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Proc. Natl. Acad. Sci. USA
Vol. 93, pp. 739–743, January 1996
Neurobiology
Formation of mnemonic neuronal responses to visual paired
associates in inferotemporal cortex is impaired by
perirhinal and entorhinal lesions
(memoryymedial temporal lobeybackward connectionylearningyprimate)
SEI-ICHI HIGUCHI
AND
YASUSHI MIYASHITA*
Department of Physiology, The University of Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan
Communicated by Larry R. Squire, University of California, San Diego, CA, July 18, 1995
preparation so that individual IT neurons became devoid of
the backward signals but could receive forward visual signals
when visual stimuli were presented. We found selective loss of
the ability of IT neurons to represent associations between
picture pairs, whereas the ability of the neurons to respond to
particular visual stimuli was left intact.
ABSTRACT
Functional roles of the cortical backward
signal in long-term memory formation were studied in monkeys performing a visual pair-association task. Before the
monkeys learned the task, the anterior commissure was
transected, disconnecting the anterior temporal cortex of each
hemisphere. After training with 12 pairs of pictures, single
units were recorded from the inferotemporal cortex of the
monkeys as the control. By injecting a grid of ibotenic acid, we
unilaterally lesioned the entorhinal and perirhinal cortex,
which provides massive direct and indirect backward projections ipsilaterally to the inferotemporal cortex. After the
lesion, the monkeys fixated the cue stimulus normally, relearned the preoperatively learned set (set A), and learned a
new set (set B) of paired associates. Then, single units were
recorded from the same area as for the prelesion control. We
found that (i) in spite of the lesion, the sampled neurons
responded strongly and selectively to both the set A and set B
patterns and (ii) the paired associates elicited significantly
correlated responses in the control neurons before the lesion
but not in the cells tested after the lesion, either for set A or
set B stimuli. We conclude that the ability of inferotemporal
neurons to represent association between picture pairs was
lost after the lesion of entorhinal and perirhinal cortex, most
likely through disruption of backward neural signals to the
inferotemporal neurons, while the ability of the neurons to
respond to a particular visual stimulus was left intact.
METHODS
The cerebral cortex is organized so that hierarchically different
subareas communicate by forward and backward neuronal
projections (1); however, no functional role of the backward
connections has so far been experimentally demonstrated at
the single-neuron level. Neuropsychological studies have proposed a hypothesis for the role of the backward connections
from limbic cortex to neocortex in the formation of long-term
memory for facts and events (declarative memory) (2–5).
Behaviorally the declarative memory has often been tested in
humans by learning of a series of paired words or figures (2–3,
5–8).
Previous work with monkeys identified a group of neurons
which acquired associative mnemonic codes for pictures
through paired-associate learning in the anterior inferotemporal (IT) cortex (9), a visual memory storehouse in primates
(2–5, 8). There is strong evidence that IT cortex receives direct
and indirect backward projections from the perirhinal and
entorhinal cortex (10–13). The hypothesis for the role of the
backward connections predicts that the lesion of the perirhinal
and entorhinal cortex would impair the formation of the
associative code for pictures in the IT cells. The present study
tested this prediction. We combined single-unit recording
techniques with a surgically manipulated chronic monkey
Animals and Surgical Procedures. Two adult monkeys
(Macaca fuscata) were used in accordance with the University
of Tokyo Animal Care Committee.
Surgery on the anterior commissure (AC) was carried out
under aseptic conditions and anesthesia with sodium pentobarbital (25–30 mgykg). The right hemisphere was retracted
from the falx with a brain spoon. An aspirator was used to make
a sagittal incision #5 mm in length in the corpus callosum,
entering the lateral ventricle at the level of the interventricular
foramen. The AC was sectioned at the floor of the lateral
ventricle lateral to the fornix. Antibiotics were delivered to
prevent infection, and the monkeys were given sufficient rest for
recovery for at least 2 weeks.
The lesions of the entorhinal and perirhinal cortex were
made by injecting a small volume of the neurotoxin ibotenic
acid (Ibo). Ibo has been reported to destroy cell bodies
selectively while leaving fibers of passage in the underlying
white matter undamaged (14, 15). With the help of electrophysiological mapping, we inserted a Hamilton syringe needle
into the anteroventral temporal lobe. A grid of 1-ml injections
of Ibo (15 mgyml, 0.03 mlymin) was made with '2 mm between
tracks. One monkey (M) received injections at 22 tracks, and
the other monkey (N) at 19 tracks.
