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The Journal of Neuroscience, August 15, 1998, 18(16):6568-6582
Object Recognition and Location Memory in Monkeys with
Excitotoxic Lesions of the Amygdala and Hippocampus
Elisabeth A.
Murray and
Mortimer
Mishkin
Laboratory of Neuropsychology, National Institute of Mental Health,
Bethesda, Maryland 20892
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ABSTRACT |
Earlier work indicated that combined but not separate removal of
the amygdala and hippocampus, together with the cortex underlying these
structures, leads to a severe impairment in visual recognition. More
recent work, however, has shown that removal of the rhinal cortex, a
region subjacent to the amygdala and rostral hippocampus, yields nearly
the same impairment as the original removal. This raises the
possibility that the earlier results were attributable to combined
damage to the rostral and caudal portions of the rhinal cortex rather
than to the combined amygdala and hippocampal removal. To test this
possibility, we trained rhesus monkeys on delayed nonmatching-to-sample, a measure of visual recognition, gave them selective lesions of the amygdala and hippocampus made with the excitotoxin ibotenic acid, and then assessed their recognition abilities by using increasingly longer delays and list lengths, including delays as long as 40 min. Postoperatively, monkeys with the
combined amygdala and hippocampal lesions performed as well as intact
controls at every stage of testing. The same monkeys also were
unimpaired relative to controls on an analogous test of spatial memory,
delayed nonmatching-to-location. It is unlikely that unintended sparing
of target structures can account for the lack of impairment; there was
a significant positive correlation between the percentage of damage to
the hippocampus and scores on portions of the recognition performance
test, suggesting that, paradoxically, the greater the hippocampal
damage, the better the recognition. The results show that, within the
medial temporal lobe, the rhinal cortex is both necessary and
sufficient for visual recognition.
Key words:
amygdala; hippocampus; limbic system; ibotenic acid; visual memory; delayed nonmatching-to-sample; spatial memory; recognition memory
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INTRODUCTION |
Earlier ablation studies (Mishkin,
1978 ; Zola-Morgan et al., 1982; Murray and Mishkin, 1984; Saunders et
al., 1984) had led to the conclusion that combined damage to the
amygdala and hippocampus produces a severe impairment in visual
recognition. However, more recent studies have indicated that combined
damage to the perirhinal and parahippocampal cortical regions located
ventral to the amygdala and hippocampus results in substantial deficits
in stimulus recognition (Zola-Morgan et al., 1989; Suzuki et al.,
1993). Indeed, lesions limited to the rhinal cortex (i.e., entorhinal
and perirhinal cortex; see Fig. 1) also yield a pronounced recognition
impairment (Meunier et al., 1993; Eacott et al., 1994), one nearly as
severe as that observed after the original amygdala and hippocampal
removals, thereby raising doubts about the initial conclusion. There
are two possible interpretations of these several findings. First, the
behavioral impairment originally observed after the combined amygdala
and hippocampal removals could be attributable entirely to the
concomitant rhinal cortical damage. If so, then selective lesions of
the amygdala and hippocampus that spare the rhinal cortex should yield
no impairment in visual recognition. Alternatively, the effects of
rhinal cortex lesions might reflect a visual corticolimbic disconnection, inasmuch as the amygdala and hippocampus receive their
major visual input via the rhinal cortex (Van Hoesen and Pandya, 1975;
Herzog and Van Hoesen, 1976; Aggleton et al., 1980; Van Hoesen, 1981;
Saunders and Rosene, 1988; Witter et al., 1989; Suzuki and Amaral,
1990; Stefanacci et al., 1996). Thus both the rhinal cortex, on the one
hand, and the amygdala plus hippocampus, on the other, might serve as
serial processing stages in a circuit mediating visual recognition,
much as originally envisaged (Mishkin, 1982). If this were the case,
then selective lesions of the amygdala and hippocampus would be
expected to reproduce the severe recognition deficit observed
originally (Mishkin, 1978). These contrasting possibilities were tested
in Experiment 1. Monkeys were trained on a standard test of visual
recognition, delayed nonmatching-to-sample (DNMS) with trial-unique
objects, given selective lesions of the amygdala and hippocampus made
with the excitotoxin ibotenic acid, and then assessed for their
recognition ability with varying delays and list lengths. The surgical
procedure was intended to produce complete cell loss in the amygdala
and hippocampus but to spare the underlying rhinal cortex as well as
any fibers passing nearby or through these medial temporal lobe
structures.
