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Neurobiology of Learning and Memory 89 (2008) 192–198

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q
Electrolytic lesions of dorsal CA3 impair episodic-like memory in rats
Jay-Shake Li *, Yuen-Shin Chao
Department of Psychology, National Chung Cheng University, 168, University Road, Min-Hsiung, Chia-Yi, Taiwan, ROC

Received 7 May 2007; revised 7 June 2007; accepted 30 June 2007

Available online 16 August 2007

Abstract

Episodic memory is the ability to recollect one’s past experiences occurring in an unique spatial and temporal context. In non-human
animals, it is expressed in the ability to combine ‘‘what’’, ‘‘where’’ and ‘‘when’’ factors to form an integrated memory system. During the
search for its neural substrates, the hippocampus has attracted a lot of attentions. Yet, it is not yet possible to induce a pure episodic-like
memory deficit in animal studies without being confounded by impairments in the spatial cognition. Here, we present a lesion study evi-
dencing direct links between the hippocampus CA3 region and the episodic-like memory in rats. In a spontaneous object exploration
task, lesioned rats showed no interaction between the temporal and spatial elements in their memory associated with the objects. In sep-
arate tests carried out subsequently, the same animals still expressed abilities to process spatial, temporal, and object recognition mem-
ory. In conclusions, our results support the idea that the hippocampus CA3 has a particular status in the neural mechanism of the
episodic-like memory system. It is responsible for combining information from different modules of cognitive processes.
 2007 Elsevier Inc. All rights reserved.

Keywords: Episodic memory; CA3; Spontaneous exploration; Rats

1. Introduction
Human episodic memory is very closely related to con-
sciousness. Some authors describe it as a mental time tra-
vel, and set the conscious awareness of ‘‘self’’ as one of
the pre-conditions of this memory system (Tulving,
2002). Although controversial, many researchers try to
develop animal models of episodic-like memory based on
its behavioral characteristics (for reviews see: Dere, Kart-
Teke, Huston, & Silva, 2006). It has been suggested that
the episodic-like memory in non-human animals is
expressed in the ability to combine ‘‘what’’, ‘‘where’’ and
‘‘when’’ factors to form an integrated memory system.
The scrub jays have been found to be able to utilize this
ability in food caching (Clayton & Dickinson, 1998).
Recently, rodent models of episodic-like memory were also
successfully established (Babb & Crystal, 2005; Dere, Hus-
q
CA3—episodic memory.
*
Corresponding author. Fax: +886 5 2720857.
E-mail address: psyjsl@ccu.edu.tw (J.-S. Li).
ton, & Silva, 2005; Kart-Teke, Silva, Huston, & Dere,
2006).
Ever since the formulation of the episodic memory
theory, the hippocampus has been thought to play a
prominent role in its neural mechanism (Eichenbaum &
Fortin, 2003; Tulving & Markowitsch, 1998). For exam-
ple, patient studies link human’s ability to find his way
around an environment and remember events occurring
within it to the hippocampus and the medial temporal
lobe (Burgess, Maguire, & O’Keefe, 2002). However,
patients seldom have strictly localized lesions. Further-
more, well controlled manipulations in human studies
are limited due to ethical reasons. Under these circum-
stances, animal models for the episodic-like memory
become an indispensable tool for the study of its
neurobiology.
Numerous animal studies indicated that hippocampus
damage strongly impairs various kinds of learning and
memory (Broadbent, Squire, & Clark, 2004; Squire,
Stark, & Clark, 2004). More specifically, the hippocam-
pus subregion CA3, with its characteristic recurrent col-
lateral connections at the anatomical level, has inspired

