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The Journal of Neuroscience, February 1, 1999, 19(3):1142-1148
Different Contributions of the Hippocampus and Perirhinal Cortex
to Recognition Memory
Huimin
Wan1,
John P.
Aggleton2, and
Malcolm W.
Brown1
1 Department of Anatomy, University of Bristol, Medical
School, Bristol, BS8 1TD, United Kingdom, and 2 School
of Psychology, University of Wales, College of Cardiff, Cardiff, CF1
3YG, United Kingdom
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ABSTRACT |
Brain regions involved in visual recognition memory, including the
hippocampus, have been investigated by measuring differential neuronal
activation produced by novel and familiar pictures. Novel and familiar
pictures were presented simultaneously, one to each eye, using a paired
viewing procedure. Differential neuronal activation was determined
using immunohistochemistry for the protein products of c-fos as an
imaging technique. The results establish that the regions of the rat
brain associated with discriminating the novelty or familiarity of an
individual item (such as a single object) differ from those responding
to a spatial array of items (such as a scene). Perirhinal cortex and
area TE of the temporal lobe are activated significantly more by
pictures of novel than of familiar individual objects, but the
hippocampus is not differentially activated. In contrast, pictures of
novel arrangements of familiar items produce significantly greater
activation than familiar arrangements of these items in postrhinal
cortex and subfield CA1 of the hippocampus but significantly less
activation in the dentate gyrus and subiculum; perirhinal cortex and
area TE are not differentially activated. Thus, the hippocampus is
importantly involved in processing information essential to recognition
memory concerning the relative familiarity of arrangements of items, as
needed for episodic memory of scenes, whereas the perirhinal cortex
processes such information for individual items.
Key words:
Fos; immunoreactivity; rat; recognition memory; hippocampus; rhinal cortex
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INTRODUCTION |
There has been much recent interest
in defining those brain regions responsible for recognition memory and,
in particular, uncovering the involvement of the hippocampus. The
results of electrophysiological and recent lesion experiments have
thrown doubt on the importance of the hippocampus for the performance of tasks such as delayed matching to sample that are soluble by judging
the relative familiarity or recency of occurrence of discrete, individual stimulus items while emphasizing the crucial role of perirhinal cortex in such tasks (Brown, 1996 ; Murray, 1996; Suzuki, 1996; Brown and Xiang, 1998; Xiang and Brown, 1998; Aggleton and Brown,
1999).
More generally, recognition memory requires discrimination of the
novelty or familiarity of previous experiences. These experiences may
be of an individual item such as an object or of a complete environment
or scene made up of a spatial arrangement of many items. Thus for
example, we immediately recognize that someone has placed a new chair
in a room of our home. Equally, we immediately recognize that someone
has made a new arrangement of the familiar items of furniture in a room
of our home. To model these situations and thereby assess whether the
same brain regions are involved in judging the relative familiarity of
individual items as for arrangements of items, rats were exposed to
pictures of such stimuli. In the first experiment, the novel and
familiar pictures were of individual stimulus items; in the second
experiment, the pictures were of novel or familiar arrangements of
familiar items.
The activation produced by these pictures in different regions of the
intact brain was imaged using immunohistochemistry for the protein
products (Fos) of the immediate early gene c-fos (Sheng and Greenberg,
1990; Morgan and Curran, 1991; Dragunow, 1996; Larea, 1997). This
technique makes possible the simultaneous examination of the activity
of populations of neurons in multiple brain regions. However, the
results of such imaging are only easily interpretable if the behavioral
and stimulus presentation conditions are closely controlled. For this
reason, in the present experiments each rat was trained to hold its
head in an observing hole while pictures were displayed in front of it
on two computer monitors using a paired viewing procedure (Zhu et al.,
1996). In this procedure a rat sees simultaneously a familiar picture
with one eye and a novel picture with the other eye (Fig.
1). The procedure thus ensures that both
pictures are seen under the same conditions of alertness and with
similar eye movements. The two pictures are spaced apart to each side
of the rat so that one stimulus is viewed by the monocular visual field
of the right eye while the other was similarly viewed by the left eye.
Information from each eye initially passes chiefly to the contralateral
cerebral hemisphere (Sefton and Dreher, 1995).
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Figure 1.
Apparatus for the paired viewing procedure. A
novel and a familiar picture appeared simultaneously, one on each of
the two computer monitors, when the rat's head was in the observing
hole. The two monitors were spaced apart to each side of the rat so
that one was viewed by the monocular visual field of the right eye
while the other was similarly viewed by the left eye. When the rat's
head was in the observing hole, the partition prevented the right eye
seeing the left monitor and vice versa.
