non- matching to sample. However, research which stresses the importance of the perirhinal cortex in object recognition memory has cast doubt on the usefulness of either of these methods as a test of episodic memory in monkeys [15, 34]. An alternative approach, which stresses the spatial nature of episodic memory, has been proposed [21, 24, 40]. This is supported by the finding that damage to the fornix or mamillary bodies results in an impairment in object-in-place memory [21, 38]. The object-in-place memory task is based on the premise that the primary function of the Delay-Brion circuit is to form a memorial representation of objects and their associated context [20, 21, 39]. Earlier research with this task [21] compared visual object discrimination learning, in normal and fornix-transected monkeys, under two conditions: one in which the background context was constant for each object discrimination problem, and another in which there were randomly varying backgrounds for each presentation of the object discriminanda. It was found that

the two groups performed equally well when context varied randomly, but when each pair of discriminanda had a unique background context permanently associated with them, performance in the normal group was much facilitated, but the fornix-transected group was now severely impaired [21]. The condition in which context varied randomly is similar to human semantic memory, where knowledge about objects is acquired from many different events set in different contexts, but the condition in which each pair of objects was set in a constant context is similar to human episodic memory, which is memory for an event set in its own unique context. The most severe impairment in the fornix-transected group in the initial study [21] was in the object-in- place task, in which the objects, the background context and the spatial position of the objects in the background context all remain unchanged from one presentation of the scene to the next. In this task, normal monkeys remember lists of 16 or 20 scenes very well after only one trial, but animals with fornix transection or mamillary body lesions [38] are severely impaired. To summarize, the object-in-place task is similar to human episodic memory in the relationship between context and objects; it reveals severe impairments in monkeys with lesions that are similar to those which are believed to produce amnesia in man, and these impairments are not merely representative of a general impairment in object discrimination learning, since such learning with randomly varying contexts is not impaired [21]. On all these grounds impairment in the object-in-place memory task in the monkey is the best available model of human episodic memory impairment in amnesia.

Using the object-in-place task, and the same meth- odology as the previous experiments in this series [21, 23, 38], the present experiment investigated whether lesions of the main target of the mamillary bodies and the fornix, the anterior thalamic nuclei, would produce an impairment in episodic memory. In a further group of animals we examined the effects of cingulate lesions, as the cingulate gyrus has traditionally been regarded as the primary output target of the anterior thalamic nuclei. The measurement of impairment using the present method takes place after a long period of pre-training on the task, which allows a stable level of performance to develop. We can then be confident that the changes in performance which are observed in each individual animal are due to lesion effects.

Methods

Subjects

These were six young adult male Rhesus monkeys (Macaca mulatta). At the time of surgery they weighed on average 6.9 kg. They had participated as normal animals in other studies before taking part in the present experiment. Their previous experience had been in tasks in an automated apparatus similar to that used in the present experiment.

A. Parker and D. Gaffan/Effects of anterior thalamic and cingulate lesions 1095

There were two groups of three monkeys each. After preoperative training to a stable level, the first group received bilateral stereotaxic anterior thalamic lesions and the second group were given bilateral cingulate cortex lesions. After a period (10-24 days) of recovery, their performance on 10 sessions of the same object-in-place task was assessed.

Surgery

Operations were carried out under aseptic conditions, and the monkeys were anaesthetized throughout surgery with bar- biturate (thiopentone sodium) administered through an intra- venous cannula.

