Neuropharmacology 37 (1998) 657 – 676
Differential neuronal encoding of novelty, familiarity and recency
in regions of the anterior temporal lobe
J.-Z. Xiang, M.W. Brown *
Department of Anatomy, Uni6ersity of Bristol, Bristol BS8 1TD, UK
Accepted 25 February 1998
Abstract
Activity of 2072 neurones was recorded in the anterior temporal lobe — in area TE, perirhinal cortex, entorhinal cortex and
hippocampus—during performance of a visual recognition task by monkeys. In area TE, perirhinal cortex and entorhinal cortex,
454 neurones (38% of the 1162 visually responsive neurones) responded differentially on the basis of the relative familiarity or
recency of presentation of the stimuli; in the hippocampus only one (3% of its 40 visually responsive neurones) did so. The
differentially responsive neurones were classified into those signalling information concerning the recency (19%), familiarity (37%)
or novelty (38%) of stimuli. For 98% of these neurones a decreased response signalled that stimuli had occurred previously: no
large response increments were observed. The mean differential latency of each of these types of neurone was shorter ( 75 ms)
in area TE than in the other areas. Examples of each of these types of neurone with memory spans of 24 h were found in each
region. The mean memory span of recency neurones was significantly longer in perirhinal cortex than area TE. For familiarity
neurones a significant mean response decrement took 4– 8 min to develop, indicating a slow underlying plastic change, in contrast
to the rapid change seen for recency and novelty neurones. The implications of these results are discussed in relation to the
neuronal basis of recognition memory. © 1998 Elsevier Science Ltd. All rights reserved.
Keywords: Memory; Recognition memory; Visual response; Perirhinal cortex; Hippocampus; Inferior temporal cortex
1. Introduction
Cooling and ablation studies have established that
the perirhinal cortex within the anterior temporal lobe
of monkeys is essential for visual recognition memory
(Horel et al., 1987; Gaffan and Murray, 1992; Meunier
et al., 1993; Suzuki et al., 1993; Eacott et al., 1994;
Meunier et al., 1996; Murray, 1996). Electrophysiological recordings from single neurones in behaviourally
trained monkeys have demonstrated that certain neurones in perirhinal and adjacent cortex signal information of potential importance to recognition memory
concerning the prior occurrence of visual stimuli
(Brown et al., 1987; Riches et al., 1991; Eskandar et al.,
1992; Fahy et al., 1993; Li et al., 1993; Miller et al.,
1993; Sobotka and Ringo, 1993; Miller and Desimone,
1994; Brown, 1996; Brown and Xiang, 1998). Indeed, it
has been established (Fahy et al., 1993) that there is
* Corresponding author. Tel.: + 44 117 9287408; fax: + 44 117
9291687; e-mail: [email protected].
0028-3908/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0028-3908(98)00030-6
separable neuronal encoding of information concerning
a stimulus’s relative familiarity (whether a stimulus is
unfamiliar or highly familiar) and recency of occurrence
(whether or not a stimulus was last encountered recently). Thus the responses of recency neurones encode
whether or not a particular stimulus has been seen
recently regardless of whether it is relatively familiar or
is unfamiliar. In contrast, the responses of familiarity
neurones encode whether a particular stimulus is highly
familiar or relatively unfamiliar whether or not the
stimulus has been seen recently (Fahy et al., 1993).
Nevertheless, relatively little is known of the properties of these neurones with responses that encode information concerning the prior occurrence of stimuli.
Importantly, although a few examples of neurones
whose responses demonstrate that they have access to
information held in memory for a period (the memory
span) of more than 24 h, it is not known whether such
neurones are common or rare. Do such neurones include recency neurones as well as familiarity neurones?
Are there other categories of neuronal response sig-
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J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
nalling information of potential use to recognition
memory? This is possible because not all neurones that
changed response when stimuli were repeated could be
categorised as recency or familiarity neurones in the
study of Fahy et al. (1993). Moreover, that study did
not explore the responses of neurones to familiar stimuli across different delays during performance of a
serial recognition memory task, nor did it explore how
the responses of familiarity neurones developed as stimuli became familiar through being shown repeatedly.
This study set out to provide information on these
issues. Characteristically, signalling that a stimulus is
familiar or has been seen recently is by a reduction in
the neurone’s response compared to that to the first
presentation of a novel stimulus. Previous studies have
suggested that increments rather than such decrements
in neuronal responses are rare (Riches et al., 1991;
Fahy et al., 1993; Miller et al., 1993; Sobotka and
Ringo, 1993). In the present study particular attention
was paid to this matter because of its importance to
theories of the generation of new representations
(Amari, 1989; Rolls, 1995).
Another incompletely explored topic concerns the
location and extent of the anatomical distribution of
the neurones signalling the prior occurrence of stimuli
within the anterior and medial temporal lobe. In particular, are there differences in the incidence or properties
of such neurones in area TE of the anterior inferior
temporal cortex compared to those in the perirhinal
cortex? Are such neurones also common in entorhinal
cortex or is their distribution more limited, as previously suggested (Fahy et al., 1993)? Further, there is
controversy concerning the incidence of such neurones
in the hippocampus. Claims (Brown et al., 1987; Riches
et al., 1991) that such neurones are not to be found in
the hippocampus have been challenged (Rolls et al.,
1989, 1993). It was therefore decided to compare the
incidence of such neurones in the rhinal cortices and
area TE with that in the hippocampus, using the same
stimuli within the same experiment.
This study used a serial recognition memory task
(Gaffan, 1974) as this task requires an animal to remember the occurrence of more than one stimulus at a
time even when these stimuli may not re-occur until
many other stimuli have been seen. Thus this task does
not allow the use of attentive or short-term memory
mechanisms for its solution. Certain findings of this
study have been published in abstract form (Xiang and
Brown, 1997a).
2. Materials and methods
2.1. Subjects
Data were obtained from two monkeys (Macaca
mulatta) weighing 7 and 9 kg. Procedures were performed in accordance with the UK Home Office Licensing regulations and animal welfare was overseen by
a veterinary officer. Many methodological details have
been published previously (Fahy et al., 1993) and will
be mentioned only briefly here.
2.2. Beha6ioural training
The behavioural tasks were of two types: serial recognition and conditional visual discrimination. During
training and recording sessions the animal was seated in
a primate chair in an illuminated light-proof, sound-attenuating cubicle. A video monitor (20× 27 cm) was
placed 22 cm in front of the animal. A touch screen
(Microvitec), modified to give an enhanced speed for
detecting responses, was fixed in front of the monitor.
Once trained, the animals performed the tasks at
greater than 90% accuracy for more than 1000 trials per
day.
For the serial recognition task (Gaffan, 1974) the
animal was taught to discriminate novel or unfamiliar
stimuli from familiar or recently seen stimuli. A single
stimulus (picture) appeared on each trial. When a stimulus appeared on the screen, the correct behavioural
response was a left touch for a novel stimulus and a
right touch for its repetition or a familiar stimulus.
Each trial (Fig. 1) started with a cueing light (1.5 s, C),
a dim red neon bulb situated centrally at the top of the
screen. After the cueing light had been on for 1 s, a
picture (S) filling the screen was shown for 2 s. Touches
(T) to the correct side between 0.5 and 2.5 s following
the onset of the stimulus were rewarded with approximately 0.3 ml fruit juice (R). Other responses were
counted as errors and the lights in the cubicle were
dimmed for 3 s. Successive trials were separated by a
randomly variable interval of 3–5 s. A computer (Viglen 486 PC) initiated the sequences, controlled a
videodisk player (Lasermax LDP1500, Sony) and governed all the other features of the behavioural tasks.