While the present study was in progress, Alvarez et al. (1995)
published a report showing that monkeys with radiofrequency lesions of
the hippocampus, although unimpaired on DNMS with relatively short
delays (up to 1 min), were impaired significantly when delays of 10 and
40 min intervened between sample and choice. Because the longest delay
intervals in our first assessment were below 5 min, we retested a
subset of our monkeys with delays that included the longer intervals
used by Alvarez et al. (1995). For this second assessment the test was
designed to determine the precise delay at which visual recognition
might start to be dependent on the deep temporal lobe structures.
In Experiment 2 we tested the monkeys on a delayed
nonmatching-to-location task to assess their spatial memory ability in a manner analogous to that used to assess their object recognition memory.
Portions of this work have appeared earlier in abstract form (O'Boyle
et al., 1993; Murray and Mishkin, 1996).
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MATERIALS AND METHODS |
Experiment 1
Subjects. The subjects were 11 experimentally naive
male rhesus monkeys (Macaca mulatta) weighing 3.6-6.5 kg at
the beginning of the study. The monkeys were housed individually in
rooms with automatically regulated lighting (12 hr light/12 hr dark
cycle). They were fed a diet of monkey chow (PMI Feeds, St. Louis, MO) supplemented with fruit; water was always available.
Apparatus and materials. Training was conducted in a
modified Wisconsin General Testing Apparatus (WGTA) inside a darkened room. Sound masking was provided by a white-noise generator. The test
tray contained a row of three food wells spaced 18 cm apart (center to
center) and aligned 16 cm in front of the animal's cage. A single
banana-flavored pellet (300 mg, P. J. Noyes, Lancaster, NH) or
one-half of a peanut, concealed in one of the wells, served as the
reward. Gray cardboard plaques, 7.5 cm on a side, and three junk
objects reserved for the purpose were used in preliminary training.
Test material consisted of over 1120 additional objects that varied
widely in size, shape, color, and texture. A particular object
reappeared in testing only approximately once per month.
Preoperative training. The monkeys were trained first by
successive approximation to displace a cardboard plaque to obtain a
food reward hidden in the well beneath it and then to displace the
three pretraining objects, which were presented singly over one of the
three wells. Then the monkeys were given 20 pseudotrials to familiarize
them with the structure of the task. For this purpose, one of the three
pretraining objects was presented as the "sample" over the baited
central well; 10 sec later the two others were presented over the
lateral wells, both or neither of which were baited, in pseudorandom
order. The monkey was allowed to displace only one of them. The
pseudotrials were separated by 30 sec intervals. During the 10 sec
delay intervals and the 30 sec intertrial intervals, an opaque screen
separated the monkey from the test tray. During stimulus presentations,
when the opaque screen was raised, a one-way vision screen blocked the
monkey's view of the experimenter. This preliminary training was
completed in 3-10 d.
The formal trials were like the pseudotrials except that two new
objects were used on every trial and the sample object was presented
again on the choice test but was not baited, whereas the novel object
was always baited. The left-right position of the novel object on the
choice test followed a balanced pseudorandom order, and there was no
correction for errors. Monkeys were trained at a rate of 20 trials per
day, 5 d per week, to a criterion of 90 correct responses in 100 consecutive trials over five consecutive sessions.
After learning the basic DNMS rule, the monkeys were assigned to two
groups matched on the basis of their preoperative learning scores. One
group (n = 4) remained as normal controls, whereas the
other (n = 7) received bilateral excitotoxic lesions of
the amygdala and hippocampus.
