nonselective neonatal hippocampal lesions impair visual ...

NEONATAL ASPIRATION LESIONS OF THE HIPPOCAMPAL FORMATION

IMPAIR VISUAL RECOGNITION MEMORY WHEN ASSESSED BY PAIRED-

COMPARISON TASK BUT NOT BY DELAYED NONMATCHING-TO-SAMPLE TASK

Olivier Pascalis and Jocelyne Bachevalier

Department of Neurobiology and Anatomy

University of Texas Health Science Center, Houston, TX, USA

Published in Hippocampus. Volume 9, Issue 6, Pages: 609-616

Abbreviated Title: Hippocampal lesions and recognition memory

Number of text pages: 18

Number of figures: 4

Number of tables: 1

Corresponding author: Jocelyne Bachevalier, Department of Neurobiology and Anatomy,

University of Texas Health Science Center, 6431 Fannin Street, Houston, TX 77030, USA.

Phone: 713-500-5626, Fax: 713-500-0623, Email: [email protected]

Grant sponsor: NIMH, Grant number: IRP, MH54167, and MH58846

Grant Sponsor: John D. and Catherine T. MacArthur Foundation (JB) and the “Fondation

Fyssen” (OP)

Olivier Pascalis is now at The University of Sheffield, Department of Psychology, Sheffield S10

2TP, UK.

Key Words: preference for novelty – parahippocampal gyrus - monkeys

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ABSTRACT:

Previous experiments showed that neonatal aspiration lesions of the hippocampal formation in

monkeys yield no visual recognition loss at delays up to 10 min, when recognition memory was

assessed by a trial-unique delayed nonmatching-to-sample (DNMS) task. The present study

examined whether the neonatal hippocampal lesions will also have no effects on visual

recognition when assessed by a visual paired-comparison (VPC) task. In the VPC task, animals

are looking at visual stimuli and their preference for viewing new stimuli is measured. Normal

adult monkeys showed strong preference for looking at the novel stimuli at all delays tested. By

contrast, adult monkeys with neonatal hippocampal lesions, which included the dentate gyrus,

CA fields, subicular complex, and portions of parahippocampal areas TH/TF, showed preference

for novelty at short delays of 10 sec but not at longer delays of 30 sec to 24 hrs. This visual

recognition loss contrasts with the normal performance of the same operated animals when tested

in the DNMS task. The discrepancy between the results obtained in the two recognition tasks

suggest that, to perform normally on the DNMS task, the operated monkeys may have used

behavioral strategies that do not depend on the integrity of the hippocampal formation. In this

respect, the VPC appears to be a more sensitive task than DNMS to detect damage to the

hippocampal region in primates.

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INTRODUCTION

Monkeys with extensive damage to the medial temporal lobe (including hippocampus,

amygdala, and surrounding cortex) show severe impairment on the trial-unique delayed

nonmatching-to-sample task (DNMS) as soon as the delays were increased from 10 sec to 30 sec

(Mishkin, 1978; Squire, Zola-Morgan and Chen, 1988). Recent studies revealed that this

recognition memory deficit is due to damage to cortical areas adjacent to the hippocampal

formation (Zola-Morgan et al., 1989; Gaffan and Murray, 1992; Meunier et al., 1993). Thus,

selective lesions of either the entorhinal and perirhinal cortex (Gaffan and Murray, 1992), or the

perirhinal cortex and parahippocampal cortex (Zola-Morgan et al., 1989; Suzuki et al., 1993)

yielded severe recognition memory loss even at the short delays. [Conversely, selective

damage to the hippocampal formation resulted in either a mild impairment at the longest

delays only (Zola-Morgan et al., 1992; Alvarez et al., 1995), or no impairment (Murray and

Mishkin, 1998).] Similar results have now been reported in rodents (Mumby et al., 1992; Otto

and Eichenbaum, 1992a, b; Mumby and Pinel, 1994). This pattern of results seems also to apply

when the lesions are done in infancy, since neonatal damage restricted to the hippocampal

formation and sparing most of the entorhinal and perirhinal cortex yielded no impairment in the

DNMS even at long delays of 10 min (Bachevalier et al., 1999). These data suggest that the

DNMS task that has been used to assess hippocampal-dependent memory functions in primates

is in fact measuring memory processes of the cortical areas on the parahippocampal gyrus.