1074-7427/$ - see front matter  2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.nlm.2007.06.006
 J.-S. Li, Y.-S. Chao / Neurobiology of Learning and Memory 89 (2008) 192–198
computational models incorporating auto-associative
networks, and has been proposed as the key structure
for the storage of episodic memory (Daumas, Halley,
& Lassalle, 2004; Ishizuka, Weber, & Amaral, 1990;
Marr, 1971; Vazdarjanova & Guzowski, 2004). How-
ever, researchers still face another challenge when try-
ing to link the hippocampus to the episodic memory.
Since manipulations on hippocampus often impair
spatial learning and memory (Broadbent et al., 2004;
Gilbert & Kesner, 2006; Holscher, 2003), the deficits
observed in a what–where–when task can be simply
interpreted as secondary to impairments in spatial cog-
nitions (Eichenbaum & Fortin, 2003). Some authors
thus turned to study only the temporal component in
the episodic memory (Eichenbaum & Fortin, 2003,
2005).
Here, we present a lesion study marking out the hip-
pocampus subregion CA3 as an essential part in the neu-
ral mechanism of episodic-like memory in rats. We
applied the what–where–when task recently introduced
by Kart-Teke et al. (2006) to measure impairments in
the episodic-like memory caused by bilateral electrolytic
lesions in the dorsal CA3. Furthermore, to exclude the
confounding caused by impairments in the other memory
systems, the same animals were tested in subsequent
experiments for their spatial, temporal order, and object
recognition memory separately (Ennaceur & Delacour,
1988; Ennaceur, Neave, & Aggleton, 1997; Hannesson,
Vacca, Howland, & Phillips, 2004; Mitchell & Laiacona,
1998).
The principles of these tasks are based on the sponta-
neous exploratory behaviors of rats. It has been previ-
ously shown that, when there are two choices, rats
show preference for the novel object/place over the
familiar one (Ennaceur & Delacour, 1988; Ennaceur
et al., 1997; Hannesson et al., 2004), thus evidencing
their ability to remember which object/location they have
previously encountered. When both objects/places are
familiar, they can remember the temporal order of their
previous encounters and show preference for the older
one (Mitchell & Laiacona, 1998). In the episodic-like
memory task designed by Kart-Teke et al. (2006), the
rats have four choices. It has been demonstrated that
timing and location of objects interact in animals’ explor-
atory preference. For the recent objects, rats spend more
time to explore the displaced one, as might be predicted
by a correctly functioning spatial recognition memory.
For the older objects, however, the one in the same loca-
tion is preferred. The inverse preference pattern implies
that animals can build an integrated memory system
which combines ‘‘what’’, ‘‘where’’ and ‘‘when’’ informa-
tion together, thus evidencing the ability to form an epi-
sodic-like memory. We hypothesize that the CA3
lesioned rats will fail to show this inverse preference pat-
tern, yet they can still express ability to process memo-
ries for locations, objects, as well as the temporal order
of their encounters.
193
2. Materials and methods
2.1. Animals
Thirty male Wistar rats weighed 270–320 g were used in the study.
They were housed individually in wire cages maintained in a temperature
and humidity controlled room on an artificial 12 h light/dark cycle (light
on at 7 am). Food and water were available ad libitum.
2.2. Surgery
Animals were randomly assigned to three groups: untreated, sham,
and CA3 lesion. Only the sham and the CA3 lesion groups underwent
the surgery. Animals were first given atropine sulfate (0.2 mg/kg i.p.),
and then anesthetized with sodium pentobarbital (Nembutal; 60 mg/kg,
i.p.). Tungsten dipolar electrodes were inserted in six sites with coordinates
(AP, ML, DV; mm relative to bregma): ( 2.8, ±3.0, 3.9), ( 3.3, ±3.4,
3.9), and ( 4.1, ±4.2, 4.0). The CA3 lesion group received 5 s
0.7 mA AC-current to induce the lesion. All animal care and experimental
procedures were performed under the supervision of the Institutional Ani-
mal Care and Use Committee, Chung Cheng University.
2.3. Apparatus
Behavioral tests took place in a sound-attenuated experimental room.
During the experiments, illuminations were provided by four 20 W bulbs
placed in four different locations surrounding the apparatus. Different
rooms were used for the open field and the radial-arm maze tasks. An
acrylic square chamber (100 · 100 · 50 cm) without cover served as the
open field for the episodic-like memory and the combined temporal
order/object recognition memory tasks. The open field was divided into
nine equal squares. Except the center one, the other eight squares could
be chosen to place one object in the center.
Five different sets of objects in quadruplicate were used. The objects
had enough weight to make sure that the rats could not move them. Pilot
studies ensured that rats can discriminate the objects. Assignments of
objects for each task and their locations were counterbalanced. Different
sets of objects were used for the episodic-like and the combined temporal
order/object recognition memory tasks, so that all the testing objects were
introduced to the animals for the first time in the beginning of both tasks.
For the spatial recognition test an acrylic, homemade radial-arm maze
was used. The maze had a central octagonal platform (45 cm in diameter)
and eight removable arms (80 cm in length and 10 cm in width and wall
height). The entire maze was elevated 50 cm high above the floor. A digital
camera took the activity of animals in tapes for off-line behavior analysis.
2.4. Procedures
Before the beginning of behavioral tests, animals were left in their
home cages for 2 weeks to recover from the surgery. Then they underwent
4 days of episodic-like memory task in an open field according to the pro-
cedure described by Kart-Teke et al. (2006). After a 7-day pause, rats
received a spatial recognition task in a radial-arm maze according to a
procedure described by Hannesson et al. (2004). After another 7 days of
pause, rats were sent to an open field to run a combined temporal
order/object recognition task analog to those developed by Ennaceur
and Delacour (1988) and Mitchell and Laiacona (1998). All behavioral
experiments were carried out during the dark period (between 20 pm
and 1 am).
2.5. Episodic-like memory task
Before the task, rats were first habituated to the testing environment
for three consecutive days, with daily one 10-min session. The task consists
of two sample trials and one final testing trial. Retention periods between
two adjacent trials were 60 min. In each of the two sample trials, animals
were allowed to freely explore two sets of four identical, novel objects
194 J.-S. Li, Y.-S. Chao / Neurobiology of Learning and Memory 89 (2008) 192–198