Surgery. Before surgery each monkey was anesthetized with a
mixture (10:1, v/v; 0.1 ml/kg, i.m.) of ketamine hydrochloride (100 mg/ml) and xylazine (20 mg/ml), placed in a specially constructed nonferrous stereotaxic frame, and given a brain scan using the magnetic
resonance imaging (MRI) technique. The MRI scans were used to obtain
measurements of the amygdala and hippocampus relative to the midline
and the interaural plane, marked by the earbars, which also were
visible on the scan (Saunders et al., 1990). From these
measurements we determined stereotaxic coordinates for the injection
sites. Those for the amygdala were separated from each other by a
distance of ~2 mm in each plane, and the number of sites (18-26) was
tailored to the individual subject. The injection sites for the
hippocampus included one in the uncus and five more in the body of the
hippocampus, each site separated from the other by 3 mm in the
anteroposterior plane and each aimed at the center of the structure as
viewed in the coronal plane. Based on empirical findings, the selection
of sites was intended to allow diffusion of the excitotoxin ibotenic
acid (Regis Chemical, Morton Grove, IL, or Sigma, St. Louis, MO)
throughout the entire amygdaloid complex and hippocampus (i.e.,
Ammon's horn and dentate gyrus). Figure
1 illustrates the extent of the intended
lesion.
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Figure 1.
Shaded regions indicate the
location and extent of the intended lesion of the amygdala
(oblique hatching) and hippocampus
(gray) on standard coronal sections. Ventral
(top right) and medial (bottom left)
views of a standard rhesus monkey brain show the locations of these
deep temporal lobe structures: amygdala, dotted line;
hippocampus, dashed line. In addition, small
arrows mark the boundaries of the entorhinal
(ERh) and perirhinal (PRh) cortex,
regions we intended to spare, on the coronal sections only (left
hemisphere; +18, +16, +13, +10). The
numerals indicate the distance in millimeters from the
interaural plane.
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For the surgery each monkey was reanesthetized with ketamine
hydrochloride (10 mg/kg, i.m.), followed by isoflurane (1-2%, to
effect), and then treated with atropine sulfate (0.04 mg/kg, i.m.) to
reduce secretions. Then the monkey was replaced in the stereotaxic
frame, and heart rate, respiration rate, body temperature, expired
CO2 level, blood oxygen level, and blood pressure were monitored throughout the procedure, which was performed
aseptically.
A large bone flap was turned over the dorsal aspect of the cranium. The
flap extended ~25 mm rostral to bregma, 20 mm caudal to bregma, and
20-25 mm to each side of the midline. Lesions were made according to
the method described by Murray et al. (1996) and Malkova et al. (1997).
Small slits were cut in the dura to allow the needle of a 10 µl
Hamilton syringe, held in a Kopf electrode manipulator (David Kopf
Instruments, Tujunga, CA), to be lowered to the proper coordinates. In
the amygdala, 1.0 µl of ibotenic acid (10-15 mg/ml) was injected at
each site. In the hippocampus, 1.8 µl of ibotenic acid was injected
at each site in the first three cases (cases AH1-AH3) and 2.0 µl at
each site in the remaining cases (cases AH4-AH7). To minimize tissue
damage and still allow diffusion of the ibotenic acid, we made all
injections at a rate of 0.2 µl/min. Because a large and potentially
lethal amount of ibotenate would be required to complete the lesions in
both hemispheres in a single stage of surgery, the monkeys received the
amygdala plus hippocampal lesions in two stages, left hemisphere
followed by right, separated by a minimum of 2 weeks.
When the injections at each stage of surgery were completed, the bone
flap was replaced, the wound was sutured in anatomical layers, and the
monkeys typically received mannitol (30%, 30 ml, i.v., over 30 min) to
prevent edema and thereby promote recovery from surgery. All monkeys
received dexamethasone sodium phosphate (0.4 mg/kg) and Di-Trim (0.1 ml/kg, 24% solution, i.m.) on the day before surgery and daily for 1 week after surgery to reduce swelling and to prevent infection,
respectively. Monkeys also received acetaminophen (40 mg) or Banamine
(1.0 mg/kg) for 3 d after surgery for relief of pain.
Histology. At the end of the experiment the monkeys in the
operated group were given a lethal dose of barbiturates and perfused intracardially with a saline solution (0.9%), followed by 10% buffered formalin. The brains were removed, photographed, frozen, and
cut at 50 µm in the coronal plane on a freezing microtome. Every
fifth section was mounted on a gelatin-coated slide, defatted, stained
with thionin, and coverslipped.
Regions of cell loss and gliosis, determined with a stereoscopic
microscope, were plotted on standard sections of a rhesus monkey brain,
and the volume of the lesion was calculated with a digitizer (see
Meunier et al., 1993). The results are shown in Table
1 and Figures
2-8.