Behavioral Task. The pair-association task was described
previously (9). Colored fractal patterns were used as the visual
stimuli (see Fig. 3A). We generated the patterns according to
the algorithm described previously (16) and arranged them
into 12 pairs. In the task, following a fixation stimulus, a cue
stimulus was presented in the center of the video monitor for
0.5 s. After a delay period, the paired associate of the cue
stimulus and one stimulus from a different pair were shown.
The monkey obtained fruit juice as a reward for touching the
correct paired associate. Eye position was monitored with a
magnetic search coil. The criterion for acquisition of preoperative learning (the set A stimuli) was two consecutive days
of 26 correct responses in 30 trials. Monkey M and monkey N
took 270 and 383 trials per picture to reach this criterion,
respectively. The criterion after the Ibo lesion was made
slightly easier (two consecutive days of 23 correct responses in
30 trials). In relearning the set A paired associates after the
lesion, 10 and 50 trials per picture were necessary for monkeys
The publication costs of this article were defrayed in part by page charge
payment. This article must therefore be hereby marked ‘‘advertisement’’ in
accordance with 18 U.S.C. §1734 solely to indicate this fact.
Abbreviations: AC, anterior commissure; IT, inferotemporal; CC,
correlation coefficient; PI, pair index; Ibo, ibotenic acid.
*To whom reprint requests should be addressed.
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Proc. Natl. Acad. Sci. USA 93 (1996)
Neurobiology: Higuchi and Miyashita
M and N, respectively. In learning the new set (set B) after the
lesion, one monkey (M) took 101 trials and the other (N) took
93 trials per picture to reach the criterion.
Electrophysiology and Data Analysis. Recording and analysis of extracellular spike discharges of single neurons have
been described (9, 17). At the beginning of unit recording
before the lesion, locations of responsive cells were mapped in
the anterior IT cortex and an area (about 2 mm 3 3 mm,
hatched in Fig. 2) with a high density of responsive cells was
identified. All neuronal recordings were done from this cortical area both before and after the lesion. Each location of the
electrode track was measured by x-ray imaging and verified
histologically at the end of the experiments.
Evaluation of cue responses was done by collecting number
of spikes over 80–480 ms after the presentation of each picture
cue, and for 400 ms immediately preceding the appearance of
the fixation stimulus. A neuron was regarded as responsive to
the picture if the two distributions were significantly different
(paired t test, P , 0.05) and as selective if the response to a
stimulus was significantly different from others by analysis of
variance (ANOVA, P , 0.05). Two indices were used to
analyze pair-coding responses of these cells: the standard
correlation coefficient (CC) and the pair index (PI) (9). The
CC was calculated from xi and x9i (i 5 1–12) for each cell, where
xi denotes a mean discharge rate during the cue period for the
ith picture (the ith and i9th pictures belong to a pair):
O
12
CC 5
HF O
12
i51
i51
@~xi 2 x!~x9i 2 x9!#
~xi 2 x!2
GF O
12
i51
~x9i 2 x9!2
GJ
1y2
,
where x and x9 are the means of xi and x9i (i 5 1–12),
respectively. The PI was defined (9) as the difference of two
correlation indices, CIp and CIr, where for paired associates,
CIp 5
1
Np
OO
i
j
~ i, j ! ~ j5i9 !
~xi 2 b!~xj 2 b!
3 100,
~xbest 2 b!~x2nd-best 2 b!
and for other combinations,
CIr 5
1
Nr
OO
j
i
~ i,j) (jÞi9)
~xi 2 b!~xj 2 b!
3 100,
~xbest 2 b!~x2nd-best 2 b!
where b is a spontaneous discharge rate, xbest is the mean
discharge rates for the stimulus that produced best responses
in each cell, and x2nd-best is the mean discharge rate for the
second-best cue-optimal pictures. Np and Nr are the total
number of combinations for two cases. The CC and PI were
calculated for each cell.