Fig. 1. Experimental design. This drawing shows one example of a possible arrangement of objects for the open field episodic-like memory task. Animals
receive three 5 min trials and there are 60 min retentions between successive trials. In the test trial, two old and two recent objects from the sample trials are
presented to the animals. One object from each of the two sets is placed in the same location as in the sample trials (Os and Rs). The remaining two objects
are displaced to new locations (Od and Rd).

(designated as O and R; e.g. Fig. 1 left and middle). In the final testing trial
animals encountered a mixed set consisting of two O and R objects (e.g.
Fig. 1 right). One from each of the two sets of objects was placed in the
same location as in the sample trials (Os and Rs in Fig. 1 right). The other
two objects were placed in new locations (Od and Rd in Fig. 1 right). Time
spent for exploring the objects was recorded.
2.6. Spatial recognition task
Rats were first familiarized with the testing environment for one day,
in which all arms were removed and doors were closed. Animals could
freely explore only the central platform for 10 min. On the following
day they first received a sample trial during which two randomly chosen
non-adjacent arms were open for 5 min. After a retention period of
60 min, animals were sent to a 5 min test trial in which one old arm and
one randomly selected new non-adjacent arm were open. Dwell time in
each arm was recorded.
vs. Od and Rs vs. Rd only. Exploring one object/arm will prevent explo-
ration on the others. Hence, the exploring time recorded for each object/
arm is not independent from each other. As a consequence, paired t-test is
used for the comparisons. The sign of exploring preference is important
for the interpretation. Thus, the one-tailed statistical comparison is
applied throughout the present study. The p-values are reported in the
text, and the significance levels are given in figure legends.
3. Results
3.1. Histology
Fig. 2 shows the sites and extents of CA3 damages. The
black area marks the smallest lesion and the grey area the
largest one. Animals with lesions other than the target
region were excluded from the data analysis.