Although the findings imply that the hippocampal formation plays a relatively minor role

in recognition memory, they appear to contradict data in amnesic humans showing either mild

(Aggleton and Shaw, 1996) or enduring (Reed and Squire, 1997) visual recognition loss in

human subjects with damage to the hippocampal region. In a reinvestigation of the effects of

hippocampal damage on recognition memory in humans, Reed and Squire (1997) clearly

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indicated that, for the same subject, a recognition memory deficit could be evident with one

recognition task but not another. They stressed the need to use several recognition tasks to

reveal the visual recognition memory deficit that follows hippocampal damage. Because only

one task, the DNMS, was used in all previous lesion studies in monkeys, it is possible that this

specific task failed to fully engaged the specific memory processing functions mediated by the

hippocampal formation, such that accurate performance might have been supported by alternate

strategies that are independent of the hippocampus (Ridley and Baker, 1991). The main goal of

the present study was to investigate such a possibility.

A visual recognition task widely used to assess memory in human infants is the visual

paired comparison (VPC) task (Fantz, 1964; Fagan, 1970). [The VPC task exploits the subject's

preference to look longer at novel stimuli]. The subject is first presented with a stimulus for a

brief familiarization period. Thereafter, a pair of stimuli, the familiar and a novel one, is

presented for viewing. The relevant parameter in this task is the amount of time spent looking at

both stimuli. Longer duration of looking to one stimulus, generally the novel one, indicates

recognition memory. This task has also been used to investigate the development of recognition

memory in infant monkeys (Gunderson and Sackett, 1984) and to measure long-term memory

(24 hours) in both human infants (Pascalis et al., 1998) and infant monkeys (Gunderson and

Swartz, 1985). Interestingly for the purpose of the present experiment, the ontogenetic studies

have provided different findings depending on the recognition tasks used. That is, in both human

infants (Diamond, 1990; Overman et al., 1993; Pascalis and de Schonen, 1994) and infant

monkeys (Gunderson and Sackett, 1984; Bachevalier et al., 1993), good performance on the

VPC task emerges earlier in life than that on the DNMS. This difference in the developmental

time table of these two recognition memory tasks is important because it suggests that the

DNMS task might require cognitive processes different than, or in addition to those required for

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the VPC task (Bachevalier et al., 1993). These different cognitive processes may entail different

neural circuits subserving the two tasks, and, thus, the two recognition tasks may not be equally

sensitive to hippocampal damage.

As yet, few studies have employed the VPC to investigate the effects of hippocampal

lesions on recognition memory. Recognition memory loss was found in both infant and adult

monkeys with damage to the medial temporal lobe, including the hippocampal formation,

amygdala and surrounding tissue, with both the VPC (Bachevalier et al., 1993) and DNMS

(Bachevalier and Mishkin, 1994) tasks. Similarly, using the VPC task, McKee and Squire

(1993) demonstrated a recognition memory loss in amnesic subjects with hippocampal damage.

The VPC task was thus used in the present study to assess the contribution of the hippocampal

formation to recognition memory in adult monkeys with early nonselective hippocampal lesions

(Bachevalier et al., 1998) that had showed normal performance on the DNMS task.

METHOD

Subjects

Six rhesus monkeys (Macaca mulatta) of both sexes participated in the present study.

Three monkeys (2 males and 1 female) had received neonatal hippocampal lesions (Group H)

and three (2 males and 1 female) were unoperated controls (Group N). Subjects were 11 years of

age and weighing 3.8 – 7.1 kg at the beginning of the experiment.

A detailed description of their rearing conditions as infants and juveniles was given in an

earlier report (Bachevalier et al., 1999). Briefly, all monkeys were born at the breeding colony

of National Institute of Health Animal Center (Bethesda, MD) and raised in the primate nursery

of the Laboratory of Neuropsychology (National Institute of Mental Health, Bethesda, MD).