The synchronised pulses of the various video signals
Fig. 1. Trial events. C: cue light on; S: stimulus on; T: the period
within which a behavioural response is required; R: reward. The
reward was given as soon as a correct response was made. The
dashed lines before and after the trial indicate the intertrial interval
(3 – 5 s).
J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
659
for control purposes and will be reported only briefly,
as pertinent. For this task a stimulus was one of four
geometric triplets (Fig. 2). The task involved a conditional rule in that whether a touch to the triangle or the
square was correct depended on the orientation of the
central shape. The task employed the same stimulus
presentation timings and behavioural responses as the
serial recognition task. Different types of trial were
arranged into pseudorandom sequences of 40–120 trials in length.
Fig. 2. Details of the behavioural tasks. A. Serial recognition memory
task using pictures of naturalistic scenes or objects. S1– S3 are
examples of different types of sequences of trials. Each letter represents a particular picture; in S1 the upper-case letters are novel
stimuli and the lower-case letters familiar stimuli. Sequence types S2
and 3 contained repeats of the same novel (S2) or different novel (S3)
stimuli. B. Conditional visual discrimination task using triplets of
geometric shapes. For each of the four types of trial containing a
specific triplet, the animals needed to touch the left (L) or right (R)
side of the screen as indicated to get a reward.
were all locked to each other, and the display on an
video monitor (Cub 653, Microvitec) was gated on and
off by a video switch, so that the pictures were presented as complete still frames starting at a known
time.
The stimuli were complex, videodisk pictures of abstract or naturalistic scenes from commercially available videodisks, or digitised images of 3-dimensional
objects, pre-selected for salience. A subset of over 40
pictures (familiar stimuli) were shown to the animal
each day so that they were highly familiar to the
animal. Other pictures (novel stimuli) were used only
twice a day and not again for at least 2 months; some
pictures had been encountered rarely if at all by the
animal. In a sequence, various numbers of other novel
and highly familiar stimuli intervened between the first
and the subsequent appearances of each particular
stimulus. Several different pseudorandomly balanced
sequences of 40–120 trials’ length were used so that the
animal could not predict what would appear on any
given trial (Fig. 2). Sequences (S1) were constructed so
that the repetition of a novel stimulus occurred after 0,
2, 4, 8, 16, 32 or 64 intervening trials. On some trials
stimuli seen the preceding day were re-shown so as to
investigate memory storage over even longer intervals
( 24 h). Two other types of sequence were also used.
To explore further the effects of stimulus repetition, in
sequences of type S2 the same novel stimulus was
shown on up to five successive trials before another
novel stimulus appeared. In sequences of type S3 the
first and second presentations of a novel stimulus were
separated by trials on which one to four other novel
stimuli were presented.
The conditional visual discrimination task was used
2.3. Neuronal recording
When an animal could perform the behavioural tasks
at over 90% correct, it was anaesthetised and prepared
for neuronal recording using aseptic techniques (Fahy
et al., 1993). Postoperative analgesia was provided by
buprenorphine. Two weeks were allowed for recovery
before recording commenced. Neuronal activity was
recorded through a moveable microelectrode (Elgiloy
0.228 mm in diameter). The amplification, monitoring
and display of neuronal potentials were conventional.
At the start of recording from each new site, a few
video pictures were shown to the animal as a means of
screening for visual responsiveness, using audio monitoring. Only sites that were judged by this means to be
visually responsive were further investigated. The activity of simultaneously recorded single neurons was analogue-to-digital converted (at 17 kHz) and
discriminated from multi-neuronal activity by on-line
spike-sorting software (1401 Plus interface and Spike2,
CED, Cambridge) using a template-matching algorithm
(see Zhu et al., 1995; Nicol et al., 1998). Up to eight
separable spike trains could be recorded at the same
time. Peristimulus-time histograms, rasters and counts
of action potentials for the separated spike trains were
displayed on-line and were stored in the computer for
further, off-line analysis. The animal’s hand and eye
movements were monitored using a video camera and
were stored on video tape together with the stimulus
presentations using a video mixer (Videomat VM2E).
Eye position was subsequently determined by measuring pupil position at 200 ms intervals from stimulus
onset and converted into direction of gaze relative to
the centre of the screen. The animals maintained their
fixation during the period when the data were collected
and there was no consistent change in saccadic eye
movements preceding or at the onset of the presentations of the stimuli.
2.4. Data analysis
All neurones recorded for at least one sequence of
trials were subjected to analysis. Analyses used only
data from correctly performed trials; those on which
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J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
the animal failed to fixate on the stimuli or made errors
were excluded. There were too few error trials for these
to be statistically analysed. Each neurone was first
analysed to determine whether it was visually responsive. The mean firing rate in the 0.5 s immediately
following stimulus onset was compared to that during
the 3 s period before cue onset for each trial. Visually
responsive neurones were those for which the mean
change in firing rate across all the trials for which the
neurone was recorded was significant (paired t-test,
P B0.05). These neurones were further analysed to
determine whether they responded differentially to the
different categories of visual stimuli. An analysis of
variance (ANOVA, P B 0.05) with factors repeat (first
or subsequent presentation), relative familiarity (novel
or familiar stimulus) and period (time period after
stimulus onset) was performed across all trials on the
change in firing rate from that in the 3 s pre-cue period
to that in the two 0.25 s periods immediately following
stimulus onset on each trial. Neurones for which the
interaction between the factors repeat and relative familiarity was significant, or for which both factors were
significant, and for which the response to the first
presentations of novel stimuli differed significantly from
their second presentations and from first or second
presentations of familiar stimuli were categorised as
novelty neurones. Neurones for which the factor repeat,
but not the factor relative familiarity nor the interaction between the two factors was significant were categorised as recency neurones. Neurones for which the
factor relative familiarity, but not the factor repeat nor
the interaction between the two factors was significant
were categorised as familiarity neurones. Neurones for
which there was a significant interaction between period
and repeat or period and relative familiarity were categorised as recency or familiarity neurones respectively.
Neurones for which there was a significant three-way
interaction between period, repeat and relative familiarity were categorised as differentially responsive but
were not counted as belonging to any of these types:
their numbers were not large (B7%). Differences in
incidence of different categories of responsive neurones
in different areas were established using two-way
ANOVA based on a generalised linear model (GLIM)
assuming a binomial error distribution (Baker and
Nelder, 1978; Aitkin et al., 1989). The variations (deviances) associated with the factors monkey, area, and
hemisphere were determined and are given as BEM x 2
values. For every analysis the residual deviance was less
than that expected by chance, i.e. the model gave an
adequate fit to the data. The different characteristics of
the different types of neuronal responses (latencies,
memory spans) across the different areas were analysed
by analyses of variance with repeat measures (Systat for
Windows: Statistics, Version 5, Systat, Evanston, IL).