2.7. Combined temporal order/object recognition task

3.2. Behavioral tests
Before the task, rats were first habituated to the testing environment
for one day, with one 10-min session. The task consists of four trials. The time spent for exploring objects in the final testing
Two sets of novel objects (designated as old and recent), each consisted trial in the episodic-like memory task is shown in Fig. 3.
of two identical copies, were presented for 5 min in each of the first two
sample trials, respectively. In the third trial one old and one recent object
were presented for 5 min exploration at the same locations. Animals’ pref-
erences for the old object revealed their temporal order memory. Finally,
one recent and one novel object were presented at the same locations for
5 min to assess animals’ object recognition memory. Retention periods
between two adjacent trials were 60 min.

2.8. Data analysis

Behaviors were fist video taped, then post hoc analyzed by well trained
personals that were blind to the experimental design (episodic-like and
temporal order/object recognition memory tasks), or by a software devel-
oped previously in our group (spatial recognition task; Li & Huang, 2006).
Exploration of an object was assumed when the rat approached and had
physical contact with it, either with its snout or forepaws. Entering an arm
was assumed when the center point of rat located in the arm area. The
analysis of variance for a mixed design, with objects as the within subject
and treatment as the between subject factors, was applied to deliver an
overview of treatment and object effects, as well as their interactions on
the exploring time. For the episodic-like memory task, additional 2 · 2
ANOVAs with two within subject variables: object recency and location
novelty were carried out for each group separately. The tests could give
us an overview for the main effects and interaction of object recency
and location novelty. Since only the comparisons between Os vs. Od Fig. 2. CA3 damages reconstructed from coronal sections of the rat brain.
and Rs vs. Rd within each group were crucial for testing our hypotheses, Numbers indicate anterior–posterior (AP) distances (in mm) from bregma.
a priori multiple t-tests on exploring time were applied for object pairs Os Black: smallest lesion; Gray: largest lesion.
 J.-S. Li, Y.-S. Chao / Neurobiology of Learning and Memory 89 (2008) 192–198
Fig. 3. Results of the episodic-like memory test. Ordinate: mean explo-
ration time ± SEM spent for each object in the final test trial. Abscissa:
animal groups. Note the distinct preference pattern of CA3 lesioned rats.
Statistics: pair-wise comparison of exploring time for objects Od vs. Os
and Rd vs. Rs, *p < .05, **p < .01; one-tailed pair t-test; n = 10 for all
groups.
The 3 (group) · 4 (object-place combination), mixed design
analysis of variance reveals significant main effects for
groups (F(2, 27) = 5.24, p  .012), objects (F(3, 81) =
21.12, p < .001), as well as their interactions (F(6, 81) =
3.55, p  .004). The 2 (object recency) · 2 (location nov-
elty) analysis of variances with two within subject factors
were carried out for the three groups separately. For the
untreated and sham controls there are significant main
effects of object recency (untreated: F(1, 9) = 5.15,
p  .049; sham: F(1, 9) = 41.94, p < .001), and significant
interaction between locations and object recency
(untreated: F(1, 9) = 42.03, p < .001; sham: F(1, 9) =
34.80, p < .001). The main effect of locations is not signif-
icant (untreated: F(1, 9) = .028, p  .871; sham: F(1, 9) =
.004, p  .948). For the CA3 lesioned rats there is a signif-
icant main effect of locations (F(1, 9) = 20.61, p  .001), as
well as object recency (F(1, 9) = 9.56, p  .013). The inter-
action between locations and object recency is not signifi-
cant (F(1, 9) = 0.28, p  .609).
The comparisons between object pairs located in differ-
ent locations indicate that both the untreated and the sham
surgery rats spent more time to explore the old familiar
object placed in the same position (Os) than that placed
in a different location (Od; Fig. 3 left and middle). The
paired t-test reveals that the difference is significant
(untreated: p  .017, sham p  .042; one tailed). For the
recent objects, both the untreated and the sham surgery
rats explored the displaced one (Rd) significantly longer
than that located in the same position (Rs; untreated:
p  .046, sham: p  .004; paired t-test, one tailed). The