During the first year of life, they were tested on a series of cognitive tasks including the 24-hr

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ITI task at the age of 3 months, and the visual DNMS task at 10 months of age (Bachevalier et

al., 1999). In addition, their social interactions with peers were measured at 2 months, 6 months,

and 5 years (Bachevalier, 1994). Upon reaching adulthood, they were sent to the Department of

Neurobiology and Anatomy (University of Texas, Houston) where they received further

cognitive testing, which included re-tests on the 24-hr ITI and visual DNMS tasks at 6 and 7

years of age, respectively, and training on a DNMS for locations task at 9 years of age, before

participating in the present experiment. At the time of testing, they were housed in individual

cages and maintained on a diet of Purina Monkey Chow plus fresh food. Water was always

available, except for 5 hours prior to testing.

Surgery and Lesion assessment

A detailed description of the neonatal surgical procedures is available elsewhere

(Bachevalier et al., 1998). The two-stage neonatal aspiration lesions were performed aseptically

under anesthesia when the animals were approximately 7 and 20 days of age. The hippocampal

removal included the dentate gyrus, all CA fields, the subicular complex as well as the

underlying parahippocampal gyrus (cortical areas TH and TF) lying medial to the

occipitotemporal sulcus. The extent of the lesions was verified histologically in one case (see

case H-6, Bachevalier et al., 1998, Fig. 2) and through Magnetic Resonance Imaging in the two

remaining cases (cases H-1 and H-3, Bachevalier et al., 1998, Fig. 3) when the animals were 5-7

years old. MR images through the extent of hippocampal removal of one representative case (H-

3) are shown on Figure 1. In all cases, the lesions were as intended, including the hippocampus

proper, subicular complex, and portion of cortical areas TH and TF. The entorhinal cortical area

28 and perirhinal cortical areas 35 and 36 were spared, except for the most caudal dorsomedial

portion of the entorhinal cortex, bilaterally in cases H-3 and H-6, and unilaterally in case H-1.

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Finally, small unintended damage was found in the inferior temporal cortical area TEO,

unilaterally in cases H-3 and H-6 and bilaterally in case H-1. This damage was judged to be

potentially significant only in case H-1 where it extended caudally on the ventromedial surface

of the right hemisphere to include the occipital cortex (see Fig. 3, Bachevalier et al., 1998).

Apparatus

Behavioral testing was carried out in a standard Wisconsin General Testing Apparatus

(WGTA), which was located inside a darkened sound-shielded room. Extraneous sound masking

was provided by a white-noise generator. As previously described (Pascalis and Bachevalier,

1998), a Plexiglas cage was used to constrain the monkey during behavioral testing. At the

center-front of the cage, a sipper tube was attached and delivered orange juice during training.

This procedure restrained the animal in front of the testing area while its eye movements were

videorecorded during stimulus presentation. The front of the cage was positioned 30 cm in front

of a translucent screen onto which the stimuli (slides of objects) were rear projected. A camera

mounted above the screen captured the monkey's eye movements during testing. Measures of

the cumulative looking time at the stimulus during the familiarization period were made during

testing by the experimenter. The time spent looking at each stimulus (novel or familiar) during

retention tests was measured with the aid of a frame by frame video-recording system which

allowed detailed analyses of the corneal reflection of the stimuli. Figure 2 illustrated the corneal

reflection of the stimuli when the monkey looked at the stimulus on its left (top), at the center

(middle), or on its right (bottom). Percent looking time at a stimulus was expressed by dividing

the looking time to one stimulus (novel or familiar) by the total looking time at both stimuli and

multiplying this ratio by 100.

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Black and white slides of objects were used as stimuli. The size and brightness of the

objects were kept uniform on each slide. When projected onto the screen, the size of the stimuli

was 15 cm X 10 cm, and when two stimuli were present, they were separated by a 12-cm gap.