Histology. At the end of the experiment, the monkey was
deeply anesthetized with an overdose of sodium pentobarbital
(45 mgykg, i.m.) and then perfused through the aorta with
0.9% NaCl followed by 10% formalin in phosphate buffer (pH
7.4). The brain was sectioned coronally at 40 mm. Serial
sections were stained with cresyl violet and with the modified
Gallyas method (18). Seventeen (monkey M) or 18 (monkey N)
sections were sampled at 760- to 960-mm separation, and a
two-dimensional unfolded map was constructed (19). The
shrinkage due to histological procedures was estimated and
adjusted by a correction factor, but a possible local atrophy due
to the Ibo lesion (see Results) was not corrected.
RESULTS
Two macaque monkeys were trained in a pair-association task
(9). We sorted a set of 24 geometrically distinct pictures into
12 pairs, so that the monkeys learned the combinations of the
paired associates and retrieved the other pair member associated with each cue picture. Before the monkeys learned the
task, the AC was surgically transected (Fig. 1 A and B) just to
the right of the midline (arrow in Fig. 1B). The septal nuclei,
the fornix, and the underlying diencephalic structures were
spared. This surgery disconnected the anterior temporal cortex
of each hemisphere from the other, since most commissural
fibers of this area traverse the AC rather than the corpus
callosum (20–22). After recovery, the monkey was trained with
a set (set A) of the paired associates to the criterion performance level, and then extracellular spike discharges of single
neurons were recorded as a prelesion control in the anterior IT
cortex (9, 23, 24).
We deprived IT neurons of backward neural information by
unilateral Ibo lesions of the entorhinal and perirhinal cortex.
Fig. 1 C–E show photographs of a cross section from the
anterior temporal cortex of a lesioned monkey. The lesion
covered both the medial and lateral banks of the rhinal sulcus
completely, and most of the entorhinal and perirhinal cortex.
The lesioned cortex suffered atrophy, but fibers in the underlying white matter were left undamaged. Higher magnification
(Fig. 1E) of the area framed in Fig. 1D indicates the border
FIG. 1. Unilateral Ibo lesion of the
perirhinal and entorhinal cortex. (A)
Lateral (Left) and ventral (Right) view
of a monkey brain, indicating the locations of sections in B (no. 1), C–E
(no. 2), and Fig. 2 (nos. 3 and 4). (B)
Fiber-stained coronal section through
the AC. The AC was cut (arrow) just to
the right of the midline (M). The fornix
(Fx) was left intact. (Bar 5 2 mm.) (C)
Cresyl violet-stained section showing
the left (intact) entorhinal and perirhinal cortex. (Bar 5 2 mm.) (D) Same
section as C, but showing the right
(lesioned) cortex. (E) Higher magnification of the area framed in D. Double
arrowheads indicate the border between the intact area (to the right) and
incompletely lesioned area. Arrowheads indicate the border between the
completely (to the left) and incompletely lesioned area. H, hippocampus.
amts, anterior middle temporal sulcus.
sts, superior temporal sulcus. rs, rhinal
sulcus.
Neurobiology: Higuchi and Miyashita
FIG. 2. Location and extent of the ibotenic acid lesion in monkey
M (A) and monkey N (B), illustrated on flat maps of the temporal lobe.
Anterior (A), posterior (P), medial (M), and lateral (L) directions are
indicated. Dot-dash lines represent cut lines of map; thick lines indicate
the lips of sulci. Completely (coarsely stippled) and incompletely
(finely stippled) lesioned areas are shown. In the flat map of monkey
M, the location of sections 1 and 2 of Fig. 1 A is illustrated with thin
line, and the dot-dash lines correspond to sections 3 and 4 of Fig. 1 A.
Locations of recorded neurons are also indicated on the maps (hatched
area). PA, periamygdaloid cortex. PreS, presubiculum. amts, anterior
middle temporal sulcus. ots, occipito-temporal sulcus. sts, superior
temporal sulcus. rs, rhinal sulcus.
between the intact and lesioned area. In the intact area (to the
right) the laminar organization of the normal neocortex remained, while in the lesioned area (to the left) no neurons were
found (only glial cells). Fig. 2 shows the location and extent of
the lesions on flat maps of the temporal lobe for each monkey.