These analyses included the factors: animal, area, type
(recency, novelty or familiarity neurone), and time or
interval. The factors time and interval and any interactions involving them were treated as within neurone
(repeated) measures, other factors and interactions as
between neurone measures. As appropriate, time or
interval was treated as a covariate (unless otherwise
stated by using the rank order rather than the absolute
values). Only results that were consistent across monkeys are reported. All tests were two-tailed and used a
significance level of P = 0.05. Probability values for
repeated measures analyses of variance were adjusted
for any failures of compound symmetry by using the
more conservative values based on Huynh-Feldt statistics (Systat).
2.5. Histological localisation
The depth of each neurone was noted at the time of
its recording. At the end of certain recordings microlesions were made by passing a DC current (10–60 mA
for 15–30 s) through the microelectrode at known
positions near responsive cells. Anterior-posterior and
lateral X-ray photographs were taken at the end of each
electrode penetration to show the position of the electrode in situ in relation to both skull landmarks and
fixed reference electrodes. Perfusion and histological
processing of the brain were by standard techniques.
Coronal sections were cut at 50 mm on a freezing
microtome and were stained with cresyl violet. The
microlesions were identified by the Prussian blue reaction. Using this information the positions of the
recorded neurones were marked onto line-drawings of
brain coronal sections (every 1 mm apart); corrections
were made for X-ray expansion and tissue shrinkage.
The boundaries of the various areas followed Lorente
de Nó (1934) and Burwell et al. (1995).
3. Results
3.1. Visual responsi6eness in the serial recognition task
Neurones were recorded between A22 and A8
(Snider and Lee, 1963; see also Fig. 3) in four hemispheres of two monkeys from the entorhinal and
perirhinal cortices, area TE of inferior temporal cortex,
and the ‘hippocampus’ (i.e. chiefly from subfield CA3,
the dentate gyrus and the subiculum), during the performance of the behavioural tasks. The monkeys used
both hands to touch the response screen and no obvious preference for hand usage was observed. No differences in responsiveness between the right and left
hemispheres were found. Results from left and right
hemispheres have therefore been combined.
Of 2072 neurones recorded during the serial recognition task, 1162 (57%) were visually responsive (Table
J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
661
Fig. 3. The locations of the differentially responsive neurones. A. A lateral view of a macaque brain. The distances are numbered posterior (P)
to the outline of the sphenoid bone (Aggleton and Passingham, 1981), which is approximately 20 mm anterior to the interaural line. B. A line
drawing of coronal section at level 4P indicating brain regions. amts: anterior medial tempral sulcus; rhs: rhinal sulcus: sts: superior temporal
sulcus. C. Drawings of sections at levels indicated in A. The locations of the recency (
), familiarity (), and novelty (“) neurones are shown
in the left, middle and right columns respectively.
1). However, in the rhinal cortices and area TE the
proportion of the neurones that were visually responsive was significantly higher than in the hippocampus
(63% c.f. 14%); see Table 1 and legend for details.
There was no significant difference between the proportions of visually responsive neurones found in area TE,
perirhinal cortex and entorhinal cortex. In these three
areas all responses were excitatory. Across the population of visually responsive neurones in these three areas,
the mean firing rate in the 0.5 s following stimulus
onset was more than twice (2.259 0.07) that during the
pre-cue period. In the hippocampus the mean response
was significantly smaller (mean change in firing rate
1.709 0.25). Responses of individual neurones were not
the same for all the tested stimuli, but the reported
results are independent of this aspect of the neurones’
responsiveness and it will not be further considered in
this paper.
3.2. Incidence of differential responses
Stimuli seen many times previously by the animal will
be termed familiar. Stimuli that have been seen infrequently if at all at the start of a particular recording
session will be termed novel, even when such stimuli are
shown for a second time in a particular session. A total
of 455 neurones (39% of the 1162 visually responsive
neurones) responded differently depending on the relative familiarity or repetition of stimuli. The locations of
these neurones are illustrated in Fig. 3.
The incidence of such differentially responsive neurones was very much lower in the hippocampus than in
the remaining three regions (3% c.f. 38%; see Table 1
legend for details); indeed, the hippocampal incidence
might be explained by chance (expected mean chance
incidence 5%; significance of change for single differential hippocampal neurone: P = 0.04). There was no
significant difference in the incidence of such neurones
between area TE, the perirhinal cortex and the entorhinal cortex. As only one such neurone was found in the
hippocampus the remaining analyses concentrate on
neurones in the other three areas.
Almost all the response changes were in the direction
that the response to familiar stimuli compared to novel
stimuli or to second presentations compared to first
presentations entailed a respose reduction. Only eight
(1%) of 1122 visually responsive neurones (2% of the
454 differential neurones) in rhinal cortex and area TE
showed increased activity and none of these increases
was significant at the 1% level. Thus the incidence of
response increments is significantly (binomial test, P=
0.0002) less than would be expected by chance (5%) and
there are no neurones in this large sample that had very
large increases in response.
26
41
18
0
85
5
4
5
4
9
7
9
7
38
87
42
1
168
14
13
14
20
D/V (%)
8
8
9
12
D/T (%)
49
91
31
0
171
D (n)
15
17
15
15
D/V (%)
D/T (%)
8
10
10
9
123
234
97
1
455
D (n)
D/V (%)
D/T (%)
39
42
38
46
22
26
25
28
201
622
209
40
1162
D (n)
D/T (%)
D (n)
D/V (%)
V(n)
Subtotal
Familiarity
Recency
Novelty
Visual
Visual-differential
61
67
61
14
57
V/T (%)
477
923
344
283
2027
T(n)
Total
D, differentially responsive neurones; V, visually responsive neurones; T, total neurones recorded; n, number of neurones.
The incidence of visually responsive neurones (V) differed significantly between the four regions (BEM x 2 =467.1, df = 3, PB0.0001). In particular the incidence was significantly lower in the
hippocampus than in the other three regions (BEM x 2 = 442.6, df =1, PB0.0001), but incidence did not differ significantly amongst the other three regions. Also the magnitude of the mean
response was significantly lower in the hippocampus than that for the other areas (independent t-test with non-equal variance: t58 = 2.39, P= 0.03). Similarly, the incidence of differentially
responsive neurones (D) as a proportion of visually responsive neurones (V) differed significantly between the regions (BEM x 2 =29.0, df = 3, PB0.001). In particular it was significantly lower
in the hippocampus than in the other three regions (BEM x 2 = 28.7, df =1; PB0.001), but did not differ significantly amongst the other three regions. The incidence of differentially responsive
neurones in each of these three regions (though not in the hippocampus) was significantly (binomial test, PB0.001) above chance (5%).
Regions
Entorhinal cortex
Perirhinal cortex
Area TE
Hippocampus
Total
Responses:
Table 1
Incidence of recognition-related visual responses in the rhinal cortices, area TE and the hippocampus
662
J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
26
41
18
85
Regions:
Entorhinal cortex
Perirhinal cortex
Area TE
Total
5.7 91.0
3.9 90.4
5.2 9 0.5
4.6 90.4
First
2.790.7a
2.0 9 0.3a
2.19 0.5a
2.290.4a
Repeat
53
49
60
52
%
38
87
42
167
n
4.7 90.6
3.6 90.6
4.6 9 0.5
4.1 90.4
Novel
Familiarity
2.9 9 0.7b
2.3 90.4b
2.4 9 0.8b
2.5 9 0.4b
Familiar
38
36
48
39
%
49
91
31
171
n
4.7 9 0.7
3.3 9 0.4
3.6 9 0.7
3.8 9 0.3
N1
Novelty
1.59 0.3cd
1.3 9 0.3cd
1.3 9 0.3cd
1.3 90.2cd
N2
68
61
64
66
%
2.69 0.3c
2.39 0.3c
2.59 0.5c
2.49 0.2c
F1
45
30
31
37
%
2.49 0.4c
2.29 0.4c
2.2 9 0.3c
2.39 0.2c
F2
49
33
39
39
%
Data are shown as the ratio of the firing rate (mean9 S.E.M.) in the post-stimulus period (0.5 s) compared to that (1.0) in the pre-cue period (3 s). Also shown is the mean percentage (%) change
in response from that for novel first stimuli to that for the other types of stimuli.