Visual paired-comparison task

An adaptation period of 4-5 days was given to acclimate the monkey to sit quietly in the

front of the cage and to drink from the sipper tube while looking at stimuli. Thereafter, formal

training began. Each trial involved new stimuli and was made of two parts. In the

familiarization period, a sample stimulus was presented in the middle of the screen and remained

on until the monkey had looked at it for a total cumulative time of 20 sec. After a delay, two

retention tests separated by a 5-sec interval were given. In the retention tests, the familiar

stimulus and a new stimulus were simultaneously projected onto the screen and their left-right

positions were reversed from one retention test to the other. A retention test began when the

monkey started to look at one of the two stimuli and lasted 5 sec. Monkeys were first tested at

delays of 10 sec, 2 min, 10 min, and 24 hrs. During daily session, the left-right position of the

new stimulus in the first retention test and the delays were counterbalanced across trials. For the

24-hour delay, the familiarization period of one stimulus was given at the end of a daily session,

and the two retention tests for this stimulus were given the next day at the beginning of the daily

session. Monkeys were tested for a total of 10 trials at each delay. All monkeys, except case H-

6, were then tested with two additional delays (30 sec and 1 min) in the same manner as before.

The percent looking time at the novel stimuli at each delay was then compared with the

percent choosing novel objects when the same animals were tested on the DNMS task earlier as

adults, using the same delays, except the longest delay of 24 hrs (Bachevalier et al., 1999,

Experiment 2).

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RESULTS

Familiarization

The total amount of time needed for the control and operated monkeys to reach the

criterion of 20 cumulative seconds of looking at the stimulus across all delays averaged 38.5 ±

15.8 sec for the control monkeys and 44.6 ± 17.7 sec for the operated animals. A two-way

ANOVA using group and delay as the main factors and with repeated measures for the second

factor revealed no significant effects of group [F(1, 3) = 4.76, ns] and delay [F(5, 5) = 4.04, ns]

and no significant interaction [F(5, 5) = 1.08, ns].

Total Looking time during the two retention tests

For each delay, the total looking time at the two stimuli during the two retention tests was

summed and then averaged across the 10 trials. As shown in Figure 3, both Groups N and H

explored the stimuli for the same amount of time at each delay (mean of 3.14 ± 1.1 sec and 3.14

± 0.95 sec for Group N and Group H, respectively).

Percent looking time at each stimulus during the two retention tests

[The mean percent looking time at novel stimuli at each delay is depicted in Figure 4A

for each group. A two-way ANOVA using Group and Delay as main factors and with repeated

measures for the Delay factor revealed that both main factors were significant [Group: F (1, 3) =

28.051, p < .02; Delay: F(5, 15) = 3.365, p < .03], as was their interaction [F(5, 15) = 4.52, p <

.01]. This significant interaction indicated that in operated monkeys preference for novelty was

not present at all delays tested. Thus, separate analyses of variance at each delay revealed

significant group differences at all delays, except delay of 10 sec [10 sec: F(1-4) = 1.03, p > .05;

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30 sec: F(1-3) = 11.2, p < .05; 1 min: F(1-3) = 13.14, p < .04; 2 min (F(1-4) = 64.68, p < .001);

10 min: F(1-4) = 12.56, p < .03; 24 hours: F(1-4) =11.57, p < .03]. In addition, while in the

normal controls percent looking at novelty at 10 sec did not differ from any other delays, in the

operated monkeys percent looking at novelty was significantly greater at the 10 sec delay than at

any other delays (all p < .05). This different pattern of results in the two groups of animals was

also demonstrated when analyzing the amount of looking time at the novel vs the familiar objects

for each delay (Table 1). Whereas monkeys in Group N spent significantly longer time looking

at the novel stimulus than the familiar one at all delays, monkeys in Group H looked

significantly longer at the novel than the familiar objects at the shortest delay of 10 sec, but not

at any of the longest delays. These findings demonstrate that normal monkeys displayed

significant preference for looking at the novel stimuli at all delays, whereas those with

hippocampal damage engaged in this behavior only at the shortest delay of 10 sec.