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MATERIALS AND METHODS |
Subjects and apparatus. Subjects were 16 male
pigmented rats (DA strain; Bantin and Kingman, Hull, UK), weighing from
175 to 220 gm. All animal procedures were performed in accordance with
United Kingdom Home Office Licensing Laws. Each of the two experiments
(with pictures of individual items or arrangements of items) used eight
rats. Each rat was trained in a viewing chamber (30 × 30 × 35 cm). The top of the chamber was open, the bottom and sides were
black; the front was transparent (Perspex) with a central observing
hole 3 cm in diameter, 6 cm above the floor. In the chamber, 4.5 cm to
either side of the observing hole, ran two small barriers (12 cm
long × 9 cm high); these kept the rat's body at 90° to the
front screen when its head was in the observing hole. When the rat's
head was positioned in the observing hole, an infrared beam was
interrupted, signaling the computer (Viglen Pentium PC) to start a
trial. After a variable interval of 3-4 sec, provided the head
remained in the hole, two pictures (each 15 × 12 cm) were shown
simultaneously for 4.5 sec, one on each of the two computer monitors
placed 30 cm from the observing hole ("paired viewing procedure";
Fig. 1). A black partition ensured that the rat's left eye could not
see the right monitor screen, and his right eye could not see the left
screen. After the pictures had been shown for 4 sec a drop of diluted
blackcurrant juice was delivered by a metal tube that the rat could
just reach and lick. No other behavioral contingency was required, and
the procedure ensured that the rat's behavior (which was monitored by
camera and videorecorded) was the same for the novel and familiar pictures.
Stimuli. In the first experiment, each picture was of a
different individual item (chosen from MicroSoft Clipart). In the second experiment, each picture was of a different arrangement of
items, each arrangement being constructed from three individual items.
The arrangements comprised six sets of three individual items in ten
different spatial arrangements (five familiar, five novel). Novel and
familiar arrangements used the same spatial locations on the computer
screen, but with different members of the set in the particular locations.
Behavioral procedure. From 1 week before training started,
each rat was kept on a 12 hr dark/light cycle, with the dark phase being during daylight. During training the rats were allowed ad libitum access to water for 2 hr each day. Each rat was
pretrained for 2 d, without stimulus presentation, to go to the
observing hole for juice reward. The subsequent training period lasted
6 d, with two morning sessions and one afternoon session each day. The second morning session followed the first without a break; the
afternoon session was 3 hr later. In each session two sets of 30 different pictures were presented, one set on each monitor, a picture
from each set being shown simultaneously on each of the 30 trials. In
both morning sessions the same two sets of pictures were used. In each
afternoon session one eye was exposed to a set of novel pictures while
the other eye saw a particular one of the two sets of pictures
presented in the morning (the "familiar set"). A different novel
set of stimuli was shown each afternoon to familiarize the animal with
seeing novel and familiar stimuli simultaneously. The different sets of
novel and familiar stimuli were presented so that by the end of the
experiment each eye had seen the same number of novel and familiar sets
of stimuli, and both eyes had seen the familiar set the same number of
times; the familiar set had then been seen 18 times (9 times by each eye). The "novel set" of stimuli was shown with the familiar set on
the last afternoon, 1.5 hr before the animal was anesthetized deeply
with pentobarbitone and perfused with 0.1 M phosphate
buffer and 4% paraformaldehyde, pH 7.4. The familiar set for one
animal became the novel set for the next so that stimulus materials
were counterbalanced across rats. Further, the eye (left or right) that
viewed the novel set was also counterbalanced across animals.
Tissue-processing procedure. After perfusion, the brain was
removed and placed for 12 hr in 4% paraformaldehyde followed by 24 hr
in 30% sucrose. The immunohistochemical and counting procedures followed those of Zhu et al. (1995). Briefly, coronal sections (25 µm) were cut on a cryostat, and floating sections were processed using a primary antibody and the avidin-biotin complex (ABC, Vector Laboratories, Burlingame, CA) method. The primary antibody, kindly provided by Dr. D. Hancock (Biochemistry of the Cell Nucleus
Laboratory, Imperial Cancer Research Institute), was a rabbit
polyclonal directed against the N-terminal region of rat c-fos peptide
and is c-fos-specific (Brennan et al., 1992). The secondary antibody
was biotinylated goat anti-rabbit (Vector Laboratories). DAB was used
for visualization of Fos immunoreactivity, and the automated counting
of stained nuclei was performed using an image analysis system (SeeScan
Ltd.) (McCabe and Horn, 1994; Zhu et al., 1995b). Processing and
counting were done without the experimenter knowing which eye had seen the novel set. Counts above threshold were obtained from the right and
left hemispheres for rectangular areas (0.94 × 0.67 mm) from two
sections for each brain region (Fig. 2).