The lesion was nearly complete along most of the anteroposterior extent of the rhinal sulcus. However, the most anterior
portion of the rhinal sulcus on the temporal pole is not shown
in the flat maps, and the cortex in this area was not damaged
in either monkey. The most lateral part of the perirhinal cortex
in one monkey (N) was spared. After the lesion, extracellular
spike discharges of single neurons were recorded from the
same area (hatched in Fig. 2) as in the prelesion control.
Proc. Natl. Acad. Sci. USA 93 (1996)
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Average performance for set A stimuli during neural recording
was 81% (before lesion) and 80% (after the lesion), and for set
B stimuli, 72% after the lesion.
In spite of the lesion of the entorhinal and perirhinal cortex,
the sampled neurons responded strongly to both the set A and
set B patterns during the cue period of the task. The responses
of one cell are shown in Fig. 3 B and C. This cell was activated
selectively by a few stimuli of set B (Fig. 3D) and very weakly
by the stimuli of set A (Fig. 3E). The lesion did not affect the
monkey’s fixation to the cue stimulus as shown in the eye
position traces of Fig. 3 B and C. In contrast to these unaffected
properties, the strongest and the second-strongest responses of
the cell were not ascribed to a particular pair of the set (Fig.
3D), and thus the cell did not encode the pair association.
We recorded from 256 neurons prior to the Ibo lesion and
tested the responses to the set A stimuli. One hundred nine of
them were unresponsive. Since weak responses could not be
ascribed to the optimal stimulus (25), we examined 92 cells
whose maximum discharge rates were distributed beyond 20
spikes per second (the leftmost saddle point in the distribution
of all responsive cells in the control and lesioned cortices). Of
the 92 cells, 10 cells were nonselective to the stimuli. We
analyzed pair-coding responses of these cells by calculating the
CC and the PI for each neuron. Fig. 4A (●) shows the
cumulative frequency distribution of CC values in the 92 cells.
The distribution of CC was shifted toward the positive values
and showed that the paired associates elicited significantly
correlated responses in the prelesion control (P , 0.01;
Wilcoxon signed-rank test, n 5 92). Fig. 4B (●) similarly shows
the cumulative frequency distribution of PI values in the 92
cells. The curve also shows that paired associates elicited
significantly correlated responses in the control (P , 0.01, n 5
92). These results confirmed the conclusion of a previous
report (9).
We recorded from 363 neurons after the lesion, and tested
the responses to set A stimuli for 341 cells and the responses
to set B stimuli for 332 cells. Of those cells tested with the set
A stimuli, 202 were unresponsive and 67 gave weak responses.
FIG. 3. Responses of anterior IT
neurons in the pair-association task.
(A) Examples of pairs of fractal patterns. (B) Single-neuron response after the Ibo acid lesion, shown by rastergrams (Top), spike-density histograms (Middle), and eye position
traces (Bottom; H, horizontal. V, vertical). Bin width, 40 ms. The green
square for fixation or the cue stimulus
was presented during the time period
denoted as f or c. These trials were
collected for a cue picture 7 in the
stimulus set B. (C) Same as B, but
showing trials for cue 1 of set B. (D)
Mean discharge rates for each cue
presentation from set B (mean 6
SEM) relative to the spontaneous discharge (arrowhead) in the same cell as
in B and C. Twelve pairs of stimuli are
labeled on the abscissa. The stippled
and open bars in pair no. 1 refer to the
responses to the picture 1 and 19, respectively. This neuron selectively responded to patterns of set B but did
not code pair associations. (E) Mean
discharge rates of the same cell as in D,
but for pictures of another set (set A).
The fractal patterns of pairs 7, 9, and
1 of set B are shown in the top, middle,
and bottom rows of A.
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Neurobiology: Higuchi and Miyashita
Proc. Natl. Acad. Sci. USA 93 (1996)
correlated responses before the lesion (11 cells) was larger
than that after the lesion for set A (5 cells) or set B (1 cell), and
the percentages of the correlated cells were statistically significantly different (x2 5 7.06, P , 0.05). The frequency
distributions of PI after the lesion (Fig. 4B) also show that the
paired associates did not elicit significantly correlated responses either for set A (V, P . 0.3) or for set B (‚, P . 0.4).