DNMS

The results obtained with the VPC task contrasts sharply with that obtained earlier for the

same animals in the DNMS task (Bachevalier et al., 1998). In the performance test of the DNMS

task, as shown in Fig. 4B, animals in both Groups N and H did not differ significantly and

displayed excellent recognition of objects even at the longest delay of 10 minutes [Groups: F(1,

3) = 0.122, p = .75; Delays: F(4, 12) = 0.999, p = 0.44; Groups * Delays: F(4, 12) = 0.31, p =

0.86].

DISCUSSION

The results show that visual recognition memory, as assessed by VPC, is abolished in

animals with neonatal hippocampal lesion for delays of 30 sec or longer. These findings confirm

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those of McKee and Squire (1993) indicating that human amnesics have impaired recognition

memory, as assessed by VPC, when delays were increased from 5 sec to 2 minutes. The visual

recognition loss found in hippocampectomized monkeys can not be attributed to a more general

deficit in visual exploration since these operated animals displayed a mean total fixation time at

the two stimuli during the retention tests similar to that found in control monkeys (see Fig. 3). In

addition, the memory loss after hippocampectomy can not result from a lack of preference for

novelty since the operated animals demonstrated good preference for novelty at the shortest

delay of 10 sec. Finally, the additional training that the monkeys received prior to VPC testing

(e.g. tactual DNMS) is unlikely to have caused the recognition loss. Given the extensive

experience the animals gained in purposely selecting novel objects in the past (visual and tactual

DNMS), one would expect that these animals had developed greater interest towards novelty,

which was not the case. Therefore, the data indicate that the VPC is a recognition memory task

sensitive to hippocampal lesions in primates. This conclusion should still be considered with

caution, however, since the hippocampal lesions in the present study were done by aspiration and

thereby included not only the hippocampal formation but also the parahippocampal cortical

areas. While the additional damage to these cortical areas could be responsible by itself for the

visual recognition loss (Zola-Morgan et al., 1989; Gaffan and Murray, 1992; Meunier et al.,

1993, 1997), recent findings suggest otherwise. Thus, selective hippocampal lesions, performed

by injections of excitotoxins (Nemanic, Alvarado, and Bachevalier, unpublished results) or by

radiofrequency (Clark et al., 1996), resulted in a loss of preference for novelty at long delays but

not at the short ones. Yet, whether restricted damage to the parahippocampal cortex alone could

result in a loss of visual recognition as well remains to be directly tested.

The visual recognition loss found in hippocampectomized animals with the VPC task

contrasts sharply with the remarkable visual recognition performance that the same operated

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animals obtained earlier when tested in the DNMS task (Bachevalier et al., 1999). One possible

explanation for the normal performance of monkeys with neonatal hippocampal lesions on the

delay condition of the DNMS task could have resulted from overtraining on the task. Indeed, all

animals had received training on the DNMS task first when they were 10 months of age and then

when they reached adulthood (i.e. 7 years of age). Nevertheless, at both ages, their performance

on the task did not differ significantly from that of unoperated controls, indicating that their

normal performance at 7 years of age was not simply due to an effect of experience on the task.

Thus, the discrepancy in the results of the two recognition tasks suggests that processes required

for good performance on the VPC differ from those required to perform on the DNMS task. One

important difference between the two tasks relies on the behavioral responses required to solve

them. In the VPC task, visual orientation to the stimuli is the only behavioral response required

to perform on the task. Recognition of the familiar stimulus is inferred by a significantly longer

duration of looking time to the novel stimulus. The VPC, thus, involves an incidental or

automatic learning of stimuli naturally occurring in the visual field, and no rule learning is

necessary. In the DNMS, by contrast, the subject is not only required to visually orient towards

stimulus objects, but to also displace them in order to retrieve food rewards. Furthermore, the

animals must associate a positive reinforcement with an object during the sample presentation

and must effortfully remember this rewarded stimulus during the delay, to avoid it in favor of the

novel object being rewarded during the choice test. Hence, in DNMS, the subject must first

learned the rule to displace the novel objects on any given trial to a 90% criterion and, then,

perform when memory demands are increased with longer delays. Given this difference between

the two tasks, it could be possible that hippocampectomized monkeys with poor recognition

memory could purposely used a different behavioral strategy to solve the DNMS at delays up to

10 min (Ridley and Baker, 1991).