Cingulate lesion. Following incision of the skin and galea, a D-shaped bone flap was raised in the cranium over the area of operation, large enough to enable one hemisphere to be exposed up to the midline, and the dura mater was then cut and retracted. Veins draining into the sagittal sinus were cauterized and cut. The hemisphere was retracted from the falx to enable access to the interhemispheric fissure. A small-gauge metal aspirator, insulated to the tip, was used to aspirate the tissue in the lower bank of the cingulate sulcus and ventral to the cingulate sulcus. The intended ablation is shown in Fig. 1. The caudal limit of the lesion was an imaginary line drawn from the caudal end of the cingulate sulcus to the splenium of the corpus callosum. The rostral limit of the lesion was the rostral sulcus. Strips of tissue were left in place behind the ascending branches of the anterior cerebral artery, to avoid the danger of arterial collapse and interruption of the blood supply to the cortex outside the area of the intended ablation. Once the lesion to the exposed hemisphere was complete, the falx was cut and the contralateral hemisphere was ablated in a similar manner. The lesion was intended to include both the tissue in the subgenual area and the retrosplenial cortex. At the completion of the operation the wound was closed in layers and the bone flap was replaced.

Anterior thalamic lesion. For making the anterior thalamic lesions, two identical stereotaxic headholders were used. The animal was placed in one of the headholders and remained in

that headholder throughout the operation. Using a stereotaxic micromanipulator, a needle was lowered into the lateral ventricle until cerebrospinal fluid entered the attached syringe. Radio-opaque dye (Omnipaque, 0.8 ml) was then injected into the ventricle. An X-ray picture was taken from the side, giving a lateral view of the ventricles in relation to the tip of the needle. A frontal X-ray was taken after a second injection of radio- opaque dye at the same site. From the frontal and lateral X- rays, and given the stereotaxic coordinates of the needle tip, we calculated the stereotaxic coordinates of the anterior commissure at the midline in relation to the known position of the needle tip. Using the atlas of Ilinsky and Kultas-Ilinsky [27]4 we then calculated the intended lesion sites in each hemisphere in relation to the anterior commissure as follows: laterally 0.8 mm from the midline there were three lesions, at 2.5 mm dorsal to the anterior commissure and 3.3 mm posterior to the anterior commissure, at 3.3 mm dorsal and 4.0 mm posterior, and at 4.1 mm dorsal and 4.7 mm posterior: laterally 1.8 mm from the midline there were three lesions, at 4.5 mm dorsal to the anterior commissure and 3.0 mm posterior to the anterior commissure, at 4.8 mm dorsal and 4.1 mm posterior, and at 5.1 mm dorsal and 5.2 mm posterior; laterally 2.8 mm from the midline there were three lesions, at 5.2 mm dorsal to the anterior commissure and 4.2 mm posterior to the anterior commissure, at 5.2 mm dorsal and 5.2 mm posterior, and at 5.2 mm dorsal and 6.2 mm posterior. The micromanipulator holding the injection needle was transferred from the first stereotaxic headholder to a second, identical and empty, headholder. For each of the nine lesions in each hemisphere, the micromanipulator was used to place the needle tip in the empty headholder at the intended lesion site as calculated by reference to the anterior commissure. A further micromanipulator held the heat probe with which the lesion was to be made. This second micromanipulator was angled so that the heat probe did not move in the conventional dorsoventral, anteroposterior and mediolateral directions, but instead could reach the anterior thalamus without going through the fornix. The heat probe was inclined 50 from the vertical and approached from the side, at an angle rotated 2 0 anteriorly from a perfectly lateral approach. Using the angled

Intended S!

Fig. I. Tile intended cingulate lesion, and reconstruction of the cingulate lesion in CIN1 (S1), CIN2 ($2) and C1N3 ($3).


micromanipulator, the heat probe was placed against the needle tip in the empty headholder for each lesion site. The coordinates necessary to place the heat probe at that site were read from the empty headholder for each of the intended lesion sites, and the micromanipulator holding the heat probe was then transferred to the first headholder, which held the animal, in order to place the heat lesion at each intended site by repro- ducing the coordinates which had been read from the empty headholder. The effect was that the heat probe entered the brain laterally near the central sulcus, and moved anteriorly and medially towards the thalamus. Access for the heat probe in each hemisphere was through one drilled burr hole. At each lesion site the tip of the heat probe was raised to a temperature of 80:'C and held at that temperature for at least 1 min. Fol- lowing completion of the heat lesions, the dura was replaced over the cortex and sewn, and the wound was closed in anatomical layers.