Fig. 5 compares the responsiveness of the cells in the three
groups (two-way ANOVA and t test). The results for the two
monkeys were not significantly different (P . 0.25) in the
two-way ANOVA in any of the following indices [F(1, 233) 5
0.01 for CC, F(1, 233) 5 1.11 for PI, F(1, 233) 5 0.69 for SPON,
F(1, 233) 5 0.00 for MAX] and have been pooled. The CCs
were reduced after the lesion compared with that before the
lesion (P , 0.05). The CCs in the control were significantly
larger than zero (P , 0.01) but those after the lesion were not,
either for set A (P . 0.4) or for set B (P . 0.6). The PIs were
also reduced after the lesion compared with that before the
lesion (P , 0.05). The PIs before the lesion were significantly
larger than zero (P , 0.05) but those after the lesion were not,
either for set A (P . 0.6) or for set B (P . 0.4). After the lesion,
the cells responded to both the set A and set B pictures, even
more strongly than the control (MAX, P , 0.05). The spontaneous discharge rates (SPON) were not significantly different among the three groups (P . 0.2). We conclude that lesion
of the entorhinal and perirhinal cortex disrupted the associative code of the IT neurons between the paired associates,
without impairing the visual response to each stimulus.
FIG. 4. Response correlation to paired associates. Analysis by the
CC (A) and by the PI (B). The ordinates indicate the cumulative
number of cells, which was normalized by the total number of cells in
each group. The curves show the cumulative frequency histograms in
the three cell groups: neurons tested with the set A stimuli prior to the
lesion of the entorhinal and perirhinal cortex (●, n 5 92), those tested
after the lesion with the set A stimuli (V, n 5 72), and those tested after
the lesion with the set B stimuli (‚, n 5 75).
Of those cells tested with the set B stimuli, 195 were unresponsive and 62 gave weak responses. Thus, 72 of the 341 cells
for set A and 75 of the 332 cells for set B were analyzed after
the lesion. The fraction of responsive cells (72y341 for set A,
75y332 for set B) dropped in the lesion groups (P , 0.01)
compared with that before the lesion (92y256), which may
reflect some physiological effects of the lesion. Seven of the 72
cells and 8 of the 75 cells were nonselective to the stimuli in the
two postlesion groups. Thus, the fraction of visually selective
cells after the lesion (65y72 and 67y75) did not differ significantly from that before the lesion (82y92) (P . 0.8). We also
compared the response selectivity by calculating the number of
effective stimuli (NES) for each cell. The 50%, 10%, and 90%
points of the cumulative distributions of the NES were determined. There was a slight tendency that the cells in the lesioned
groups were less selective (50%, 10%, and 90% values of NES
were 3.0, 1.4, and 12.0 before lesion; 5.0, 1.8, and 17.3 for set
A; and 5.0, 1.5, and 15.9 for set B after the lesion). However,
the tendency was not statistically significant (P . 0.15; Kolmogorov–Smirnov test) between the control group and the
lesioned group for either set A or set B.
Fig. 4A shows that the cumulative frequency distributions of
CC after the lesion (V and ‚) were significantly different from
the distribution before the lesion (●) (P , 0.05; Kolmogorov–
Smirnov test) and that the distributions after the lesion did not
differ from each other (P . 0.5). The paired associates did not
elicit significantly correlated responses after the lesion either
for set A (V; P . 0.9; Wilcoxon signed-rank test) or for set B
(‚; P . 0.9). We also used the CC to evaluate the number of
individual cells which showed significantly correlated responses (at P , 0.05); the number of cells with significantly
DISCUSSION
The results support the hypothesis that the backward signal
from the medial temporal lobe to the IT neurons plays a crucial
role in visual pair-association memory in the primate. The
hypothesis raised a specific prediction that the lesion of the
perirhinal and entorhinal cortex would impair the formation of
the associative code for pictures in the IT cells. The present
study tested this prediction and confirmed it.