The damage averaged 88% (range, 81-100%) of the total extent of the
amygdala and 73% (range, 55-98%) of the hippocampus (i.e., Ammon's
horn plus dentate gyrus). As these results indicate, the ibotenate
injections were not consistently effective, despite the fact that the
solution was prepared in the same way each time and that the patency of
the syringe needle was verified before each penetration. The
explanation for the inconsistency is therefore still unclear. However,
the MRI-based stereotaxic surgical approach was quite accurate, as
evidenced by the small amount of damage that occurred outside the
targeted structures. In particular, damage to the entorhinal cortex
averaged 24% (range, 0-70%), and to the perirhinal cortex it
averaged only 4% (range, 0-20%). Also, the tissue was typically free
of holes and vacuoles, suggesting that there was little or no damage
either to white matter or to fibers coursing through the amygdala or hippocampus.
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Figure 2.
Photomicrographs of Nissl-stained coronal sections
showing the region of the medial temporal lobe in intact monkeys
(a, c) and monkeys with excitotoxic
lesions (b, d). a, Intact
amygdala and portions of underlying rhinal cortex. b,
Excitotoxic amygdala lesion in monkey AH7, photographed at the same
magnification as a. Note the massive neuronal cell loss,
gliosis, and atrophy in the amygdala, with relative preservation of
neurons in the surrounding structures. c, Intact
hippocampus, subicular complex, and underlying parahippocampal cortex.
d, Excitotoxic hippocampal lesion in monkey AH1,
photographed at the same magnification as c. Note the
massive neuronal cell loss, gliosis, and atrophy in the hippocampus,
partial cell loss in the subicular complex, and relative preservation
of the surrounding regions.
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Figure 3.
Shaded regions on standard coronal
sections indicate the location and extent of the excitotoxic amygdala
and hippocampal lesions in monkeys AH1-AH3. Numerals
indicate the distance in millimeters from the interaural plane.
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Figure 4.
Photomicrographs of Nissl-stained coronal sections
from monkey AH1. From top to bottom, the
sections are approximately +17, +13, +8, and +4 mm from the interaural
plane, respectively. Compare with Figures 2 and 3.
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Figure 5.
Photomicrographs of Nissl-stained coronal sections
from monkey AH3. Left, top to
bottom, The sections through the amygdala are
approximately +18.5, +17, +16, and +14.5 mm from the interaural plane,
respectively. Right, top to
bottom, The sections through the hippocampus are
approximately +11, +8, +6, and +4 mm from the interaural plane,
respectively. Compare with Figures 2 and 3. Figure
continues.
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Figure 6.
Shaded regions on standard coronal
sections indicate the location and extent of the excitotoxic amygdala
and hippocampal lesions in monkeys AH4-AH6. Numerals
indicate the distance in millimeters from the interaural plane.
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Figure 7.
Photomicrographs of Nissl-stained coronal sections
from monkey AH4. From top to bottom, the
sections are approximately +17, +13, +8, and +4 mm from the interaural
plane, respectively. Compare with Figures 2 and 6.
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Figure 8.
Photomicrographs of Nissl-stained coronal sections
from monkey AH5. From top to bottom, the
sections are approximately +17, +13, +8, and +4 mm from the interaural
plane, respectively. Compare with Figures 2 and 6.
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Postoperative testing. At ~9 weeks after the completion of
preoperative training (range for control monkeys, 3-12 weeks; for operated monkeys, 6-16 weeks) the monkeys were retrained on the basic
DNMS task to the same criterion as before. All monkeys then were given
a performance test in which, first, the delay between sample
presentation and choice test was lengthened in stages from the initial
delay of 10 sec to 30, 60, and 120 sec, and then the list of sample
objects to be remembered was increased in steps from the original
single object to 3, 5, and, finally, 10 objects. In the list-length
tests, the sample objects were presented one at a time at 20 sec
intervals, and then each sample was paired successively with a
different novel object, also at 20 sec intervals. Consequently, the
minimum retention interval for each trial was 20 sec multiplied by the
length of the list. For each delay condition the monkeys received five
consecutive daily sessions of 20 trials each, whereas for each
list-length condition they received five consecutive daily sessions of
30 trials each.