CA3 lesioned rats explored the displaced objects (Od and
Rd) significantly longer than those in the same locations
(Os and Rs), regardless when they had first encountered
them (Fig. 3 right). The paired t-tests reveal that the differ-
ences in exploring time are significant for both the old and
the recent object pairs (Od vs. Os: p  .007; Rd vs. Rs:
p  .019; one tailed).
195
The same animals were tested subsequently in a radial-
arm maze task for their spatial recognition memory. One
rat in the sham control group fell out after accomplishing
the episodic-like memory task, so the sample size for this
group reduced to 9. Sample sizes for the other two groups
remained 10. The time spent in the old and new arms in the
testing trial is shown in Fig. 4. The 3 (group) · 2 (arm),
mixed design analysis of variance reveals significant differ-
ences between arms (F(1, 26) = 14.43, p < .001). Neither
the main effect for groups nor the interaction between arms
and groups is significant (Group: F(2, 26) = 0.18, p  .834;
Interaction: F(2, 26) = 0.29, p  .750). All animals spent
significantly more time to explore the novel arm than the
familiar one (Untreated: p  .036; Sham: p  .045; CA3
lesion: p  .020; paired t-test, one tailed).
Finally the same animals were tested in another open
field paradigm for their temporal order and object recogni-
tion memory. The time spent for exploring objects in the
third and fourth trials are shown in Figs. 5 and 6, respec-
tively. The 3 (group) · 2 (object), mixed design analysis
of variances reveal significant main effects for objects in
the temporal order (F(1, 26) = 5.04, p  .034) as well as
in the object recognition memory tasks (F(1, 26) = 48.84,
p < .001). Neither the main effect for groups (Temporal
order: F(2, 26) = 0.99, p  .384; Object recognition:
F(2, 26) = 0.31, p  .740) nor the interaction between
objects and groups (Temporal order: F(2, 26) = 0.63,
p  .540; Object recognition: F(2, 26) = 0.17, p  .848) is
significant. All animals spent more time to explore the
objects they had encountered earlier (old object) than that
encountered later (recent object) in the third trial, as might
be predicted if they can remember the temporal order of
their encounters with the objects (Fig. 5). The difference
in the exploring time is significant for the CA3 lesioned rats
(p  .034; paired t-test, one tailed). Finally, they preferred
exploring the novel object newly introduced in the open
field in the fourth trial to the familiar one which they had
Fig. 4. Results of the spatial recognition test. Ordinate: mean exploration
time ± SEM Abscissa: animal groups. All animals spent more time to
explore the new arm. Statistics: pair-wise comparison of exploring time
between old and new arms, *p < .05; one-tailed pair t-test; n = 9 for the
sham control group; n = 10 for the other two groups.
196 J.-S. Li, Y.-S. Chao / Neurobiology of Learning and Memory 89 (2008) 192–198
Fig. 5. Results of the temporal order memory test. Ordinate: mean
exploration time ± SEM Abscissa: animal groups. All animals spent more
time to explore the old than the recent object. Statistics: pair-wise
comparison of exploring time between old and recent objects, *p < .05;
one-tailed pair t-test; n = 9 for the sham control group; n = 10 for the
other two groups.
Fig. 6. Results of the object recognition memory test. Ordinate: mean
exploration time ± SEM Abscissa: animal groups. All animals spent more
time to explore the new than the recent object. Statistics: pair-wise
comparison of exploring time between old and recent objects, **p < .01;
one-tailed pair t-test; n = 9 for the sham control group; n = 10 for the
other two groups.
already encountered previously (Fig. 6). The differences
between time spent for the two objects are significant for
all groups (Untreated: p  .002; Sham: p  .004; CA3
lesion: p < .001; paired t-test, one tailed).
4. Discussion
In summary, results of our study indicate that the CA3
lesioned rats, unlike the untreated and sham controls,
failed to show interactions between the timing and loca-
tion information associated with the objects in the
what–where–when task, implying that they lose the ability
to combine the spatial and temporal components to form
an integrated memory system. The results cannot be
explained by a total loss of memory for the objects and
their locations, since the lesioned animals still showed
preferences for the displaced objects in the episodic-like
