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The Journal of Neuroscience, February 15, 2003, 23(4):1517
Time-Dependent Relationship between the Dorsal Hippocampus and
the Prefrontal Cortex in Spatial Memory
Inah
Lee1 and
Raymond P.
Kesner2
1 Departments of Neurobiology and Anatomy, University
of Texas Houston Medical School, Houston, Texas 77025, and
2 Department of Psychology, University of Utah, Salt Lake
City, Utah 84112
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ABSTRACT |
The prefrontal cortex and the dorsal hippocampus have been studied
extensively for their significant roles in spatial working memory. A
possible time-dependent functional relationship between the prefrontal
cortex and the dorsal hippocampus in spatial working memory was tested.
A combined lesion and pharmacological inactivation technique targeting
both the dorsal hippocampus and the medial prefrontal cortex was used
(i.e., axon-sparing lesions of the dorsal hippocampus combined with
reversible inactivation of the medial prefrontal cortex, or vice versa,
within a subject). A delayed nonmatching-to-place task on a radial
eight-arm maze with short-term (i.e., 10 sec) versus intermediate-term
(i.e., 5 min) delays was used as a behavioral paradigm. Here we report
that the dorsal hippocampus and the medial prefrontal cortex process short-term spatial memory in parallel, serving as a compensatory mechanism for each other. The role of the dorsal hippocampus, however,
becomes highlighted as the time-window for memory (i.e., delay) shifts
from short-term to a delay period (i.e., intermediate-term) exceeding
the short-term range. The results indicate that the time window of
memory is a key factor in dissociating multiple memory systems.
Key words:
dorsal hippocampus; medial prefrontal cortex; spatial working memory; ibotenic acid; quinolinic acid; short-term
memory; intermediate-term memory
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Introduction |
It is widely accepted that damage of
the hippocampal system typically produces an episodic or spatial memory
loss (Scoville and Milner, 1957 ; Jarrard, 1993; Eichenbaum, 2000).
However, a large number of studies indicate that
short-term memory is spared, whereas intermediate-term memory is
relatively impaired with damage to the hippocampal system in both
humans (Scoville and Milner, 1957; Eichenbaum et al., 1994;
Holdstock et al., 1995; Eichenbaum, 2000; Kesner and
Hopkins, 2001) and animals (Mishkin, 1978; Kesner and
Novak, 1982; Kesner and Adelstein, 1989; Winocur, 1992; Jarrard, 1993;
Alvarez et al., 1994; Eichenbaum et al., 1994; Steele and Morris,
1999; Eichenbaum, 2000; Clark et al., 2001). The relatively intact
short-term memory with hippocampal dysfunction in the above literature,
however, is somewhat in contrast to the computational models of the
hippocampus, because those models suggest that the hippocampus mediates
short-term memory mainly by virtue of the recurrent collaterals in CA3
brain region (Granger et al., 1996; Wiebe et al., 1997; Kesner and
Rolls, 2001).
To address the null effects of hippocampal damage on short-term memory
observed in previous literature, neocortical contributions have been
suggested (Eichenbaum et al., 1994; Eichenbaum, 2000). Among
neocortical areas, there is good evidence that the
prefrontal cortex (PFC) plays an important role in short-term memory,
especially in a delayed matching-
or nonmatching-to-sample task in which a correct choice
response for a stimulus (e.g., object or spatial location) is required
after a delay period (Delatour and Gisquet-Verrier, 1996; Floresco et
al., 1997; Porter et al., 2000; Fuster, 2001; Izaki et al., 2001).
Strong electrophysiological correlates can be identified during a
short-term delay period within PFC in nonhuman primates in
delayed-choice tasks (Rainer et al., 1998; Constantinidis et al.,
2001). The rodent medial PFC (mPFC) also plays an equivalent role in
tasks in which a delayed choice response to stimuli is required and
lesions of mPFC impair performance in delayed choice tasks (Shaw and
Aggleton, 1993; Delatour and Gisquet-Verrier, 1996).