After they had completed the performance test with delays and
lists, the stimulus recognition abilities of all of the control monkeys
and a subset of operated monkeys (AH4-AH7) were examined with still
longer lists and delays. First, they received DNMS with a list length
of 20 objects (LL20) for 5 d consecutively. The procedure was the
same as before except that the daily sessions consisted of only 20 trials instead of 30. Because one-half of the animals in each group
(N3, N4, AH6, AH7) obtained unexpectedly low scores on LL20, they were
given supplemental training on lists of 3, 5, and 10 objects and then
retested on LL20; only these retest scores are included in the LL20
analysis. For the final stage all the monkeys received DNMS with a list
length of 40 (LL40) objects but with reverse-order testing. That is,
after the 40 samples were presented for familiarization, they were
presented on the choice test in reverse order, such that the last
sample in the list appeared on the first choice test and the first
sample appeared on the last choice test. All stimulus presentations in the LL40 test were separated by 30 sec. Consequently, the 40 delay intervals within the session ranged from ~1 min (0.5 min) to 40 min
(39.5 min). Each monkey was tested on LL40 for a total of 40 d.
Experiment 2
On completion of the object recognition test, we presented a
test of location memory, on the supposition that spatial ability would
be especially vulnerable to the effects of hippocampal damage in
particular. This supposition is based on a long history of research in
both rodents and primates implicating the hippocampus in a wide variety
of spatial memory functions (for review, see O'Keefe and Nadel, 1978;
Eichenbaum et al., 1994). The task selected was delayed
nonmatching-to-location both because of its analogy to DNMS and because
Malkova et al. (1995) recently found a pronounced deficit on it in
adult monkeys with neonatal removals of the medial temporal lobe. The
deficit was attributed to damage to the hippocampus, the
parahippocampal cortex, or their combination, on the basis of an
earlier report of impairment on a similar task in adult monkeys with
neonatal removals of this hippocampal region (Mahut and Moss,
1986).
Subjects. The subjects were the same monkeys that
participated in the final stage of Experiment 1, except for one of the
unoperated control monkeys (NC2) who had died of bloat after the
completion of Experiment 1.
Apparatus and materials. The monkeys were tested in the same
WGTA as in Experiment 1, but with a different test tray. This tray,
measuring 70 cm wide and 25 cm deep, had 10 food wells, each 4 cm in
diameter, arranged in horizontal rows of three, four, and three. The
rows were 9 cm apart, and the wells within a row were 16 cm apart,
center to center. The stimuli were gray cardboard squares, ~5 cm on a
side, and these were renewed frequently.
Testing procedure. The test procedure was the same as that
used by Malkova et al. (1995). As in DNMS with objects, each trial was
composed of two parts: sample presentation followed by choice test. On
the sample presentation one of the wells was covered with a gray
plaque, which the monkey displaced to obtain a food reward. On the
choice test, 10 sec later, two wells were covered by identical gray
plaques, one on the sample location and the other on a randomly
selected alternative. The monkey could obtain another food reward by
displacing the plaque in the new location. Daily sessions consisted of
20 trials, separated by 30 sec intervals, and criterion was set at 90 correct responses in 100 trials over five consecutive sessions. After
attaining criterion, the animals were given a performance test with
delays of 10, 30, 60, and 120 sec for five trials each, mixed within
each session. The test was given for 20 d, yielding 100 trials per
delay. Finally, the monkeys were tested with a list length of two
locations to remember (LL2). For this procedure two consecutive sample
presentations were followed by two consecutive choice tests. That is,
the monkey saw a single gray plaque overlying a well, which it
uncovered for the food reward, and then, 10 sec later, a single plaque
overlying another well, which it also uncovered for a reward. After an
additional 10 sec the monkey was given the choice test for the first
sample and, 10 sec later, the choice test for the second sample.
Training proceeded at the rate of 20 trials per day, for a total of
20 d.
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RESULTS |
Experiment 1
As shown in Table 2, the two
groups were well matched for rate of preoperative learning. Both
attained criterion, on average, within six to seven daily sessions
(Mann-Whitney U tests, trials: U = 12.0, p = 0.70; errors: U = 13, p = 0.85). Further, there was no effect of the lesions
on postoperative relearning, inasmuch as six of the seven operated
monkeys, like three of the four controls, showed perfect postoperative
retention of the DNMS rule (Mann-Whitney U tests,
U = 12.5, p = 0.67, for both trials and
errors).