memory task, as revealed by the significant main effect
of location novelty, evidencing that they could actually
remember where they had previously encountered them.
Neither can the lost of temporal order memory account
for the results, since the lesioned animals also explored
the older objects more often, which is indicative for their
memory on the timing for their first encounters with the
objects. Furthermore, results of subsequent tests indicate
that the memory systems for all the three components,
‘‘what’’, ‘‘where’’, and ‘‘when’’, of an episodic-like mem-
ory were still functioning when assessed separately. There
is no evidence to argue that the behaviors of the CA3
lesioned rats differed significantly from the control ani-
mals in these supplementary tests.
The Os vs. Od comparison reflects preference patterns
based on a place change for old objects. The Rs vs. Rd
comparison reflects a place change for new information.
Based on previous findings, one would have predicted that
animals prefer exploring the displaced objects regardless
the object recency (Ennaceur et al., 1997). It is the control
animals that reversed their preference patterns for the case
of the older objects in the four objects what–where–when
task. That is the main finding of Kart-Teke et al. when they
carried out their episodic-like memory task (2006). The
reversal of preference patterns is based on the object rather
than on the spatial recency.
The Os vs. Rs comparison reflects preference patterns
based on the recency of objects placed on the same loca-
tions. The Od vs. Rd reflects the effects of both a time
and place change. According to previous studies, we would
have predicted that animals preferred exploring the older
objects in both cases (Mitchell & Laiacona, 1998). Indeed,
animals in all groups explored the Os longer than the Rs.
However, previously only the simple effect of the object
recency was examined. If, as hypothesized in the present
study and in the study by Kart-Teke et al. (2006), the tim-
ing and place components form an integrated system, the
interaction term cannot be ignored. As a consequence,
the preference pattern for Od vs. Rd might differ from
the one determined by the simple object recency effect. That
is the case for the Od vs. Rd comparison in the untreated
and sham control animals.
The CA3 lesion rats showed, in both older and recent
object pairs, preferences for the displaced ones. Thus, the
effect of lesions in CA3 is actually the undoing of prefer-
ence reversal observed in control animals. No evidence
for an impairment caused by the CA3 lesion in the spatial
cognition or temporal processing can be found. In conclu-
sions, our study suggests that dorsal CA3 lesions spare ani-
mals’ ‘‘what’’, ‘‘where’’, and ‘‘when’’ memory per se, but
impair their ability to integrate the three elements, thus evi-
dencing the crucial role of CA3 in the neural mechanism of
episodic-like memory. It is, to our knowledge, for the first
time direct evidence can be provided to support the causal
link between hippocampus and the episodic memory
system.
 J.-S. Li, Y.-S. Chao / Neurobiology of Learning and Memory 89 (2008) 192–198
The episodic-like memory task applied here makes use
of the instinctive exploratory preference of rats. Truly it
cannot assess the ‘‘conscious’’ recollection of animals. An
alternative what–where–when paradigm for rats has been
suggested recently (Babb & Crystal, 2005), in which ani-
mals have to utilize their episodic-like memory to retrieve
favorable foods. However, it is still possible that animals
simply follow implicitly conditional rules established via
extensive training. Furthermore, in an extensively trained
and food-rewarded paradigm like this, animals might
encode ‘‘what’’, ‘‘where’’, and ‘‘when’’ information during
the sampling phase semantically, thus, confounds the inter-
pretations for the episodic-like memory (Dere et al., 2006;
Hampton & Schwartz, 2004; Schwartz, Hoffman, & Evans,
2005).
Numerous animal studies indicate that hippocampus
damage strongly influences various kinds of learning and
memory, such as associative memory, spatial learning
and memory (Ainge et al., 2006; Broadbent et al., 2004;
Gold & Kesner, 2005; Squire et al., 2004). There are also
studies applying manipulations specifically in the CA3 sub-
region that revealed impairments of spatial learning (Gil-
bert & Kesner, 2006; Handelmann & Olton, 1981;
Meilandt, Barea-Rodriguez, Harvey, & Martinez, 2004).