Histology

At the conclusion of the behavioural experiments, the animals were deeply anaesthetized, then perfused through the heart with saline followed by formol-saline solution. The brains were blocked in the coronal stereotaxic plane posterior to the lunate sulcus, removed from the skull and allowed to sink in sucrose formalin solution. The brains were cut in 50-/~m sections on a freezing microtome. Every fifth section (anterior thalamus group) or tenth section (cingulate group) was retained and stained with Cresyl Violet.

Figure 1 shows the intended cingulate lesion and reconstruction of the cingulate lesion in each of the three monkeys in the group. Representative sections from CIN3 are shown in Fig. 2. The lesions were largely as intended in animals CIN2 and CIN3. In monkey CIN1 there was an extensive area of unintended damage in the left hemisphere, including the frontal pole, dorsolateral and supplementary motor cortex. We assume that this damage was caused by the interruption of the blood supply following arterial closure as a result of the cingulate lesion. A similar, but much smaller, area of unintentional damage was observed in animal CIN3.

Figure 3 shows the intended anterior thalamic lesion and reconstruction of the actual lesions. Representative sections from ANT2 are shown in Fig. 4. Microscopic examination of the stained histological sections confirmed that in all three cases a compete bilateral lesion of the anterior thalamic nuclei had been made. In all three animals there was also some damage to midline nuclei. In animal ANT3 there was slight unintended unilateral damage to the caudate nucleus and to the ventral anterior nucleus. In all three animals there was some fornix degeneration, caused by later fornix transection for purposes unrelated to this experiment.

In all three animals who received anterior thalamic lesions there was widespread neural degeneration and gliosis in the mamillary nuclei. Degeneration was found in the anterior thalamic nuclei in the cingulate lesioned animals, as shown in Fig. 5. The degeneration was most severe in the medial region of the anterior ventral nucleus (AV), but less severe in the lateral region. In the lateral region of the anterior medial nucleus (AM), there was moderate degeneration, whereas in the medial region of the AM there was no sign ofgliosis or neural degener-

)

Fig. 2. A series of sections from animal CIN3, from anterior at the top to posterior at the bottom, showing the cingulate cortex ablation. The section second from the top shows one of the cortical strips spared to support overlying branches of the

anterior communicating artery.

A. Parker and D. Gaffan/Effects of anterior thalamic and cingulate lesions

Fig. 3. The intended anterior thalamic lesion (far left), and reconstruction of the lesion in ANTI, ANT2 and ANT3.

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ation. The anterior dorsal nucleus (AD) was degenerated bilat- erally in ANTI and ANT2 and unilaterally in ANT3. In all three animals there was also substantial degeneration in the lateral dorsal nucleus.

Apparatus

The monkey was brought to the training apparatus in a wheeled transport cage, which was then fixed to the front of the apparatus. The monkey could reach out through bars at the front of the transport cage to touch a touch-sensitive monitor screen which was 150 mm from the front of the cage. The screen was 380mm wide and 280ram high. Each scene in the experiment, as described below under stimulus material, occupied the whole of the screen. A closed-circuit television system allowed the experimenter in another room to watch the monkey, Small food rewards (pellets, 190rag) were delivered into a hopper placed centrally underneath the monitor screen. A single large food reward was delivered at the end of each training session by opening a box which was set to one side of the centrally placed hopper. The box contained peanuts, raisins, proprietary monkey food, fruit and seeds. The amount of this large reward was adjusted for individual animals in order to avoid obesity. The small and large rewards dispensed in the training apparatus provided the whole daily diet of the monkeys on days with a training session. Opening of the box with the large food reward. like all other aspects of the stimulus display and the experimental contingencies during any session of training, was under computer control.