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Performance on delayed matching (or nonmatching) tasks requires the subject to engage

in retrospective processing (Colombo et al., 1996), i.e. in remembering aspects of the sample

stimulus during the delay period. Since the animal is eager to retrieve the food reward and, thus,

is highly motivated, it may use a strategy that helps in remembering the stimulus it just saw. We

can postulate that the operated animals may be able to use such a strategy to solve the DNMS

task at the short delays usually tested. By contrast, in the VPC task, the animal does not know

that it has to remember the stimuli and, thus, it will not make use of that specific strategy to

remember them. In fact, in the presence of poor recognition memory, the hippocampectomized

animals may rely on a working memory buffer to maintain normal performance on the DNMS

task at delays up to 10 min. Such a proposal is easily testable by introducing during the delay

interval of the DNMS trials a manipulation that will interfere with the strategy that the animals

use to maintain the memory trace of the sample object. The performance of monkeys with

neonatal hippocampal lesions in the list conditions of the DNMS task (Bachevalier et al., 1999)

seems to support this view. In the list conditions, the animal is first presented with a series of

sample objects, varying from 3 to 10 objects, and, at the end of the list, each sample object is

then paired with a new one. Thus, in this version of the task, they have to maintain a larger

amount of visual information into a working memory buffer and, in addition, they have to

disentangle possible similarities between perceptual attributes of multiple objects. Scores of

monkeys with neonatal hippocampal lesions dropped of an average of 7% from the delay

conditions to the list conditions as compared to a drop of only 2 % in the normal controls.

Furthermore, we have directly tested this possibility by introducing a distractor during the delay

trials of the standard DNMS task. While scores of unoperated controls did not differ between

standard trials and distraction trials, those of monkeys with neurotoxic hippocampal lesions

dropped significantly on distraction trials as compared to standard trials (Nemanic et al., 1999).

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These data thus suggest that the standard DNMS task may not be sensitive enough to detect

recognition memory impairment resulting from damage to the hippocampal formation.

The pattern of results thus suggests that hippocampectomized monkeys used alternative

strategies to perform normally on the DNMS task. These alternative strategies may recruit

additional brain areas, such as the perirhinal cortex and orbital prefrontal cortex, which have

already been shown to be crucial for normal performance on the DNMS task (Zola-Morgan et

al., 1989; Gaffan and Murray, 1992; Meunier et al., 1993, 1997).

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Figure Legends

Figure 1: Coronal MR images (left) through the extent of hippocampal lesions in case H-3 and

coronal sections (right) through a normal monkey brain at levels corresponding to the MR

images. The gray shading on the coronal sections of the right column depicts the extent of

damage seen on the MR images. Abbreviations: amt, anterior medial temporal sulcus; ERh,

entorhinal cortex; ot, occipitotemporal sulcus; PRh, perirhinal cortex; rh, rhinal sulcus; st,

superior temporal sulcus; TE, anterior inferior temporal cortical area (from von Bonin and

Bailey, 1947); TF/TH, parahippocampal cortical area (from von Bonin and Bailey, 1947).

Figure 2: Videoframes (3/100 sec) of a monkey’s eye movements during the retention tests of the

VPC task. From top to bottom, the corneal reflections of the two stimuli (two white bars inside

the monkey’s pupils) indicate that the animal looked at the stimulus on its left, then, at the center,

and finally at the stimulus on the right.

Figure 3: Mean total fixation time (sec) at the two stimuli during the two retention tests at each

delay of the VPC. Vertical bars for each data point indicate standard deviation from the mean.

Abbreviations: Group N: normal controls; Group H: adult animals with neonatal hippocampal

lesions.