FIG. 5. Effects of the lesion of the entorhinal and perirhinal cortex
upon neuronal responsiveness in the pair-association task. The CC (A),
PI (B), spontaneous discharge rate (SPON) (C), and maximum
discharge rate with spontaneous discharge subtracted (MAX) (D)
were compared among three groups: neurons that were recorded with
the set-A stimuli prior to the lesion (stippled bars, n 5 92), those
recorded with the set A stimuli after the lesion (hatched bars, n 5 72),
and those recorded with the set B stimuli after the lesion (solid bars,
n 5 75). Data are shown as mean 6 SEM.
Proc. Natl. Acad. Sci. USA 93 (1996)
Neurobiology: Higuchi and Miyashita
We combined single-unit recording techniques with surgical
manipulations in the monkey. First, the AC of the monkeys was
cut to remove influences upon anterior IT neurons from those
in the other hemisphere (20–22). Behaviorally, the monkeys
fixated the stimuli and learned the pair-association task quite
normally, just as in the previous study (9). Neuronal responses
of IT cells to complex patterns (control in Fig. 5D) were not
affected by the anterior commissurectomy, which confirmed a
previous report on anesthetized monkeys (26). The response
correlation to the paired associates was also not affected
(control in Figs. 4 A and B and 5 A and B). Then, we placed
a unilateral Ibo lesion in the entorhinal and perirhinal cortex.
The electrophysiological indices for spontaneous discharge
rates and maximum firing rates (Fig. 5 C and D) suggested that
the cortex of the recording area was not pathological after the
limbic lesion, which was also confirmed by normal histology of
the cortex at the recording sites. Visual selectivity was another
factor which may affect the pair-coding property of a cell.
However, the percentage of visually selective cells did not
differ significantly before and after the lesion. The number of
effective stimuli of each cell exhibited a slight tendency for the
control group to be more sharply tuned, but the tendency was
not statistically significant. All these data suggest that the
major effect of the lesion can be specifically related to the
pair-coding properties of IT cells.
A previous lesion study demonstrated that monkeys with
bilateral removal of the entorhinal and perirhinal cortex
neither relearn visual paired associates that were learned
preoperatively nor learn new associations among new visual
stimuli (27). In the present study monkeys with a unilateral
lesion learned both the old and new associations easily. The
mild behavioral effects of the unilateral lesion were most likely
due to the intact temporal lobe in the contralateral hemisphere. At the level of neuronal responses, the lesion destroyed
the associational ability of the IT neurons that had been
isolated from the intact temporal lobe in the contralateral
hemisphere by the anterior commissurectomy. The finding of
retrograde amnesia, in terms of neuronal responses, also
agreed with previous behavioral data (27). The pair association that was learned prior to the lesion was lost (Fig. 5 A and
B, set A after the lesion). Long and gradual learning of the
paired associates prior to the lesion (.3 months) may have
produced such longer retrograde amnesia than that found by
Zola-Morgan and Squire in an object-discrimination problem
(28).
To examine implications of the results, we need to consider
the limitations of this animal preparation. The Ibo lesion
obliterated most directly the backward projection from entorhinal–perirhinal cortex to IT neurons, but eliminated other,
indirect neural connections to IT cells as well: the lesion
damaged cells with forward projection from entorhinal–
perirhinal cortex to other structures, such as the frontal cortex,
the cingulate cortex, or the basal ganglia. Thus, the Ibo lesion
might have altered the functional circuitry for an anterior IT
neuron in a complicated manner. It remains to be examined
whether the indirect functional circuitry could explain the
observed changes of associative coding in the IT neurons.
In the primate inferior temporal cortex and part of the
superior temporal cortex, neurons selectively respond to complex objects such as faces, hands, Fourier descriptors, and
fractal patterns (5, 25, 29–31). Some, if not all, of these
responses are acquired through learning in adulthood (5, 9, 23,
31–33). The present results show that the backward connection
from the medial temporal lobe is necessary for some of these
acquired responses, such as pair-association coding, but not for
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others. Indeed, the fractal patterns introduced after the lesion
(set B) activated IT neurons highly selectively. Since this
stimulus selectivity is most likely obtained by a tuning mechanism that molds and sharpens neuronal response selectivity to
an object through repetitive stimulus presentation (33, 34), our
finding suggests at least partial preservation of the tuning
mechanism after the lesion of the entorhinal and perirhinal
cortex. These results are consistent with the proposal of
decomposition of the primate long-term memory system into
several different neural mechanisms (2, 8, 33, 34).