Procedure

Stimulus materials. The computer-generated scenes used in this experiment were generated in the same way as those described in Gaffan ([21], task 5). Foreground objects, of which there were t~o in each scene, consisted of randomly selected small typographic characters, each placed in a constant location in the scene. Backgrounds were generated using an algorithm which drew a random number of ellipses and ellipse segments (between two and seven) of random colour, position and size, on a randomly coloured initial background. The whole of the colour space was equally available to objects and to backgrounds. Each animal was tested using a different set of scenes. Feedback for a correct response consisted of the correct object flashing on and off, whilst a reward pellet was delivered. Each scene contained one correct and one incorrect object. Each of these objects was always presented in a constant place in a constant unique background.

Experimental procedure, The lists of object-in-place scenes contained 20 scenes. Each new list of 20 scenes was presented for one session of 160 trials (eight trials per scene). Each scene was presented once in each of eight blocks of 20 trials within a session. The order of presentation of the 2(1 scenes was the same in each block. Every scene had a correct response area, where the positive (rewarded) foreground object was displayed, and an incorrect response area which contained the negative (unre- warded) foreground object. On each trial, the display remained on the screen until the animal touched either the positive or the negative object. If the monkey touched the positive object it flashed on and offin the scene for 2400 msec and a reward pellet was dispatched into the hopper in front of the monkey. An


Fig. 4. A series of sections from animal ANT2, from anterior at the top to posterior at the bottom, showing the anterior

thalamic lesion.

intertrial interval of 10sec then began, ending with the presentation of the next trial in the session. In blocks 2-8 in each session, if the object touched was the negative, the screen

blanked, followed after an intertrial interval of 10sec by the next scheduled trial in the session, without any correction trials in the scene in which an error had been committed. Correction trials were presented only in the first block of 20 trials in each session, i.e. the first run through the list. A correction trial consisted of the presentation of the scene with only one object in it, the positive; when a response to the positive was emitted, flashing and food followed as in the main trials of the task. For the final scene in the session, the final reward pellet was followed by a large food reward (see Apparatus) and the animal was given at least 10rain to eat some of this food and take the remainder into the cheek pouches, before being returned to the home cage. For this trial alone among the trials after the first block of 20 trials, a correction trial was presented if an error was made (thus ensuring that the large food reward was always obtained).

Preoperative training and testing. Subjects received one training session per day, at least five days per week, until a stable level of performance was reached. Each animal received at least 60 sessions. For establishing the preoperative level of performance, 10 lists of 20 new scenes were then presented, a total of 200 scenes, one list per session for 10 sessions.

Postoperative testing. The animals were trained on 10 new lists of scenes, over 10 consecutive sessions. Each list contained 20 new scenes, which were repeated eight times. Each new set was presented in one session only.

Results

Figure 6 shows the percentage errors made by each animal in trials 2-8 for l0 sessions of 20 scenes before and after surgery. Percentage error is calculated f rom the number o f errors made in trials 2-8 for all 200 scenes each animal sees in each phase o f the experiment. All animals showed an increase in errors made post-surgery, with the increase in errors being larger for the animals in the anterior thalamic group than for those in the cingulate group.

Figure 7 shows the animals ' averaged learning curves for the cingulate- and the anterior thalamic-lesioned groups for 10 lists o f scenes in each phase o f the experiment. Every list o f 20 new scenes was presented for eight trials, one list per session. The final 10 preoperative sessions were compared with l0 postoperat ive sessions.

To compare efficiency o f learning before and after surgery in the two experimental groups, a two-way analysis o f variance using the raw data showed a significant effect o f experimental group ( F = 48.14, d.f. 1,4, P < 0.005), and a significant interaction o f group with surgery ( F = 14.57, d.f. 1,4, P<0 .02 ) . The significant interaction shows that the effect o f surgery was significantly more severe in the anterior thalamus group than in the cingulate cortex group. The overall effect o f surgery (averaged across the two groups) was not significant ( F < 1). Within this overall analysis, planned compar isons using the pooled error term were performed ([41], pp. 268-271), firstly com- paring preoperative score and postoperat ive score for the anterior thalamic group. This showed a significant effect o f surgery [t(4) = 2.4, P < 0.05]. Secondly, a planned comparison between preoperative score and postoperat ive

A. Parker and D. Gaffan/Effects of anterior thalamic and cingulate lesions 1099

Fig. 5. A reconstruction of the thalamic degeneration found in animals CIN1 (on the left), CIN2 (centre) and CIN3 (on the right) following cingulate cortex ablation. The darker areas show the regions of most pronounced degeneration.