The main goal of the current study was to examine the interactions
between PFC and the dorsal hippocampus in controlling short-term and
intermediate-term working memory for spatial information. A
double-manipulation technique consisting of axon-sparing lesion and
reversible inactivation within subjects was used in a delayed nonmatching-to-place task on a radial eight-arm maze. Our prediction is
that the dorsal hippocampus may play a more important role in
intermediate-term memory compared with mPFC based on the previous literature (Scoville and Milner, 1957; Mishkin, 1978; Kesner and Novak,
1982; Kesner and Adelstein, 1989; Winocur, 1992; Jarrard, 1993; Alvarez
et al., 1994; Eichenbaum et al., 1994; Holdstock et al., 1995; Steele
and Morris, 1999; Eichenbaum, 2000; Porter et al., 2000; Clark et al.,
2001; Fuster, 2001; Izaki et al., 2001; Kesner and Hopkins, 2001).
However, the dorsal hippocampus or mPFC may take over the function of
short-term spatial working memory when the other structure is
unavailable, because previous literature suggests that both the PFC and
the hippocampus are involved in spatial working memory with short-term
delays (Hampson et al., 1999; Fuster, 2001).
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Materials and Methods |
Subjects
Twenty-two male Long-Evans rats (260-400 gm) were housed
individually in standard rodent cages. They were maintained on a 12 hr
light/dark cycle. For behavioral testing, each rat was initially food
deprived to 80% of its free-feeding weight and allowed access to water
ad libitum. All behavioral experiments were performed during
the light phase of the light/dark cycle.
Behavioral apparatus
A radial eight-arm maze was used throughout the entire
experiment. The maze was surrounded by 8-10 distinct visual cues that were present mostly near the walls of the room. The maze had a center
platform with a diameter of 40 cm and eight arms of 60 cm long and 9 cm
wide. It also had Plexiglas walls 5.7 cm in height for each arm. All of
the arms of the maze had food wells 2.5 cm in diameter and 1.5 cm deep
at the distal ends. Rewards (Froot Loops cereal; Kellogg, Battle Creek,
MI) were placed in these wells. The center platform of the maze was
surrounded by walls and doors made of transparent Plexiglas, so that
rats could clearly see extramaze cues. Each door could be opened from
outside of the testing room. Above the center platform, there was a
cylindrical plastic bucket (38 cm in diameter and 75 cm in height) that
could be lowered from outside of the testing room. The bucket was
opaque and the inner wall was painted white, so that rats could not
detect any local cues on the inner bucket surface. The bucket, when
lowered down to the center platform, completely prevented rats from
viewing extramaze cues.
Procedures
Behavioral pretraining. Male Long-Evans rats
(n = 22) were trained on a radial eight-arm maze using
a delayed-nonmatching-to-place (DNMP) paradigm (Lee and Kesner, 2002).
After visiting an arm (i.e., study arm) for a reward, each rat was
confined in a bucket on the center platform for a 10 sec delay period
during which doors for both an adjacent arm (i.e., choice arm) and the
visited study arm were opened. The rat had to choose the unvisited
choice arm to receive a reward. If the rat selected the study arm again either by completely traversing the study arm to the end or when both
of the rear paws touched the study arm, it was recorded as an error. On
each trial, a study arm was randomly selected and a choice arm was
always an adjacent arm on either side (randomly chosen) of the study
arm. The purpose of this design was to make two arms (study and choice
arms) equally available at the time of the choice phase by preventing
the situation in which the rat might easily avoid choosing a study arm
by remembering the direction information of the study arm rather than
the spatial cues. Eight trials per day were given with an intertrial
interval of 20 sec for six blocks (two days were grouped as one block
to reduce possible daily variability from drug applications). After
pretraining to a criterion (>95% correct choices), each rat was given
surgery under Nembutal anesthesia for a cannula implant and a lesion.
Surgery. After behavioral pretraining rats
[HP/LES+mPFC/drug group (the group with dorsal hippocampal
lesions and drug injections into mPFC); n = 6] were
bilaterally implanted with guide cannulas (22 gauge) coupled
with stylets (28 gauge, 1 mm protrusion) in mPFC (i.e., prelimbic and
infralimbic areas) in addition to bilateral lesions of the dorsal
hippocampus with multiple injections of ibotenic acid (0.6 mg/ml;
0.2-0.3 µl/site) with a 10 µl Hamilton syringe
(Hamilton, Reno, NV) driven by a microinfusion pump
(Cole-Parmer, Vernon Hills, IL). Only the dorsal
hippocampus, not the ventral hippocampus, was targeted in our study on
the basis of its well known involvement in spatial learning and memory
(Moser et al., 993; Moser and Moser, 1998). The role of the dorsal
hippocampus in the current spatial working memory task was confirmed
previously in our laboratory (Lee and Kesner, 2002).