For data analysis, each count was first normalized by dividing it by
the corresponding mean for the particular area averaged across both
hemispheres for the particular rat. The normalized counts were then
subjected to an ANOVA with factors: rat, area, and novelty/familiarity. Statistical tests (two-tailed) used a significance level of 0.05.
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Figure 2.
Diagrams of coronal sections indicating areas
sampled. The distance (in millimeters) of the sections from bregma is
indicated (Paxinos and Watson, 1986). So that processing of the
different areas could be done in parallel, only the illustrated brain
levels were sampled. One area was sampled for the dentate gyrus and
postrhinal cortex, three areas for perirhinal cortex, and two for all
other regions. The significance or nonsignificance of any of the
reported effects was not dependent on these differences in the number
of sampling points. CA1, CA3, Hippocampal
subfields; DG, dentate gyrus; ENT,
entorhinal cortex; OCC, occipital cortex;
PoRH, postrhinal cortex; PRH, perirhinal
cortex; SC, superior colliculus; TE, area
TE of the inferotemporal cortex; V1, primary visual
cortex; VLG, ventral lateral geniculate nucleus of the
thalamus. The locations of PRH and PoRH are modeled after Burwell et
al. (1995).
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RESULTS |
In the first experiment, the rats saw pictures of individual items
(Fig. 3a). Counts of neuronal
nuclei stained for Fos were significantly higher for novel than for
familiar pictures in area TE of the temporal lobe (TE) and perirhinal
cortex (PRH); see Figures 2, 3b, and 4 (for statistical
details, see the legend of Fig. 3b; also see Fig.
4 for example photomicrographs of Fos staining). No significant difference was found in any other area examined, including within the hippocampal formation, i.e., hippocampal subfields CA1, CA3, the dentate gyrus (DG), and the subiculum (Sub), or
postrhinal cortex (PoRH). Counts for all areas in both experiments are
given in Table 1. Counts in the
hippocampal formation were low (mean ± SEM = 6.4 ± 1.04 mm 2), i.e., relatively few hippocampal
neurons were activated by these pictures of individual items, compared
with the higher counts in PRH (30.3 ± 6.2 mm 2),
PoRH (24.0 ± 7.3 mm2), and TE (28.7 ± 5.9 mm2).
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Figure 3.
Example pictures and normalized counts in the
brain regions sampled for novel and familiar individual items and
arrangements of items. a, Two example pictures of single
items (items were colored but are illustrated in monochrome).
b, Normalized counts of Fos-stained nuclei in the
sampled brain regions for novel and familiar pictures of single items.
An ANOVA of the normalized counts revealed a significant interaction
between area and novelty/familiarity
(F(10,360) = 2.18; p < 0.02). Further analysis revealed that the mean counts were higher for
novel than for familiar objects in areas TE and PRH (each
p < 0.01), but no other differences reached
significance. c, Two example pictures of arrangements of
items: note the different arrangements of the same items.
d, Normalized counts of Fos-stained nuclei in the
sampled brain regions for novel and familiar pictures of arrangements
of items. An ANOVA of the normalized counts revealed a significant
interaction between area and novelty/familiarity
(F(10,306) = 5.69; p < 0.001). Further analysis revealed that the mean counts were higher for
novel than for familiar arrangements in areas PoRH and CA1 (each
p < 0.01) and higher for familiar than for novel
arrangements in areas DG and Sub (each p < 0.05).
No other differences reached significance. Although the size of each
individual stimulus was larger in experiment 1 than experiment 2, the
percentage differences in activation for novel and familiar stimuli are
comparable to those found using objects that subtend approximately half
the visual angle of these stimuli (Zhu et al., 1996). Accordingly, the
size of the individual items is not critical to the results obtained
over the range of sizes explored. Novel versus familiar differences:
*p < 0.05; **p < 0.01. See
Figure 2 for abbreviations.
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Figure 4.
Activated neurons (Fos-stained nuclei) in
perirhinal cortex as a result of viewing individual items: novel
(left) or familiar (right). Note the
greater number of stained nuclei on the left
(novel). Coronal sections (5.20 behind bregma);
magnification, 83×; d, dorsal; m,
medial; rs, rhinal sulcus.
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In the second experiment, the rats saw pictures of spatial arrangements
of individual items (Fig. 3c). Activation was compared for
novel and familiar arrangements of the same familiar items. Counts of
neuronal nuclei stained for Fos were significantly higher for novel
than for familiar arrangements in PoRH and CA1, but significantly lower
in the DG and Sub; see Figure 3d and legend for details;
also see Figure 5 for examples of
photomicrographs of Fos staining. No significant difference was found
in any other area examined, including TE and PRH.