The mean scores on the subsequent performance test were analyzed by a 2 (group) × 7 (condition, i.e., four delays and three list lengths)
repeated measures ANOVA. There was no difference between the two
groups [F(1,9) = 0.051, p = 0.83], and, although there was a main effect of condition
[F(6, 54) = 17.26, p < 0.001], there was no interaction between group and condition
[F(6, 54) = 0.43, p = 0.71].
Thus, although the scores of all of the monkeys declined with
increasing memory demands (particularly, increasing list lengths; see
Fig. 9), those with AH lesions were not
affected more than the controls, nor did the two groups differ on LL20 (normal control: mean = 75%, range = 70-79%; AH: mean = 74.5%, range = 61-85%), on which both groups performed
slightly below their levels on LL10 (see Table 2).
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Figure 9.
Group mean scores on the DNMS performance test.
The curves on the left show the effects
of imposition of increasingly longer delays between sample presentation
and choice, whereas the curves on the
right show the effects of list-length testing. For each
list item the minimal delay is 20 sec × the length of the list.
SELECTIVE AH, Monkeys with bilateral excitotoxic lesions
of the amygdala and hippocampus; NORMAL CONTROL,
unoperated control monkeys.
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Scores on LL40 with reverse-order testing are shown in Table
3 and Figure
10. The data were averaged across eight
successive 5-min-delay intervals. A 2 (group) × 8 (delay condition)
repeated measures ANOVA again failed to reveal a difference between the groups [F(1,6) = 0.30, p = 0.60]. Further, although there was an effect of delay
[F(7,42) = 27.29, p < 0.001],
there was no interaction between group and delay
[F(7,42) = 0.26, p = 0.74]. Thus, just as in the initial performance test, the monkeys performed more poorly at the longer delays, but those with the excitotoxic lesions of the amygdala and hippocampus were not worse than the controls. To determine whether there might have been transient disruptions of memory performance at long delays during the 40 d
test period, we also compared the groups on each of four 10 d
blocks across the period. A 2 (group) × 4 (block) repeated measures ANOVA revealed no significant main effects [group:
F(1,6) = 0.31, p = 0.60; block:
F(3,18) = 0.08, p = 0.97] and
no group-by-block interaction [F(3,18) = 0.17, p = 0.92].
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Figure 10.
Group mean scores on DNMS administered with a
list length of 40 and reverse-order testing. Each point
represents the data obtained from a block of five sequential delays,
the longest of which is shown on the abscissa. For
example, the first point represents the mean score for
delays ranging from 0.5 to 4.5 min, the second point
represents the mean score for delays ranging from 5.5 to 9.5 min, etc.
SELECTIVE AH, Monkeys with bilateral excitotoxic lesions
of the amygdala and hippocampus; NORMAL CONTROL,
unoperated control monkeys.
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Finally, we examined the relationship between test scores at each stage
and the degree of damage to each of the structures listed in Table 1.
It is clear, first, that those monkeys with nearly complete loss of
neurons in the amygdala (AH3, AH6), hippocampus (AH3, AH4), or both
(AH3) did not perform any more poorly than the others in the group.
Second, there were no negative correlations between the percentage of
correct scores at any stage and the extent of damage to any structure.
Indeed, the only correlations obtained were positive ones, namely,
between percentage of damage to the hippocampus and mean percentage of
correct responses on (1) the three longer delays of the initial
performance test (n = 7, rs = 0.800, p < 0.05) and (2) LL20 (n = 4, rs = 1.00, p < 0.05),
suggesting that, paradoxically, the greater the hippocampal damage, the
better the recognition performance.
Experiment 2
The results (Table 4) failed to
reveal group differences in either learning [Mann-Whitney
U test, trials: U = 7.5, p = 0.59; errors: U = 7.0, p = 0.72] or on
the performance test [2 (group) × 4 (delay) repeated measures ANOVA;
main effect for group, F(1,5) = 0.71, p = 0.44]. There was a significant effect of delay
[F(3,15) = 28.62, p < 0.001]
but no group-by-delay interaction [F(3,15) = 0.81, p = 0.51]. In addition, there was no group
difference on the LL2 condition (Mann-Whitney U test,
U = 3.0, p = 0.51).