Each animal was injected with atropine sulfate (0.2 mg/kg, i.p.) and
deeply anesthetized with sodium pentobarbital (Nembutal; 60 mg/kg,
i.p.). The animal was placed in a stereotaxic instrument (David
Kopf Instruments, Tujunga, CA), and an incision was made along
the midline of the scalp. The skull was exposed, and the instrument was
adjusted to ensure a flat skull surface. Small burr holes were drilled
in the skull using the following coordinates: (1) hippocampal lesions:
(a) 2.8 mm posterior to bregma, 1.6 mm lateral to midline, and 3.0 mm
ventral from dura, (b) 3.3 mm posterior to bregma, 1.8 mm lateral to
midline, and 2.8 mm ventral from dura, and (c) 4.1 mm posterior to
bregma, 2.6 mm lateral to midline, and 2.8 mm ventral from dura; (2)
mPFC cannulas: 3.0 mm anterior to bregma, 2.0 mm lateral to midline,
and 4.6 mm ventral from dura with 25° angle from a vertical midline.
A control group [HP/CT+mPFC/drug group (the group with sham lesions in
the dorsal hippocampus and drug injections into mPFC);
n = 5] was generated using the same procedures, except
that saline was injected in the dorsal hippocampus instead of ibotenic acid.
The other group [HP/drug+mPFC/LES group (the group with drug
injections into the dorsal hippocampus and mPFC lesions);
n = 6] was implanted bilaterally with cannulas in the
dorsal hippocampus and bilateral lesions in mPFC with quinolinic acid
(0.09 M, 0.3-0.5 µl/site; Research
Biochemicals, Natick, MA). The following coordinates were used:
(1) hippocampal cannulas: 3.6 mm posterior to bregma, 2.4 mm lateral to
midline, and 2.8 ventral from dura; (2) mPFC lesions: (a) 3.5 mm
anterior from bregma, 0.6 mm lateral from midline, and 3.8 mm ventral
from dura, and (b) 2.5 mm anterior from bregma, 0.6 mm lateral from
midline, and 4.0 ventral from dura. The ventral coordinate was used to
adjust the depth of the tips of stylets coupled with the guide. A
control group [HP/drug+mPFC/CT group (the group with drug injections
into the dorsal hippocampus and control lesions in mPFC);
n = 5] was given the same surgical procedures, except
that saline was injected into mPFC. PBS, pH 7.4, or muscimol
(MUS) (0.5 µg/0.5 µl) was injected for all groups during behavioral
testing. All protocols conformed to the NIH Guide for the Care
and Use of Laboratory Animals and the Institutional Animal Care
and Use Committee at the University of Utah.
Behavioral postsurgery testing. After a recovery period,
the rats were retested in the same room used for pretraining with two
blocks of PBS injection into either the mPFC or the dorsal hippocampus
for a total of 32 trials (i.e., 4 d) using 10 sec delays. Then,
the animals were tested for 4 d with PBS injections using a
variable delay DNMP paradigm in which intermediate delays (i.e., 5 min;
four trials) were randomly intermixed with the original short delays
(i.e., 10 sec; four trials) in the session of a given day.
Finally, the rats were given 4 more days of the same variable delay
DNMP paradigm with muscimol injections.
Intracranial microinjection. The drug injection protocol
used for behavioral testing was as follows. Muscimol, a GABA agonist, was dissolved in PBS in final concentration of 0.5 µg/0.5 µl. Muscimol was chosen as an inactivating agent over other short-lasting inactivating agents [e.g., lidocaine (Martin, 1991)] considering the
relatively long testing period of our behavioral paradigm (~30 min,
especially in the 10 sec vs 5 min paradigm). Either muscimol or PBS was
injected bilaterally via an injection needle (28 gauge) 30 min before
the behavioral experiment of each day. The injection quantity was 0.5 µl/side, and the injection rate was at 0.1 µl/min. The injection
was made with a 10 µl Hamilton syringe driven by a microinfusion
pump. The injection needle was left in place for 1 min after the
injection. The rat was then returned to its home cage, and any
abnormality in movement from the drug injection was carefully examined
for 30 min before the rat was placed on the maze.