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Fig. 6. Summary of the results from both groups in each phase of the experiment. Bars show average percentage error score for all animals in each phase of the experiment. Lines show pre- post change for each animal. Symbols represent: (left) triangle, C1N1; inverted triangle, CIN2; circle, CIN3; (right) triangle,

ANTI: inverted triangle, ANT2; circle, ANT3.

score for the cingulate group did not show a significant difference in error score ( t< 1, d.f. =4).

Discussion

Anterior thalamic lesions had a clear effect on object- in-place memory, resulting in a substantial memory impairment. It has been argued [21] that this level of deficit can be considered to be analogous to the deficit in episodic memory seen in human amnesics. There is good comparison, therefore, with case study reports of human patients showing that focal lesions of the anterior thalamus result in anterograde amnesia [11, 26, 28]. Although no previous monkey experiments have been reported

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Fig. 7. Average trial-by-trial learning for each group in 10 lists of 20 scenes. Each list was presented for eight trials. (Left side) Cingulate group symbols represent: open square, preoperative; filled square, postoperative. (Right side) Anterior thalamic group symbols represent: open diamond, preoperative; filled

diamond, postoperative.

which have selectively lesioned the anterior thalamic nuclei, Aggleton and Mishkin [2, 3] compared anterior and posterior medial thalamic lesions in monkeys and found that although both anterior and posterior lesions produced a deficit in object recognition memory, a com- bined lesion had a much more deleterious effect on object recognition memory performance. However, as delin- eation of the boundaries of their anterior medial lesion did not encompass the whole of the anterior group of thalamic nuclei, direct comparison with the present study is difficult. In the rat, tasks which have a spatial com- ponent have shown large deficits after anterior thalamic lesions, whereas object recognition memory has not shown such a substantial impairment [1, 5]. This finding is in accord with the proposal that the Delay -Brion circuit is concerned with integrating information about objects and their positions in space, and dissociable in some circumstances from systems involved in object identity [22, 23, 39].

In contrast to the impairment observed in the anterior


thalamic-lesioned animals, the monkeys with cingulate cortex lesions were not significantly impaired. Two of the animals in this group showed a mean increase in error rate of less than 2%. The third (CIN 1) showed a larger increase in error rate, but this animals had a large area of unintentional cortical damage. Nonetheless, despite this variation among individuals within the cingulate group, the effect of anterior thalamic lesion was highly significantly more severe than the effect of cingulate lesion. The overall lack of deficit shown postoperatively by the cingulate group compares well with the lack of reported cases of human amnesia following discrete cingulate cortex damage-- the patient reported by Val- enstein et al. [46] had retrosplenial cortex damage, but there was a possibility of damage to both the cingulum bundle and the fornix. The results of the present experiment are also in accord with the lack of effect ofcingulate cortex lesions in monkey [33], and in rat studies where the cingulum bundle has not been damaged [5, 35]. These studies are in contrast to the results of Mishkin and Bachevalier [31], who found an impairment in spatial reversal and spatial delayed response after anterior cingulate lesion, and to a series of experiments by Sutherland and colleagues [43, 44], who posit an important role for posterior cingulate cortex in spatial memory in the rat. This is an issue which clearly is not yet fully resolved; however, reciprocal connections between the retrosplenial cortex, anterior thalamic nuclei, subiculum and presubiculum certainly suggest some role in memory [13]. One possibility is that the anterior cingulate cortex is more involved in memory for negative events. This would help to explain the difference in results between the lack of effect of cingulate cortex lesion on the present task, where learning is for reward, and the large deficits in discriminative avoidance learning found by Gabriel and colleagues [16-19], where learning is to avoid punish- ment. Anatomical connections of this region with the amygdala, hypothalamus and periaquiductal grey support a role for the anterior cingulate in this form of leaning, allowing it to be instrumental in the prediction and avoidance of noxious stimuli [16 19, 47].