The latter seems inconsistent with the present findings.
The CA3 lesioned rats in our study showed significant pref-
erences for the displaced objects in the episodic-like mem-
ory task, and demonstrated a functioning spatial
recognition memory in the radial-arm maze task carried
out subsequently. A likely explanation for the discrepancy
is the nature of behavioral tasks applied in the experiments.
Previous studies usually incorporated paradigms requiring
a long period of intensive training. The neural circuitries
involved might be very different from those in the one-trial
spontaneous exploration task used here. Our results indi-
cate that the CA3 lesion did not compromise animals’ spa-
tial recognition ability expressed in their spontaneous
exploring preferences. Since the episodic-like memory task
used here is based on the spontaneous exploratory behav-
iors as well, it is thus plausible to assume that it relies on
similar neural circuitries as in the subsequent supplemen-
tary tasks. If the CA3 lesion spares the neural substrates
needed for running the radial-arm maze spatial cognition
task, probably the neural circuitries responsible for spatial
recognitions in the four-objects, episodic-like memory task
were also intact. As a result, we can conclude that the CA3
lesion destroys only the interaction of timing and location
factors, but not the temporal and spatial cognitions them-
selves. The fact that CA3 lesions can have impacts on spa-
tial learning in tasks requiring reinforcements and extensive
trainings is of course interesting, yet it will not necessarily
jeopardize the interpretation of our results.
Some previous studies linked certain hippocampal neu-
ron firing features as well as biochemical activities to the
episodic-like memory (Dragoi & Buzsaki, 2006; Ferbinte-
anu, Kennedy, & Shapiro, 2006; Huxter, Burgess, &
O’Keefe, 2003; Kentros, 2006; Knierim, Lee, & Harg-
197
reaves, 2006). The results highlighted the differential
responding patterns of CA1 and CA3 to contextual and
temporal cues. However, they provided only correlation
information for the linkage between hippocampus and
the episodic-like memory. They can be regarded only as
indirect evidences. Our study reveals the causal relationship
between the CA3 subregion and the episodic-like memory
system. It provides direct evidence marking out the special
status of CA3 in the neural circuitry of the episodic-like
memory system. It has also been concluded in a review that
the CA3 subregion of the hippocampus supports processes
associated with spatial pattern association and separation,
novelty detection, and short-term memory (Kesner, Lee, &
Gilbert, 2004). Our findings are in line with this conclusion
in a way that the associative neural network constructed
via the CA3 recurrent collaterals plays a central role in
these processes. Besides, both the novelty detection and
the short-term memory are required to carry out the object
exploration task used in the present study. However, it was
concluded in the same review that the CA1 subregion is pri-
marily responsible for the processing of temporal informa-
tion. Our results suggest that the CA3 subregion processes
the temporal information as well. In fact, it seems that the
main function of the CA3 is the binding of different cogni-
tive processes, including both spatial and temporal
modules.
It is well known that electrolytic lesions often damage
both the adjacent neuronal structure and axons passing
through the area. The use of excitotoxins can limit the
lesions to specific types of neurons (Jarrard, 2002). How-
ever, since no previous study has ever succeeded in induc-
ing pure episodic-like memory impairment in animals, it
is not known which types of neurons, or even whether or
not the passing axons are involved in the neural mechanism
of episodic-like memory. At the present stage, it might be
preferable to produce a more complete damage, which
can better mimic brain lesions observed in most human
patient studies. In any case, our success is a starting point
for future studies aiming at clarifying the role of CA3 as
well as the hippocampus as a whole in the episodic-like
memory system. Then, the using of more specific treat-
ments might reveal more details about the neural mecha-
nism of the episodic-like memory system.
Acknowledgments
This work was supported partially by a Grant of the Na-
tional Science Council, Taiwan (NSC 95-2413-H-194-005).
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