Figure 4: Percent looking time at the novel object during each delay conditions of the VPC task

(A) and percent correct choices at corresponding delay conditions of the DNMS task (B).

Vertical bars for each data point indicate standard deviation from the mean. Abbreviations as in

Fig. 3.

17

REFERENCES

Aggleton JP, Shaw C. Amnesia and recognition memory: A re-analysis of psychometric data.

Neuropsychologia 1996; 34:51-62.

Alvarez P, Zola-Morgan S, Squire LR. Damage limited to the hippocampal region produces

long-lasting memory impairment in monkeys. J. Neurosci. 1995; 15:3796-3807.

Bachevalier J. Medial temporal lobe structures and autism: A review of clinical and experimental

findings. Neuropsychologia 1994; 32:627-648.

Bachevalier J, Beauregard M, Alvarado M. Long-term effects of neonatal damage to the

hippocampal formation and amygdaloid complex on object discrimination and object

recognition in rhesus monkeys. Behav. Neurosci. 1998; submitted.

Bachevalier J, Brickson M, Hagger C. Limbic-dependent recognition memory in monkeys

develops early in infancy. NeuroReport 1993; 4:77-80.

Bachevalier J, Mishkin M. Effects of selective neonatal temporal lobe lesions on visual recognition

in rhesus monkeys. J. Neurosci. 1994; 14:2128-2139.

Clark RE, Teng E, Squire LR, Zola S. The visual paired-comparison task and the medial

temporal lobe memory system. Soc. Neurosci. Abstr. 1996; 22:281.

Colombo M, Rodman HR, Gross CG The effects of superior temporal cortex lesions on the

processing and retention of auditory information in monkeys (Cebus apella). J. Neurosci

1996; 16:4501-17.

Diamond A. Rate of maturation of the hippocampus and the developmental progression of

children’s performance on the delayed non-matching to sample and visual paired

comparison tasks. In: Diamond A, ed. Ann. NY Acad. Sci. 1990; 608:394-426.

Fagan JF III. Memory in the infant. J. Exp. Child Psychol. 1970; 9:217-226.

18

Fantz RL. Visual experience in infants: Decreased attention to familiar patterns relative to novel

ones. Science 1964, 146:668-670.

Gaffan D, Murray EA. 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. Behav. Neurosci. 1992; 106:30-38.

Gunderson VM, Sackett GP. Development of pattern recognition in infant pigtailed monkeys

(Macaca nemestrina). Develop. Psychol. 1984; 20:418-426.

Gunderson VM, Swartz KB. Visual recognition in infant pigtailed macaques after a 24-hour

delay. Am. J. Primatol. 1985; 8:259-264.

McKee RD, Squire LR. On the development of declarative Memory. J. Exp. Psychol.: learning,

Memory and cognition 1993; 19: 397-404.

Meunier M, Bachevalier J, Mishkin M. Effects of orbital frontal and anterior cingulate lesions on

object and spatial memory in rhesus monkeys. Neuropsychologia 1997; 35:999-1015.

Meunier M, Bachevalier J, Mishkin M, Murray EA. Effects on visual recognition of combined

and separate ablations of the entorhinal and perirhinal cortex in rhesus monkey. J.

Neurosci. 1993; 13: 5418-5432.

Mishkin M. Memory in monkeys severely impaired by combined but not separate removal of the

amygdala and hippocampus. Nature 1978; 273: 297-298.

Mishkin M, Murray EA. Stimulus recognition. Cur. Op. Neurobiol. 1996; 4:200-206.

Mumby DG, Pinel JPJ. Rhinal cortex lesions and object recognition in rats. Behav. Neurosci.

1994; 108:1-8.

Mumby DG, Wood ER, Pinel JPJ. Object-recognition memory is only mildly impaired in rats

with lesions of the hippocampus and amygdala. Psychology 1992; 20:18-27.

19

Murray EA, Mishkin M. Object recognition and location memory in monkeys with excitotoxic

lesions of the amygdala and hippocampus. J. Neurosci. 1998; 18: 6568-6582.