N1, novel first; N2, novel repeat; F1, familiar first; F2, familiar repeat; n, numbers of the visual differential neurones recorded in the region.
Superscript letters refer to comparisons between response magnitudes (paired t-tests, PB0.01).
a
Recency neurones, first versus repeat.
b
Familiarity neurones, novel versus familiar.
c
Novelty neurones, N1 versus N2, F1 or F2.
d
N2 versus F1 or F2.
n
Recency
Types of visual stimuli:
Types of neurone:
Table 2
Population analyses of the neuronal responses to visual stimuli in the rhinal cortices and area TE
J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
663
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Fig. 3. The locations of the differentially responsive neurones. Top left: a lateral view of a macaque brain. The distances are numbered posterior
(P) to outline of the sphenoid bone (Aggleton and Passingham, 1981), which is approximately 20 mm anterior to the interaural line. Right: line
drawings of representative coronal sections taken at levels indicated by vertical lines on the lateral view. The locations of the recency (
),
familiarity (), and novelty (“) neurones are shown in columns A, B and C, respectively. amts: anterior medial temporal sulcus; rhs: rhinal sulcus;
sts: superior temporal sulcus.
Most (93%) of the 454 differentially responsive neurones could be classified as differing significantly (analysis of variance) in response depending on: the recency
of presentation but not the relative familiarity of stimuli (recency neurones; see e.g. Fig. 4); the relative
familiarity of stimuli but not their recency of presentation (familiarity neurones; see e.g. Fig. 5); or both
recency and familiarity information such that the response to the first presentations of novel stimuli differed from the response to their second presentations or
to the response to familiar stimuli (novelty neurones;
see e.g. Fig. 6). There were 85 (19% of the differentially
responsive neurones) recency neurones, 167 (37%) familiarity neurones, and 171 (38%) novelty neurones.
See Fig. 3 for the locations of these neurones. The
incidence of these different types of neurone did not
vary significantly between the three areas.
Population analyses of the mean changes in firing
rate on presentation of stimuli on the different types of
trial for the three different types of neurone are given in
Table 2. The mean response decrement on stimulus
repetition is 52% for recency neurones. Mean responses
to familiar stimuli are 39% less than those to novel
stimuli for familiarity neurones. For novelty neurones
the mean decrement on repetition of a novel stimulus is
66% while presentations of familiar stimuli evoke a
response 37% less than that to the first presentations of
novel stimuli. Typically, the response of novelty neurones reduced in magnitude when a novel stimulus was
repeated while, in contrast, the duration of the response
for familiar stimuli was much shorter ( B 1 s for all 171
neurones andB200 ms for 58 of them) than for novel
stimuli (2 s); see e.g. Fig. 6. As a population, novelty
neurones displayed no significant mean response decrement on the repetition of familiar stimuli. For details of
the mean decrements for the three types of neurone
across the three regions see Table 2.
3.3. Differential latencies
The mean latency to respond to stimuli for the
populations of the different types of differentially responsive neurones was analysed for the different types
of trials; see Fig. 7 and Table 3 and legends for
statistical details. For each type of neurone, the shortest
mean differential latency ( 75 ms) for the populations
was found in area TE. The corresponding latencies in
perirhinal cortex were longer at 105 ms for recency
neurones and 135 ms for familiarity neurones. They
were longer again in entorhinal cortex (Table 3). For
novelty neurones the mean perirhinal latency for novel
first versus novel second trials was 105 ms, but for
J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
665
Fig. 5. Responses of a familiarity neurone to visual stimuli during the serial recognition task. The neuronal responses to novel (left) and familiar
(right) stimuli were shown as peristimulus histograms above rasters (conventions as for Fig. 4). Note that the responses to the novel stimuli were
significantly larger in magnitude than to the familiar stimuli regardless of whether the stimulus was appearing for the first or second time in that
session, i.e. the response signalled the relative familiarity of the stimulus but not whether it had been seen recently.
novel first versus familiar first trials it was the same as
in area TE ( 75 ms); the entorhinal latency was longer
( 135 ms) in each case. Thus on average across the
recorded populations, changes for recency and familiarity neurones occurred earlier in area TE than in perirhinal cortex or entorhinal cortex. Accordingly, these data
raise the possibility that the corresponding changes in
rhinal cortex might be passive reflections of changes
transmitted from area TE. For the population of novelty neurones information concerning the familiarity of
stimuli was available in perirhinal cortex as early as in
area TE; however, information concerning the recency
of presentation of novel stimuli was available earlier in
area TE than in perirhinal cortex.
3.4. Length of memory
The memory span of a neurone may be defined as the
longest interval following initial presentation of stimuli
for which re-presentation of the stimuli results in a
significant change in activity (Fahy et al., 1993). Mean
memory spans were compared for the three different
types of differentially responsive neurone in the three
different regions (area TE, perirhinal and entorhinal
cortex). The responses of differentially responsive neurones recorded during task sequence S1 were averaged
for first presentations of novel stimuli and for their
repeat presentations after differing numbers of inter-
vening trials. Population means for the three different
types of differentially responsive neurones in the three
different areas were constructed; see Fig. 8 and legend
for details. As may be anticipated from Fig. 8, the
pattern of response decrement across the intervals differed significantly for the different types of neurone
(analysis of variance with repeat measures: interval by
type interaction: F16,1144 = 5.46; P B 0.001). The patterns of response decrement for each of the types of
neurone were therefore analysed separately.
For the recency neurones the response pattern in the
three regions differed significantly (Fig. 8 and legend).
The average population response showed decrements in
response that reduced at different rates as the time
between the first and subsequent presentations increased. In particular, in perirhinal cortex the population memory span was greater than it was in area TE:
the response decrement was significantly greater in
perirhinal cortex than in area TE at all intervals ]16
intervening trials (2–4 min). There was no overall
significant difference in the population response decrements between entorhinal cortex and either perirhinal
cortex or area TE. The population response decrement
was still significant at 24 h in perirhinal cortex, but not
in either entorhinal cortex or area TE. However, it
should be noted that there were individual examples of
neurones with memory spans of 24 h in all three areas,
though they were far more common in perirhinal cortex
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Fig. 6. Responses of a novelty neurone to visual stimuli during the serial recognition task. The neuronal responses to the first (top) and second
(bottom) presentations of novel (left) and familiar (right) stimuli were shown as peristimulus histograms above rasters (conventions as for Fig. 4).