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Figure 5.
Activated neurons (Fos-stained nuclei) as a result
of viewing arrangements of items: novel (left) or
familiar (right) in (A) postrhinal
cortex (7.80), (B) dentate gyrus (5.20),
(C) CA1 (5.20), and (D)
subiculum (5.20). Note that certain stained nuclei lie outside the
principal cell layers and hence are probably interneurons. Coronal
sections at given distances behind bregma (see also Fig. 2);
magnification, 83×; al, alveus; gr,
stratum granulosum; h, hippocampal fissure;
m, medial; py, stratum pyramidale;
v, ventral.
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Counts in the hippocampal formation were higher for pictures of
arrangements of items (20.8 ± 2.9 mm2) than for
individual items. Thus, the ratio of the counts in the hippocampal
formation to that in occipital visual association cortex (OCC) was
significantly higher (2.5 times higher) for arrangements of items than
for individual items (ratio, 0.61 ± 0.06 compared with 0.25 ± 0.04; independent t test; p < 0.01), the
counts in occipital cortex being approximately the same for both types
of pictures (34.1 ± 12.2 for arrangements and 31.0 ± 6.4 for individual items). Mean counts in other areas did not vary
significantly between the two experiments. Hence, the change in counts
was regionally specific. Many of the stained nuclei in the dentate
gyrus and the subfield CA1 of the hippocampus were located in the
principal cell body layers (stratum granulosum and stratum pyramidale), but there were some stained nuclei located outside these layers i.e.,
the activated neurons included putative interneurons (Fig. 5).
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DISCUSSION |
The results establish that pictures of novel arrangements of
familiar items produce significantly greater activation than familiar
arrangements of these items in postrhinal cortex and subfield CA1 of
the hippocampus, but significantly less activation in the dentate gyrus
and subiculum; perirhinal cortex and area TE are not differentially
activated. In contrast, perirhinal cortex and area TE of the temporal
lobe are activated significantly more by pictures of novel than of
familiar individual objects, but the hippocampus is not differentially activated.
The results of the first experiment are in agreement with previous
findings using Fos imaging for either between- or within-rat comparisons but using individual three-dimensional objects as opposed
to computer-displayed pictures (Zhu et al., 1995b, 1996). The
consistency of the Fos difference in perirhinal cortex and area TE for
novel and familiar individual items across the three experiments firmly
establishes the robustness of the findings. Moreover, the Fos results
are in accord with results of electrophysiological recordings and
ablation studies in the primate and in the rat (Brown et al., 1987;
Horel et al., 1987; Gaffan and Murray, 1992; Mumby and Pinel,
1994; Wiig and Bilkey, 1995; Zhu et al., 1995a; Ennaceur et al., 1996;
Murray, 1996; Suzuki, 1996; Aggleton et al., 1997; Brown and Xiang,
1998; Xiang and Brown, 1998; Aggleton and Brown, 1999). In particular,
novel objects or pictures of objects evoke greater neuronal responses
than do familiar objects in area TE and PRH, and such differential
responses are uncommon in the hippocampus (Riches et al., 1991; Rolls
et al., 1993; Xiang and Brown, 1998). Although Fos staining was used in
these experiments merely as a marker of neuronal activation, it is
worth noting that Fos also provides a marker for long-term depression
in the cerebellum (Nakazawa et al., 1993), another process in which
neuronal responsiveness is reduced as a result of experience.
Neuronal responses to novel and familiar arrangements of items, the
stimuli used in the second experiment, have yet to be explored in
recording experiments. Although novel pictures resulted in the
activation of more perirhinal neurons than did familiar pictures when
the pictures were of single items, no differential activation was found
when the pictures were of arrangements of items. This contrast is
explicable because all the individual items in the arrangements were
equally familiar. In contrast, a significant difference was observed in
PoRH for novel and familiar arrangements, although not for novel and
familiar single items. This finding is in accord with the idea that
postrhinal cortex in the rat is concerned with processing spatial
information and is consistent with the suggestion that rat postrhinal
cortex has homologies with areas TF and TH of the parahippocampal
cortex in the monkey (Burwell et al., 1995). Regions that process
spatial information project heavily to this parahippocampal cortex in the monkey (Burwell et al., 1995).