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DISCUSSION |
Neural substrates of visual recognition
The present findings indicate that extensive cell loss in the
amygdala and hippocampus can leave DNMS performance unimpaired even
when a 40 min period intervenes between sample and choice. Further,
there was no evidence of an impairment even in those cases that had
nearly complete cell loss in either or both of these structures. Taken
together with our recent results regarding the behavioral effects of
rhinal cortical lesions, the present data suggest that the visual
recognition impairment originally observed after combined amygdala and
hippocampal removals was attributable entirely to the concomitant
damage to rhinal cortex (Fig. 11). In
short, it now appears that, within the medial temporal lobe, the rhinal
cortex is not only necessary but also sufficient to sustain visual
recognition ability.
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Figure 11.
Comparison between the results for monkeys with
AH lesions (present study) and those for identically trained monkeys
with rhinal cortex lesions reported by Meunier et al. (1993). AH
(IBO), Monkeys with bilateral excitotoxic lesions of the
amygdala and hippocampus (n = 7);
Rh, monkeys with bilateral removals of the rhinal cortex
(n = 7); CON, unoperated control
monkeys (n = 8), consisting of the four controls
from the present study plus the four controls from Meunier et al.
(1993).
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The critical role of the rhinal cortex in recognition memory was not
easily anticipated from the initial set of findings. The medial
temporal region of greatest importance for visual recognition has
turned out to be the perirhinal cortex, with the entorhinal cortex
appearing to play a subsidiary role (Horel et al., 1987; Meunier et
al., 1993; Leonard et al., 1995). In the combined aspiration lesions of
the amygdala and hippocampus, access to these structures was always
gained by removing the underlying entorhinal cortex, in the course of
which the perirhinal cortex also sustained partial unintended damage in
some cases. However, as noted elsewhere (Murray, 1992), the inadvertent
damage to the perirhinal cortex in the initial studies (Mishkin, 1978;
Zola-Morgan et al., 1982; Murray and Mishkin, 1984; Saunders et al.,
1984) was typically neither substantial nor bilaterally symmetrical.
Therefore, direct damage to this cortical field could not account for
the severe recognition impairment that consistently followed the
combined amygdala and hippocampal ablations, and so there was little
reason to suspect that this cortical field played a critical role in
recognition memory.
Recently, however, it has become clear that combined amygdala and
hippocampal ablations can interfere with perirhinal function in another
way, namely, by disrupting perirhinal efferent fibers coursing through
the aspirated tissue. Thus, ablation of the amygdala has been shown to
transect anterior perirhinal (as well as entorhinal) fibers projecting
through the ventral amygdalofugal pathway en route to at least one
target structure, the magnocellular portion of the medial dorsal
nucleus of the thalamus (Goulet et al., 1998). Furthermore, ablation of
the hippocampal formation (i.e., Ammon's horn, dentate gyrus, and
subicular complex) now is known to transect some posterior perirhinal
(as well as entorhinal) efferents projecting through both the
fimbria-fornix and posterior thalamic pathways en route to other
medial thalamic structures, including the anterior and lateral dorsal
nuclei (R. Saunders and D. Rosene, personal communication; J. Aggleton,
M. Mishkin, and R. Saunders, personal communication).
Consequently, it now appears that combined amygdala and hippocampal
removals achieved by aspiration result in recognition failure, not
because of damage to those structures but because of combined damage
and disconnection of both the anterior and posterior portions of the
perirhinal and entorhinal cortical fields. The same explanation
presumably applies to the finding that greater impairment in visual
recognition is produced by combined transections of the amygdalofugal
pathways and fornix than by transection of either of these pathways
alone (Bachevalier et al., 1985). Together, the results suggest that
recognition memory is mediated by a cerebral circuit that includes both
the rhinal cortex and the medial thalamus (Mishkin, 1982; Mishkin and
Murray, 1994) as well as some other structures, such as the
ventromedial frontal cortex (Bachevalier and Mishkin, 1986; Meunier et
al., 1997), to which both of these regions project.