Note that the firing rate was significantly smaller to the second presentations than to the first presentations of novel stimuli, whereas the maximum
firing rate was only slightly less but the firing duration was greatly shortened for presentations of familiar stimuli. Thus this neurone responded
best to first presentations of novel stimuli and its responses signalled both the relative familiarity of a stimulus and whether it had been seen
recently.
than in the other areas. Thus memory spans of 24 h
were found for 2/13 (15%) recency neurones in area
TE, 15/19 (79%) in perirhinal cortex and 3/11 (27%)
in entorhinal cortex.
For the novelty neurones there was no consistent
difference between the response pattern in the three
regions. Thus these data did not differentiate between the responses of novelty neurones in area TE,
perirhinal cortex and entorhinal cortex. The average
population response across the three regions showed
reducing decrements in response as the time between
the first and subsequent presentations increased, i.e.
memory decreased with the passage of time for these
neurones. Significant decrements in response were
found at all intervals from 0 to 64 intervening trials,
but not at 24 h. Although the mean memory span
for the whole population of recorded novelty neurones was less than 24 h. It should not be concluded
that this restricted memory span applied to all such
neurones. Thus memory spans of 24 h were found
for 1/16 (6%) novelty neurones in area TE, 3/17
(18%) in perirhinal cortex and 6/24 (25%) in entorhinal cortex. Moreover, Fig. 9 illustrates the large
mean response decrement at 24 h for the half of the
population (28/57) of novelty neurones with the
largest response decrements at 24 h.
For the familiarity neurones there was no consistent difference between the response pattern in the
three regions. Thus these data did not differentiate
between the responses of familiarity neurones in area
TE, perirhinal cortex and entorhinal cortex. The average population response across the three regions
showed a significant monotonic decrease with increasing interval (Fig. 8 and legend). Thus the response decrement increased, i.e. memory increased,
with the passage of time, being greatest at 24 h. The
decrement in response between first and second presentations was first significant after 32 intervening
trials (4–8 min), being also significant after 64 trials
and 24 h. This result indicates that a single presentation of a stimulus after 4–8 min and two presentations of a stimulus after an interval of one day are
sufficient for the population of familiarity neurones
to respond as though these stimuli were familiar
rather than novel.
Individual examples of familiarity neurones with
memory spans of 24 h were common in all three
areas. Thus memory spans of 24 h were found for
19/21 (90%) neurones in area TE, 22/23 (96%) in
perirhinal cortex and 14/16 (87%) in entorhinal cortex.
J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
667
Fig. 7. Differential latencies of the populations of recency, familiarity and novelty neurones in the entorhinal and perirhinal cortices and area TE.
Plotted are the cumulated counts (30 ms bins, but smoothed for clarity) of action potentials from stimulus onset (time zero) for the different types
of trial. The latencies were calculated only for the sample of differentially responsive neurones recorded for more than 50 trials. Statistical details:
The mean latency to respond to stimuli for the populations of the different types of differentially responsive neurones was analysed by subjecting
the cumulative spike counts from the time of stimulus onset for each neurone in successive 30 ms epochs for each of the different types of trials
to an analysis of variance with repeat measures: there was a significant interaction between the factors for area, type of neurone and type of trial
(F6,662 = 5.27; PB 0.001), and no significant interaction involving the factor for animals. The data for each type of neurone was therefore analysed
separately for each area. The differences in cumulative counts between first and second presentations for recency neurones, between novel and
familiar stimuli for familiarity neurones, and for both these types of trial for novelty neurones were analysed for successive time bins after stimulus
onset across the populations of neurones. The mean time of the earliest bin for which the difference was significant (t-tests, P B 0.05) was taken
as the mean latency for the population of neurones. In every case all subsequent bins were also significant. Moreover, the change for the 60–89
ms bin differed significantly between area TE and perirhinal cortex, except for novel first vs. familiar first trials for novelty neurones (see also
Table 3).
3.5. Multiple repetitions of stimuli
In sequence type S2 initially novel stimuli were repeated up to five times on successive trials (i.e. within a
period of B 2 min). As illustrated in Fig. 10, such
repetition resulted in only a small, non-significant reduction in the mean response of the whole population
of familiarity neurones. Thus multiple repetitions of an
initially novel stimulus do not result in the rapid development of a response decrement in a population of
familiarity neurones. For recency and novelty neurones
there was an immediate and highly significant response
decrement for the second appearance. Unexpectedly,
this decrement did not become greater with further
repetition. There were no significant differences between the three areas in these results. No change in
mean response across the recorded populations was
found when five different novel stimuli were presented
on five successive trials (sequence type S3).
3.6. Multiple differential recordings
More than one differentially responsive neurone or a
differentially responsive and a non-differentially responsive neurone were recorded simultaneously on
many occasions (e.g. a triplet of a novelty, a familiarity
and a recency neurone on eight occasions; a pair of
differently differential neurones on 46 occasions); see
for example Fig. 11. Such differences in patterns of
response to the same stimuli for simultaneously
recorded neurones exclude generalised modulations in
arousal or attention or peripheral visual changes as
explanations for their response differences.
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J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
Table 3
Mean differential latencies (ms) by area and response type
Recency
First versus second
Familiarity
Novel versus familiar
Novelty
Novel first versus novel second
Novel first versus familiar first
Area TE
Perirhinal cortex
Entorhinal cortex
75
105
135
75
135
225
75
75
105
75
135
135
The values are times (in ms) from stimulus onset to the mean of the first bin for which there was a significant difference between the types of trial
in a given area for a given type of neuronal response. The width of the bins was 30 ms. The mean difference in counts (expressed as the normalised
% change for each neurone) between the types of trial for the 60 – 89 ms bin in area TE was compared (independent t-tests for groups with unequal
variance) to the corresponding mean difference in perirhinal cortex for each type of response: recency neurones, t41 =2.61, P =0.013; familiarity
neurones t60 =7.47, PB0.001; novelty neurones-N1 versus N2-t40 =4.06, PB0.001 and-N1 versus F1-t59 =0.89, P\0.1. Thus population latencies
were significantly shorter in area TE than in perirhinal cortex for each type of response, except for novel first versus familiar first trials for novelty
neurones.
3.7. Neuronal responses in the conditional 6isual
discrimination task
The activity of 342 neurones was recorded during
performance of the conditional visual discrimination
task; 228 (67%) of the neurones were visually responsive. The responses of 114 neurones (50% of those
visually responsive) differed significantly (analysis of
variance) for the different stimulus configurations. In
particular, there were only 21 neurones (9% of the
visually responsive neurones) that responded differently
on trials requiring a touch to the left rather than the
right side of the screen. Moreover, none of these neurones was also differentially responsive in the serial
recognition task. Indeed, no neurone was differentially
responsive in both tasks. Thus the differential responses
in the serial recognition task are not explicable solely
on the basis of the direction of the animal’s behavioural
response.