These results help to resolve an apparent conflict over the
contribution of the hippocampus to recognition memory by establishing that its involvement is dependent on the form of what has to be recognized. Thus, they add to evidence that the hippocampus is not
critical for recognition memory judgments of the relative familiarity
of individual items (Aggleton and Shaw, 1996; Ennaceur et al., 1996,
1997; Murray, 1996; Murray and Mishkin, 1998; but see Alvarez et al.,
1995). However, they establish that the hippocampus is importantly
involved in discriminating the relative familiarity of spatial
arrangements of items. Memory for such spatial arrangements is an
important aspect of episodic memory in which whether a particular scene, i.e., a particular arrangement of items, has been encountered before needs to be determined, especially if many of the individual items have been seen before but their particular configuration is
novel. Thus, recognition memory tasks that can be readily solved by
discriminating the relative familiarity of individual items, whether in
isolation or as part of a scene, would not require the hippocampus, in
agreement with previous animal lesion studies. However, the hippocampus
would provide an important contribution to recognition memory in more
complex, everyday life situations in which the memory is for an
environment or recognition is assisted by recollection of the original
episode (Brown, 1990; Gaffan, 1991, 1994; Ennaceur et al., 1996, 1997;
Gaffan and Parker, 1996; Murray, 1996; Murray and Mishkin, 1998; Nadel
and Moscovitch, 1997; Brown and Xiang, 1998; Aggleton and Brown, 1999).
In support of this view, previous evidence, both from recording and
from recent functional imaging studies, has indicated the importance of
spatial and other associational information to the responsiveness of
hippocampal neurons (O'Keefe and Nadel, 1978; Eichenbaum et al., 1994,
1996; Wiener, 1996; Maguire, 1997). It is worth noting that for human
subjects performing memory tasks it would seem normal for the subjects
to make spatial and other associative links (including attaching verbal
labels) involving the presented material whatever the nature of the material.
Importantly, our findings demonstrate that one subregion of the
hippocampal formation can be activated in the opposite way to other
subregions: subfield CA1 showed greater activation for novel than
familiar arrangements, whereas the dentate gyrus and subiculum showed
more activation for familiar than for novel arrangements. These
opposing changes could be explained by the influence of inhibitory
interneurons as such information passes from one subregion to the next
through the hippocampal formation. Consistent with this idea is the
discovery of stained nuclei outside the principal cell layers,
suggesting that at least some of the activated neurons are indeed
interneurons (Fig. 5B). In agreement with this finding of
opposite changes in different subregions of the hippocampal formation
is a recent brief report indicating that neurons in subfield CA1
respond more vigorously in a novel environment than in a familiar
environment, whereas neurons in the dentate gyrus do the converse (Nitz
et al., 1997). Different c-fos mRNA levels in hippocampal subfield CA1
compared with CA3 and the dentate gyrus have also been observed during
exploration and odor discrimination learning (Hess et al., 1995a,b). A
further possibility is that the differential activation is related to
differences in processing between the dorsal and ventral hippocampal
formation: lesion and electrophysiological studies have indicated that
the dorsal hippocampal formation is more important than the ventral for
spatial learning (Jung et al., 1994; Moser et al., 1995). However,
although in the present study the sampled part of CA1 was dorsal,
whereas that of the dentate gyrus was ventral, the ventral as well as the dorsal sample were differentially activated (the effect being opposite in the two areas). Should such differential hippocampal activation occur in the human brain, it will be important that human
functional imaging studies have a resolution sufficient to
differentiate between hippocampal subregions, because a global hippocampal average may not show a net difference. Accordingly, such
subregion differences provide yet another possible reason for failures
of functional imaging to detect significant hippocampal changes during
memory tasks (Nyberg et al., 1996; Maguire, 1997; Tulving and
Markowitsch, 1997).
The findings of the present study provide a clear demonstration of the
different contributions to recognition memory of the hippocampal
formation and perirhinal cortex. The role of perirhinal cortex is in
judgment of the relative familiarity of an individual item. The role of
the hippocampus is in judgment of the relative familiarity of an
arrangement of items. This latter capacity is necessary for episodic
memory for complex events involving relationships among many individual
items, and our findings establish an essential function for the
hippocampus in such memory.
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FOOTNOTES |
Received Aug. 6, 1998; revised Nov. 16, 1998; accepted Nov. 19, 1998.
This work was supported by the Medical Research Council. We thank Dr.
D. Hancock, Biochemistry of the Cell Nucleus Laboratory, Imperial
Cancer Research Institute for supplying the primary antibody, and L. Ni, A. Griffiths, and J. Leendertz for technical assistance.
Correspondence should be addressed to Dr. M. W. Brown, Department
of Anatomy, University of Bristol, Medical School, Bristol, BS8 1TD, UK.
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Top
Abstract
Introduction