We thank Dr. K. Sakai for helpful discussions. This research was
supported by Grants-in-Aid for Specially Promoted Research from the
Japanese Ministry of Education, Science, and Culture (02102008,
07102006) and a grant from Uehara Memorial Foundation.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
Van Essen, D. C., Anderson, C. H. & Felleman, D. J. (1992)
Science 255, 419–423.
Squire, L. R. (1987) Memory and Brain (Oxford Univ. Press, New
York).
Milner, B. (1990) in Vision, Memory and the Temporal Lobe, ed.
Iwai, E. & Mishkin, M. (Elsevier, New York), pp. 43–53.
Mishkin, M. (1982) Philos. Trans. R. Soc. London B 298, 85–92.
Miyashita, Y. (1993) Annu. Rev. Neurosci. 16, 245–263.
Wechsler, D. (1987) Wechsler Memory-Scale Revised (Harcourt
Brace Jovanovich, San Antonio, TX).
Petrides, M. (1985) Neuropsychologia 23, 601–614.
Squire, L. R. & Zola-Morgan, S. (1991) Science 253, 1380–1386.
Sakai, K. & Miyashita, Y. (1991) Nature (London) 354, 152–155.
Van Hoesen, G. W. (1982) Trends Neurosci. 5, 345–353.
Shiwa, T. (1987) Arch. Ital. Biol. 125, 139–154.
Webster, M. J., Ungerleider, L. G. & Bachevalier, J. (1991) J.
Neurosci. 11, 1095–1116.
Suzuki, W. A. & Amaral, D. G. (1994) J. Neurosci. 14, 1856–1877.
Olney, J. W. (1983) Excitotoxins (Macmillan, London), pp. 82–95.
Newsome, W. T., Wurtz, R. H., Dursteler, M. R. & Mikami, A.
(1985) Exp. Brain Res. 58, 392–399.
Miyashita, Y., Higuchi, S., Sakai, K. & Masui, N. (1991) Neurosci.
Res. 12, 307–311.
Miyashita, Y., Rolls, T., Cahusac, P. M. B., Niki, H. & Feigenbaum, J. D. (1989) J. Neurophysiol. 61, 669–678.
Hess, T. D. & Merker, B. H. (1983) J. Neurosci. Methods 8, 95–97.
Van Essen, D. C. & Maunsell, J. H. R. (1980) J. Comp. Neurol.
191, 225–281.
Pandya, D. N., Karol, E. A. & Lele, P. P. (1973) Brain Res. 49,
177–180.
Zeki, S. M. (1973) J. Comp. Neurol. 148, 167–176.
Demeter, S., Rosene, D. L. & Van Hoesen, G. W. (1990) J.
Comp. Neurol. 302, 29–53.
Miyashita, Y. (1988) Nature (London) 335, 817–820.
Miyashita, Y. & Chang, H. S. (1988) Nature (London) 331, 68–70.
Gross, C. G. (1972) in Handbook of Sensory Physiology (Springer,
Berlin), pp. 451–482.
Gross, C. G., Bender, D. B. & Mishkin, M. (1977) Brain Res. 131,
227–239.
Murray, E. A., Gaffan, D. & Mishkin, M. (1993) J. Neurosci. 13,
4549–4561.
Zola-Morgan, S. & Squire, L. R. (1990) Science 250, 288–290.
Desimone, R., Albright, T. D., Gross, C. G. & Bruce, C. (1984)
J. Neurosci. 4, 2051–2062.
Rolls, E. T. & Baylis, G. C. (1986) Exp. Brain Res. 65, 38–48.
Perrett, D. I., Mistlin, A. J. & Chitty, A. J. (1987) Trends Neurosci. 10, 358–364.
Miyashita, Y., Date, A. & Okuno, H. (1993) Neuropsychologia 31,
1119–1132.
Sakai, K., Naya, Y. & Miyashita, Y. (1994) Learn. Mem. 1,
83–105.
Squire, L. R. (1994) in Advances in the Study of Memory and
Memory Systems, eds. Schacter, D. & Tulving, E. (MIT Press,
Cambridge, MA), pp. 203–231.