The pattern of degeneration seen in the two experimental groups in the present experiment is relevant to the issue of whether the ablated structures form part of a circuit involved in episodic memory. In the anterior thalamus-lesioned animals, there was a very high degree of neuronal degeneration and gliosis in the mamillary nuclei. This was not surprising, as the anterior thalamus is their primary output target, via the mamillothalamic tract. Lesions of this tract have been reported to cause amnesia in humans [29] and memory deficits in rats [45]. Mamillary nuclei damage has long been implicated in amnesia in humans [29], and we have recently shown a substantial impairment in object-in-place memory in monkeys after mamillary body lesions [38]. We can therefore infer from this converging evidence that these three structures form part of an integrated memory circuit. The pattern of degeneration observed in the cingulate-

lesioned animals showed that the main focus of the degeneration was the centre of the AV, with a gradation to less degeneration in all directions. In all cases except one, the AD was acellular, suggesting that the cingulum bundle was damaged (Aggleton, personal communi- cation). The area of undegenerated anterior thalamus was principally the AM, which projects to the lower bank of the principal sulcus and ventral frontal cortex [25, 32]. As the only area of undegenerated anterior thalamus in the cingulate animals was the AM, and they could still do the task, a possible interpretation of the present results is that the connections from the anterior thalamus needed in the present task are those with the frontal lobe, for choosing and reaching towards a specific target on the basis of an episodic representation. As these connections are intact in the cingulate-lesioned animals, they are still able to do this task.

The performance of the animals in the present experiment can be directly compared with the performance of monkeys with mamillary body lesions and fornix transection who were tested with the same task and experimental regime [38]. As Fig. 8 illustrates, the mean increase in error score caused by anterior thalamic (12.23%), fornix (13.01%) and mamillary body lesions (18.28%) is very similar, suggesting that they form part of one integrated circuit. The mean increase in error score seen after cingulate lesion (3.55%) does not fit this pattern, suggesting that the cingulate gyrus is not a critical part of this circuit. Analysis of variance among these group means shows a significant difference (F = 3.33, d.f. 3,8, P < 0.05, one-tailed). The effect of perirhinal/fornix disconnection (17.11%) [23] is also similar, although comparison here is difficult as the unilateral perirhinal lesion in that experiment also disrupts input to memory systems other than the object-in-place (for discussion see [22, 39]). There appear to be strong simi- larities between the deficits seen in contextual memory in humans and in object-in-place memory in monkeys [21]. We can conclude from this that, as in humans [29], non-

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Fig. 8. A comparison of the increase in error score for five groups of animals from this experiment, and those of Gaffan and Parker [23], and Parker and Gaffan [38]. CIN, cingulate cortex ablation; ATH, anterior thalamic lesion; FX, fornix transection; MB, mamillary nuclei lesion; DIS, perirhinal/fornix

disconnection.

A. Parker and D. Gaffan/Effects of anterior thalamic and cingulate lesions II01

human primates show specific memory impairments when structures within the Delay-Brion circuit are damaged.

Acknowledgements--This research was supported by the U.K. Medical Research Council. Amanda Parker held a Research Fellowship f¥om the McDonnell-Pew Centre for Cognitive Neuroscience, Oxford University. We thank Robert Robertson for technical advice on ventriculography, John Aggleton for helpful comments on thalamic degeneration and Judi Wakeley for help training the monkeys.

References

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2. Aggleton, J. P. and Mishkin, M. Memory impairments following restricted medial thalamic lesions in monkeys. Experimental Brain Research 52, 199-209, 1983.

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The effect of anterior thalamic and cingulate cortex lesions on object-in-place memory in monkeys

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