4. Discussion
The results advance understanding of the neuronal
encoding of information of potential importance to
recognition memory (judgement of prior occurrence) in
several ways. (i) A third commonly occurring type of
neuronal response, namely that of novelty neurones has
been discovered to add to those of recency and familiarity neurones (Fahy et al., 1993). Novelty neurones
respond significantly differently (typically more
strongly) to the first presentations of novel stimuli than
to their subsequent presentations or to presentations of
highly familiar stimuli. (ii) It has been established that
each of the three types of neurone are found commonly
in area TE, perirhinal cortex and entorhinal cortex. A
previous report (Fahy et al., 1993) had suggested a
more restricted anatomical distribution for recency and
familiarity neurones. (iii) It has been confirmed within a
single experiment that these types of neurones (now
additionally including independent assessments of recency, familiarity and novelty neurones) are uncommon
in the hippocampus (Brown et al., 1987; Riches et al.,
1991). (iv) The memory spans of exemplars of each of
these types of neurones have been demonstrated to be
at least 24 h. (v) The mean memory span of recency
neurones recorded in perirhinal cortex has been shown
to be significantly longer than that for area TE. This
finding suggests that the differential responses of recency neurones in perirhinal cortex are more than mere
passive reflections of those in area TE. (vi) The differential latencies of populations of recency, familiarity
and novelty neurones have been compared across the
different areas. The mean latencies of recency and
familiarity neurones are significantly shorter in area TE
than in perirhinal cortex, and in perirhinal cortex than
in entorhinal cortex. This finding makes it probable
that such differential responses in area TE are not mere
passive reflections of those in perirhinal cortex. Accordingly, both area TE and perirhinal cortex may play
roles in the generation of long lasting decremental
response changes. The results neither exclude nor
provide evidence that entorhinal cortex does so. (vii)
The reduced response of familiarity neurones to a familiar compared to an unfamiliar stimulus appears to
be dependent on the passage of time rather than purely
on multiple repetitions of a stimulus. Indeed, for the
recorded population of these neurones memory for the
prior occurrence of a novel stimulus improved with the
passage of time (from 4–8 min to 24 h). (viii) The
average rate of development of the differential response
for familiarity neurones is in marked contrast to that
for novelty and recency neurones where the change
occurs as soon as an unfamiliar stimulus is repeated,
and then gradually declines. Accordingly, the plastic
process underlying the development of the differential
J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
669
Fig. 8. Mean population responses across different intervals for the three types of differentially responsive neurone in the three areas. Across the
intervals investigated, memory across the population increases with time elapsed for familiarity neurones, but decreases for novelty neurones and
for recency neurones. The sample comprised all the recorded differentially and decrementally responsive neurones for which there were data at
all intervals. * Significant difference between mean response to first and subsequent presentations within an area and type of neurone (paired t-test;
P B0.05, uncorrected for multiple comparisons). Statistical details are from analyses of variance with repeat measures. For none of the analyses
was there a significant interaction between animal and other factors, i.e. there was no evidence of a different pattern of responses between the
animals. Recency neurones: Using the rank order of the number of intervening trials from the first to the subsequent presentations (interval) as
a covariate, there was a significant interaction between region and interval (F2,37 =3.80; P =0.03); thus the rate of change (slope) of the response
decrement with interval varied between the regions. In particular, the rate of change (slope) was significantly less in perirhinal cortex than in area
TE (F1,28 = 7.63; P= 0.01). Data for the different intervals were therefore analysed separately. Significant differences (F tests, P B0.05) between
the three areas were found for all intervals ]16 intervening trials. In particular, in perirhinal cortex the population memory span was greater than
it was in area TE: the response decrement was significantly (Tukey tests) greater in perirhinal cortex than in area TE at 16 (P= 0.03), at 32
(P= 0.04) and 64 (P B 0.001) intervening trials and at 24 h (P= 0.04). Familiarity neurones: There was no significant interaction between region
and interval nor effect of region, thus the regions did not differ. However, there was a significant effect of interval (F8,432 =4.37; PB 0.001);
indeed, there was a significant monotonic decrease in response (increase in decrement) with increasing interval (F1,54 =18.49; P B0.001). The
difference in response between first and subsequent presentations was significant (paired t-tests, Bonferroni-corrected P-values) at intervals of 32
(P B 0.05) and 64 (P B0.01) intervening trials and at 24 h (PB 0.001). Novelty neurones: There was no significant interaction between region and
interval nor effect of region, thus the regions did not differ. However, there was a significant effect of interval (F8,408 =10.67; PB 0.001). The
difference in response between first and subsequent presentations was significant (Bonferroni-corrected t-values; P B0.01) at all intervals up to 64
intervening trials but not at 24 h.
response of familiarity neurones must have a much
slower time course of expression than that for recency
or novelty neurones. (ix) It has been confirmed that the
incidence of incremental rather than decremental responses on repetition of an unfamiliar stimulus is very
low (less than chance expectation).
Much evidence that the differential responses are
related to stimulus repetition per se and are not gener-
ated artefactually has been presented previously (Riches
et al., 1991; Fahy et al., 1993; Miller et al., 1993;
Sobotka and Ringo, 1993; Brown, 1996; Brown and
Xiang, 1998). As previously, the differences cannot be
explained as due to: differences in levels of alertness or
attention (types of trials were intermingled and not
predictable by the animal), differing reward values of
the stimuli (all trials were equally rewarded), differences
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J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
Fig. 9. Comparison of the responses of recency, familiarity and novelty neurones to visual stimuli presented yesterday and today. The animals were
shown the same file of visual stimuli after an interval of 24 h. Data were analysed for the 28 neurones of each type of differential response with
the most highly significant decrements. Changes in neuronal firing rate (%) were relative to the pre-cue level (spontaneous activity, SA = 0%). The
data are shown as means 9 S.E.M.. * PB 0.0001 (paired t-test).
in behavioural response (no differentially responsive
neurones in the serial recognition task were also differentially responsive in the conditional discrimination
task requiring the same behavioural response) or eye
movements (analysis of critical recordings has demonstrated that neuronal response changes occur before eye
movement changes). Additionally, in this study there
were many examples of more than one differentially
responsive neurone or a differentially responsive and a
non-differentially responsive neurone being recorded
simultaneously. Such response differences between
simultaneously recorded neurones cannot be produced
by a non-specific, generalised change in alertness. Further, consider the situation when a recency neurone and
a familiarity neurone were recorded simultaneously (19
such pairs were observed). When an unfamiliar stimulus
was seen again, the response of the recency neurone
decremented while the familiarity neurone continued to
respond strongly to the second presentation. In contrast, when a familiar stimulus was first presented, the
recency neurone responded strongly while the familiarity neurone did not. This co-occurring dissociation of
responsiveness to presentations of the same stimuli
cannot be explained as a result of a generalised change
in attention to the stimuli. It has been argued previously that, on the contrary, the differential neuronal
response changes provide a basis for producing changes
in attention or eye movements (Fahy et al., 1993; Miller
et al., 1993).
The results confirm that the change in response with
repetition or increasing familiarity is overwhelmingly a
reduction. The incidence of increases in response was
less than expected by chance. Further, none of the
observed increases in response was large in magnitude
or was unexpectedly low in probability of occurrence.
This result is in apparent conflict with certain ideas
concerning the setting up of new representations in
anterior inferior temporal cortex. It could be expected
that experiencing novel stimuli would result in the
setting up of new representations. Setting up a new
representation of a stimulus is often assumed to result
in an enhanced responsiveness to that stimulus of at
least some members of a neuronal assembly, though for
information storage capacity to be maximised, the proportion of synapses (and therefore, probably, neurones)
undergoing modification should be small (Marr, 1971;
Amari, 1989; Rolls, 1995). Nonetheless, even given such
sparse encoding, there was no evidence of the predicted
incremental neuronal responses during the performance
of a recognition memory task employing many unfamiliar stimuli. There are two possible reasons for this
unexpected result. Firstly, the representations and
hence the increased responses could occur elsewhere
than in anterior inferior temporal and entorhinal cortex, though the perceptual processing capacities of anterior inferior temporal cortex would seem to make it an
obvious place for such representations to be formed.