Otto T, Eichenbaum H. Dissociable roles of the hippocampus and orbitofrontal cortex in an odor-

guided delayed nonmatch to sample task. Behav. Neurosci. 1992a; 105:111-119.

Otto T, Eichenbaum H. Complementary roles of the orbital prefrontal and the perirhinal-

entorhinal cortices in an odor-guided delayed-nonmatching-to-sample task. Behav.

Neurosci. 1992b; 106:762-775.

Overman WH, Bachevalier J, Sewell F, Drew J. A comparison of children’s performance on two

recognition memory tasks: Delayed nonmatching-to-sample versus visual paired-

comparison. Develop. Psychobiol. 1993; 26:345-357.

Pascalis O, Bachevalier J. Face recognition in primates: A cross species study. Behav. Process.

1997; 43:87-96.

Pascalis O, de Han M, Nelson CA, de Schonen S. Long-term recognition assessed by visual

paired comparison in 3- and 6-month-old infants. J. Exp. Psychol.: Learning, Memory and

Cognition 1998, 24:249-260.

Reed JM, Squire LR. Impaired recognition memory in patients with lesions limited to the

hippocampal formation. Behav. Neurosci. 1997; 111:667-675.

Ridley RM, Baker HF. A critical evaluation of monkey models of amnesia and dementia. Brain

Res. Rev. 1991;16:15-37

Squire LR, Zola-Morgan S, and Chen K. Human amnesia and animal models of amnesia:

performance of amnesic patients on tests designed for the monkey. Behav. Neurosci. 1988;

11:210-221.

20

Suzuki WA, Zola-Morgan S, Squire LR, Amaral DG. Lesions of the perirhinal and

parahippocampal cortices in the monkey produce long lasting memory impairment in the

visual and tactual modalities. J. Neurosci. 1993; 13:2430-2451.

von Bonin G, Bailey P. The neocortex of Macaca mulatta. Urbana, IL: University of Illinois,

1947.

Zola-Morgan S, Squire LR, Amaral DG, Suzuki WA. Lesions of perirhinal and parahippocampal

cortex that spare the amygdala and hippocampal formation produce severe memory

impairment. J. Neurosci. 1989; 9:4355-4370.

Zola-Morgan S, Squire LR, Rempel NL, Clower RP, Amaral DG. Enduring memory impairment

in monkeys after ischemic damage to the hippocampus. J. Neurosci. 1992; 12:2582-2596.

21

Table 1: Mean (±) percent fixation time at the novel and familiar stimuli at each delay

Groups Delays Novel Stimulus Familiar Stimulus Two-tailed Paired T-test

10 sec 60.84 ± 1.99 39.16 ± 1.98 t = 5.4, df = 29, p < .001

30 sec 61.46 ± 2.35 38.54 ± 1.89 t = 4.8, df = 29, p < .001

Group N 1 min 61.83 ± 2.62 38.17 ± 2.62 t = 4.5, df = 29, p < .001

2 min 62.31 ± 2.11 37.69 ± 2.11 t = 5.8, df = 29, p < .001

10 min 62.38 ± 1.95 37.62 ± 1.95 t = 6.3, df = 29, p < .001

24 hr 61.40 ± 2.24 38.60 ± 2.24 t = 5.1, df = 29, p < .001

10 sec 62.31 ± 1.89 37.69 ± 1.89 t = 6.4, df = 29, p < .001

30 sec 51.00 ± 3.89 49.00 ± 3.89 t = 0.27, df = 29, p > .05

Group H 1 min 51.66 ± 2.78 48.34 ± 2.78 t = 0.59, df = 29, p > .05

2 min 54.73 ± 2.72 45.27 ± 2.72 t = 1.74, df = 29, p > .05

10 min 52.05 ± 2.64 47.95 ± 2.64 t = 0.77, df = 29, p > .05

24 hr 52.81 ± 2.30 47.19 ± 2.30 t = 1.22, df = 29, p > .05