The results of our second assessment with DNMS differ from the results
of Alvarez and colleagues (1995), who found that monkeys with
hippocampal lesions were impaired significantly in DNMS when relatively
long (10 and 40 min) delays intervened between sample and choice. The
discrepancy could be attributable to any or all of a number of factors
that merit exploration. First, the monkeys in our study were trained on
the DNMS rule preoperatively and then assessed on long delays
postoperatively only after they had received ~2 months of testing
with shorter delays; by contrast, the monkeys studied by Alvarez and
colleagues were trained only postoperatively and previously had
received only ~1 month of testing with short delays. Second, although
both studies used DNMS, the details of the test procedures in the two
studies differed. Thus, whereas we used lists of objects, Alvarez and
colleagues examined memory for single items only. Also, whereas each of
our sessions included delays that increased gradually from <1 to
nearly 40 min, each session in the study by Alvarez and colleagues
included delays of a constant length. Finally, whereas our monkeys
always remained in the test apparatus during the delay interval between sample and choice, the monkeys studied by Alvarez and colleagues (1995)
were removed from the test apparatus for the trials with long delays
(on which their hippocampectomized monkeys were impaired), but not for
trials with short delays (on which their hippocampectomized monkeys
were unimpaired). As has been suggested elsewhere (Nadel, 1995), it is
possible that the different treatment for the different delay
conditions is the source of the impairment in their hippocampectomized monkeys.
A third major difference between the two studies concerns the method of
producing the lesion. Whereas we used an excitotoxin, Alvarez and
colleagues (1995) used radiofrequency. In view of the anatomical
findings described above, it seems possible that radiofrequency lesions
disrupt rhinal cortical efferents coursing through the subiculum en
route to the thalamus and that this amount of damage to the rhinal
corticothalamic circuit (and perhaps rhinal corticofrontal circuits as
well) is sufficient to produce a recognition deficit at long, but not
at short, delays.
Neural substrates of location memory
Extensive cell loss in the amygdala and hippocampus also failed to
yield an impairment on the delayed nonmatching-to-position task. Given
the wealth of information concerning the contribution of the
hippocampus to spatial memory in rodents (O'Keefe and Nadel, 1978;
Morris et al., 1982; Jarrard, 1993; Eichenbaum et al., 1994), it has
commonly been assumed that spatial memory in monkeys likewise depends
specifically on the hippocampus (Mahut and Moss, 1986; Parkinson et
al., 1988; Angeli et al., 1993; Malkova et al., 1995). In all of the
foregoing studies in monkeys, however, the removals included not only
the hippocampus but also the subicular complex and the parahippocampal
cortex (areas TF and TH), either or both of which could well have
contributed to the spatial memory impairments. Recently, two lines of
evidence have emerged in support of a dissociation of hippocampal and
parahippocampal contributions to different aspects of spatial memory.
First, recent functional imaging studies suggest a role for the
parahippocampal cortex in topographic spatial orientation (Aguirre et
al., 1996; Maguire et al., 1996; Aguirre and D'Esposito, 1997), a role
that may reflect parahippocampal processing of the geometry of local
space (Epstein and Kanwisher, 1998). Second, recent work in rodents
(McNaughton et al., 1996; Whishaw et al., 1997) has suggested that the
hippocampus may be more important for path integration on the basis of
self-motion cues than for location memory, per se. Both of these
suggestions are consistent with the negative result we obtained in
Experiment 2 and with the positive result obtained after excitotoxic
hippocampal lesions in another recent study in which monkeys were
required to learn where to reach within two-dimensional spatial scenes (Murray et al., 1998). Because there is evidence for a hippocampal contribution as well as a parahippocampal contribution to spatial navigation (Maguire et al., 1997), the dissociation outlined above is
by no means complete. In future studies the two functions that often
are confounded in tests of spatial memory, namely, memory for the
spatial layout of a map and memory for movement within the map, will
need to be assessed separately.
| |
FOOTNOTES |
Received March 26, 1998; revised May 21, 1998; accepted June 3, 1998.
This work was supported by the Intramural Research Program of the
National Institute of Mental Health. We thank the staff of the In Vivo
Nuclear Magnetic Resonance Research Center for performing magnetic
resonance imaging scans of the monkeys; V. J. O'Boyle, Jr., M. Hall, and M. Dow for testing the monkeys and assisting in surgery; and
T. Fobbs and M. Lovorn for histological processing of the tissue. W. Hadfield and J. Sewell provided additional valuable technical
support.
Correspondence should be addressed to Dr. Elisabeth A. Murray,
Laboratory of Neuropsychology, National Institute of Mental Health,
Building 49, Room 1B80, 49 Convent Drive, Bethesda, MD 20892-4415.
| |
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Top
Abstract
Introduction