Secondly, perhaps it is not necessary to set up a new
J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
representation every time a new stimulus is encountered. It is plausible that most novel stimuli can be
classified (‘identified’) by a unique pattern of activity
across some assembly of neurones whose responses do
not change with repetition of stimuli, without there
being a need to adjust the synaptic strengths between
the elements of this assembly. Altered synaptic connections would only be necessary should the stimulus have
to be learnt in the sense that its individual components
needed to be associated together in ways for which
there was no pre-existing coding or, more commonly, to
form and store particular associations of that stimulus
with other stored or perceived stimuli. Thus, for example, encountering a new face may not result in a new
representation formed by alterations in synaptic connections within the assembly of neurones that identifies
faces. However, if so, this cannot be all that happens as
a result of the experience: there needs to be a mechanism for determining whether a particular pattern of
activity representing a particular exemplar of a class (a
particular face) has been encountered previously. This
mechanism is precisely what is provided by the assembly of neurones whose responses change with stimulus
repetition. Accordingly, the existence of the neurones
with decremental responses may greatly reduce the need
to change synaptic weights in assemblies of neurones
Fig. 10. The responses of recency, familiarity and novelty neurones to
multiple presentations of an initially novel stimulus. During sequence
type S2 of the serial recognition task an initially novel stimulus (A)
was shown on 2 – 5 successive trials before a second novel stimulus
appeared (B). Data are mean 9 S.E.M. changes in firing rate (%)
relative to the pre-cue level (spontaneous activity, SA= 0%) for 35
neurones of each type. * PB 0.05, analysis of variance.
671
responsible for the categorisation of stimuli, with consonant advantages for perceptual constancy. Under this
hypothesis, the changes in synaptic weights necessary
for the remembrance of the new stimulus occur
amongst the assembly of neurones with decremental
responses.
It has been argued previously (Fahy et al., 1993) that
the existence of both recency and familiarity neurones
necessitates the presence of either two separate underlying plastic mechanisms or of a single mechanism with
widely differing time course in different neurones. The
present study has provided more evidence concerning
this separation. In particular, across the population of
recorded familiarity neurones when novel stimuli were
presented a second time a significant mean decrement
compared to the initial response took 4–8 min to
develop. This decrement continued to increase for the
whole of the tested period (including 24 h, though for
this interval the stimuli had been seen twice previously).
The decrement for recency neurones and for novelty
neurones for novel stimuli is present as soon as test is
made, 4–8 s in these experiments, 700 ms in others
(Miller et al., 1993). Further, the mean decrement did
not increase with the passage of time for these neurones. In addition, when an initially novel stimulus was
presented on up to five successive trials within 2–4 min,
no significant decrement developed across the population of familiarity neurones. Thus repetition per se is
insufficient to generate a change in the response of
familiarity neurones, the passage of time remains necessary. Surprisingly, the population of recency neurones
did not demonstrate a progressive reduction in response
for successive presentations when the novel stimuli were
repeated in this way. Progressive reductions in neuronal
responses as an initially novel stimulus is repeated have
been observed in a study where the familiarity (though
not the recency of presentation) of the stimulus was
incidental to task performance and successive stimulus
repeats were separated by intervening trials (Li et al.,
1993).
The existence of novelty neurones probably does not
necessitate yet a third type of plastic mechanism. Although a single plastic mechanism seems unlikely to be
able to explain the different response properties of
novelty neurones for repeated novel and familiar stimuli, the response pattern might be generated though a
combination of two mechanisms—one similar to that
of recency neurones and the other similar to that of
familiarity neurones. Alternatively, the responses of
novelty neurones might be generated from complex
combinations of inputs from recency and familiarity
neurones. However, evidence from studies of the interactions between simultaneously recorded neurones (Xiang and Brown, 1997b) makes this possibility less
likely: novelty neurones provide short latency inputs to
recency and familiarity neurones rather than vice versa.
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J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
Fig. 11. Different response patterns (peristimulus histograms and rasters) for the same trials containing first or second presentations of novel or
familiar stimuli for four simultaneously recorded neurones: non-differential visually responsive, recency, familiarity, and novelty. The action
potential waveforms of the different neurones are inserted in the first panel: note the different shapes; amplitudes also differed, but have been
re-scaled.
Nevertheless, these findings do not exclude the response
pattern being generated by appropriate network connections.
There are several similarities across the perirhinal
and entorhinal cortices and area TE in neuronal responsiveness in the serial recognition memory task.
Thus the proportions of visually responsive neurones
and the proportions of each of the three types of
differentially responsive neurones are similar in each of
these areas. Moreover, the memory spans of the populations of familiarity neurones and of novelty neurones
also do not differ significantly between the areas. However, the mean memory span of the population of
perirhinal recency neurones is longer than that of recency neurones in area TE. Further the mean latency of
populations of recency and familiarity neurones is
shorter in area TE than in perirhinal or entorhinal
cortex (though this is not clearly the case for novelty
neurones). These data strongly suggest that the differential responses in area TE are at least initiated in a
way that is independent of perirhinal input, though the
possibility of feedback effects from a small population
of perirhinal neurones with very short differential laten-
cies cannot be excluded. These data therefore allow the
possibility that perirhinal familiarity responses are no
more than passive reflections of those in area TE.
However, as mean memory spans for perirhinal recency
neurones are longer than those in area TE, these recency responses must be more than passive reflections
of those in area TE–unless the perirhinal responses are
a result of inputs from a small population of neurones
with very long memory spans in area TE. Thus the
results raise the possibility that neurones in both
perirhinal cortex and area TE show independent plastic
changes. Nonetheless, in spite of the overlap in response properties, there are far more neurones with
short latencies in area TE than in perirhinal cortex and
far more neurones with long memory spans in perirhinal cortex than in area TE: accordingly, the contributions of the two regions to recognition memory are
unlikely to be equivalent.
The results provide no evidence that there are plastic
changes in entorhinal cortex (though they do not rule
out such changes): the observed entorhinal neuronal
responses could be explained as passively reflecting
inputs from perirhinal cortex and area TE. Ablation
J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
studies indicate that only transitory impairment of
recognition memory tasks follows entorhinal lesions
(Meunier et al., 1993; Leonard et al., 1995). In contrast,
lesions of perirhinal cortex (Horel et al., 1987; Gaffan
and Murray, 1992; Meunier et al., 1993, 1996; Suzuki et
al., 1993; Eacott et al., 1994; Murray, 1996) and area
TE (Mishkin, 1982; but see Buckley et al. (1997))
produce a major, lasting impairment. It is unlikely that
the responses in anterior TE are passive reflections of
those generated elsewhere. Differential responses in
posterior TE, the main source of visual information to
anterior TE, do not have long memory spans (Baylis
and Rolls, 1987; Miller et al., 1991; Vogels et al., 1995).
Few regions, including more posterior visual cortex,
have the necessary sensory processing capacity to discriminate large numbers of complex visual stimuli and
hence the capacity reliably to discriminate the prior
occurrence of many individual exemplars of these stimuli. The contribution of prefrontal cortex remains to be
established, but the latencies of its differential neuronal
responses are likely to be too long to explain those in
anterior TE (Brown, 1996; Miller et al., 1996; Brown
and Xiang, 1998) and its ablation is less devastating to
recognition memory than is that of perirhinal cortex
(Meunier et al., 1997). The role of the hippocampus will
be discussed below, but the current results provide
strong evidence against its importance for generation of
the observed differential neuronal responses. Hence the
critical synaptic plastic processes underlying these responses are most probably in perirhinal cortex and area
TE.
The involvement of the hippocampus (hippocampus
proper, dentate gyrus and subiculum) in recognition
memory is still controversial. The restricted number of
differentially responsive neurones (present results;
Brown et al., 1987; Rolls et al., 1989, 1993; Riches et
al., 1991) and limited lesion effects (O’Boyle et al.,
1993; Alvarez et al., 1995; Murray, 1996; Murray and
Mishkin, 1996), rule out a major role for the hippocampus in judging the familiarity or recency of occurrence
of individual items whose spatial locations or other
associations are not important to task solution. In this
experiment the very low incidence of recency, familiarity or novelty neurones in the hippocampus compared
to the anterior inferior temporal cortex and entorhinal
cortex has been established using the same stimuli in
the same animals in the same experiment. The comparative incidence and the short differential latencies render implausible the suggestion that the differential
responses in anterior inferior temporal cortex and entorhinal cortex are a result of feedback signals from the
hippocampus. However, these findings do not imply
that the hippocampus plays no role in recognition
memory: the role of the hippocampus in recognition
memory appears to be linked to its role in spatial
information processing (O’Keefe and Nadel, 1978;
673
Brown 1990; O’Keefe, 1993; Eichenbaum et al., 1994;
Gaffan, 1994; Wiener, 1996; Nadel and Moscovitch,
1997; Aggleton and Brown, 1998). Thus when the spatial location of repeated stimuli is made relevant, a
higher proportion of hippocampal cells have responses
that are related both to position and to prior occurrence (Rolls et al., 1989; Wiener, 1996). Further, in the
rat, a higher proportion of hippocampal neurones is
activated when a rat enters a novel as opposed to a
familiar environment or when the stimuli are arrangements of multiple individual items in a spatial relationship to each other rather than individual items (Wan et
al., 1997; Zhu et al., 1997). Moreover, novel arrangements of familiar items result in changes in the numbers
of activated hippocampal neurones compared to familiar arrangements of these familiar items (Wan et al.,
1997).
Although the described decremental responses were
recorded during the performance of a recognition memory task, such responses may additionally play a role in
repetition priming (Wilson et al., 1988; Brown, 1996).
Priming (increased perceptual fluency for previously
encountered stimuli compared to novel stimuli) is an
automatic process and therefore must presumably have
also occurred during the present experiments. Parsimony (or the likely consequence of evolutionary pressure) would suggest that the brain will not have more
than one mechanism for registering the prior occurrence of visual stimuli. Nevertheless, even should both
types of memory share initial processing, priming and
recognition memory (familiarity discrimination) cannot
have identical neural substrates. There are two reasons
for this conclusion. Firstly, priming is essentially an
unconscious (implicit) process whereas recognition is
fundamentally conscious (explicit); see for review
Schacter et al. (1993). Secondly, there are amnesic
patients whose familiarity discrimination is impaired
but whose priming is intact (Warrington and
Weiskrantz, 1974; Jacoby and Witherspoon, 1982; Cermak et al., 1985; Graf et al., 1984; Schacter et al., 1993;
Aggleton and Brown, 1998). One notable such case is
EP whose lesion includes the hippocampus, entorhinal
and perirhinal cortex (Hamann and Squire, 1997). Accordingly, if decremental neuronal responses equivalent
to those described here occur in similar regions in the
human brain, such responses in perirhinal and entorhinal cortex cannot be necessary for priming memory.
The corollary is that the operation of any mechanism
required for familiarity discrimination to be explicit
requires the integrity of perirhinal cortex or the
hippocampal formation. However, there are amnesic
patients still able to make familiarity discriminations
whose lesion includes the hippocampus but not perirhinal cortex (Aggleton and Shaw, 1996; Aggleton and
Brown, 1998). Thus the critical lesion must involve
entorhinal or perirhinal cortex. Perirhinal cortex may
674
J.-Z. Xiang, M.W. Brown / Neuropharmacology 37 (1998) 657–676
be more important than entorhinal cortex as, in the
monkey, ablation of entorhinal cortex produces only a
transient impairment in delayed matching tasks,
whereas long-lasting deficits follow lesions of perirhinal
cortex (Meunier et al., 1993; Leonard et al., 1995).
Correspondingly, decremental responses in perirhinal
cortex (and possibly entorhinal cortex) may be an
essential substrate of recognition memory (familiarity
discrimination), but not of priming. In contrast, it
remains possible for decremental neuronal responses in
anterior TE (and in the equivalent area of human visual
association cortex) to be important to both familiarity
discrimination and repetition priming for complex visual stimuli.
In conclusion, the current results provide further
evidence that the properties of neuronal response decrements in perirhinal and adjacent cortex are adequate to
explain the recognition memory (recency and familiarity discrimination, rather than contextual discrimination) capabilities of animals, as these have been
normally tested (Brown, 1996; Brown and Xiang, 1998).
Thus the response decrements: (i) provide information
necessary for judgement of the previous occurrence of
stimuli based on their recency of occurrence and relative familiarity; (ii) demonstrate single trial learning;
(iii) are stimulus selective; (iv) demonstrate a very large
storage capacity; (v) are long-lasting (\ 24 h); (vi) are
not disrupted by other experiences; (vii) are endogenous
and automatic (non-effortful); (viii) are found during
performance of explicit memory tasks; (ix) occur at
such high incidence that changes can be demonstrated
in population measures of neuronal activity, and so are
more than a minor epiphenomenon; and (x) occur in a
region (perirhinal cortex) necessary for judgement of
previous occurrence. Further, the response decrements
are found in a number of different experimental situations —for various types of stimuli in different recognition memory tasks and also in situations requiring no
behavioural contingency, in monkeys and in rats
(Riches et al., 1991; Fahy et al., 1993; Miller et al.,
1993; Sobotka and Ringo, 1993; Zhu et al., 1995,
1996)—and are consistent with positron emission tomographic (PET) changes described in humans making
familiarity judgements (Vandenberghe et al., 1995). The
response decrements cannot be explained by differences
in the reinforcement value of stimuli, the behavioural
responses emitted, eye movements or pupillary changes,
alertness or attention; hence they are not artefactual or
trivial concomitants of the learning. Moreover, no
other response changes within perirhinal cortex have
been shown to provide the information necessary to
allow solution of a wide range of recognition memory
tasks that do not require spatial or contextual discriminations. Thus neither an enhanced response to repeated
stimuli (Miller and Desimone, 1994) nor sustained (delay) activity following a stimulus that must be remem-
bered (Fuster and Jervey, 1981; Miyashita and Chang,
1988) has been shown to be capable of explaining
recognition memory when more than one item must be
remembered at a time, or the memory must span a long
and indeterminate interval. Accordingly the described
neuronal response decrements provide the best current
candidate mechanism for a neuronal substrate of recognition memory.
Acknowledgements
We thank R. Hopkins, J. Leendertz and A. Griffiths
for technical assistance and the Wellcome Trust for
financial support.
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