Histology
Histological verification of cannula positions and lesions was
performed after the completion of all behavioral experiments. Rats
received a lethal dose of sodium pentobarbital, followed by a
transcardial infusion of 0.9% saline and a 10% formaldehyde solution.
Each brain was stored in a 10% formalin-30% sucrose solution at
4°C for 72 hr. The brains were frozen, cut in coronal sections on a
cryostat, and stained with cresyl violet.
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Results |
Histology
Figure 1 illustrates the cannula
positions and the extent of neurotoxic lesions. Figure 1a
shows that all of the cannulas were implanted in the mPFC region in
rats included in final behavioral data analysis. It also shows that
ibotenic acid injected into the dorsal hippocampus was effective in
eliminating most of the dorsal hippocampus, although, in some cases,
minor overlying cortices were inevitably disrupted mainly from
mechanical damage by the injection needle. However, such cortical
damage was also observed in the control lesion groups, and, during
histological verification, most overlying cortices beyond the injection
sites were intact. No extrahippocampal damage (e.g., subiculum and
entorhinal cortex) was observed as a result of axon-sparing lesions.
Figure 1b shows that quinolinic acid injected into mPFC
region eliminated cells mostly in the prelimbic and infralimbic areas.
In some cases, ventromedial orbital areas as well as the anterior
cingulate region dorsal to the mPFC were affected as reported
previously (Ragozzino et al., 2002). Figure 1b also
illustrates histologically verified cannula positions in the dorsal
hippocampi. Most cannulas were placed in the upper dentate/hilar area
to maximize the spread of muscimol to the entire dorsal
hippocampus.
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Figure 1.
Illustration of the positions of the cannulas and
the extent of damage by excitotoxic lesions in a series of sections of
mPFC and dorsal hippocampus. a, Histological
verification of the HP/LES (or HP/CT)+mPFC/drug group. Cannula
positions are marked in mPFC ( , HP/CT+mPFC/drug group;  ,
HP/LES+mPFC/drug group). The largest and the smallest tissue damage
produced by ibotenic acid in the dorsal hippocampus (i.e.,
HP/LES+mPFC/drug group) are shown by gray and
black, respectively. b, Histological
verifications of the mPFC/LES (or mPFC/CT)+HP/drug group. Cannula
positions are shown in the dorsal hippocampus (, mPFC/CT+HP/drug
group; , mPFC/LES+HP/drug group). The largest and the smallest
tissue damage produced by quinolinic acid in mPFC are shown by
gray and black, respectively. The
anteroposterior stereotaxic coordinates for the sections were shown by
the numbers beside the sections (in millimeters)
(modified from Paxinos and Watson, 1997).
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Behavior
Spatial memory with short-term delays
Rats had to learn to choose between a visited arm (study
arm) and an unvisited arm (choice arm) with a short-term delay (10 sec)
imposed between the two arms of a radial eight-arm maze. Groups of rats
were given different combinations of neurotoxic (or sham) lesions and
cannulas implanted in the dorsal hippocampus and mPFC (i.e.,
HP/CT+mPFC/drug, HP/drug+mPFC/CT, HP/LES+mPFC/drug, and
HP/drug+mPFC/LES) (Fig. 1).
When the rats were tested for postsurgery performance in the same task
with PBS, pH 7.4, injections, both the HP/LES+mPFC/PBS (the group with
dorsal hippocampal lesions and PBS injections into the mPFC) and
the HP/PBS+mPFC/LES (the group with PBS injections into the dorsal
hippocampus and mPFC lesions) groups showed impaired performance (Fig.
2a) during the first block
(i.e., one block is 2 d of eight trials per day) compared with the
CT group [data from the HP/CT+mPFC/PBS (the group with control lesions
in the hippocampus and PBS injections into the mPFC) and the
HP/PBS+mPFC/CT (the group with PBS injections into the hippocampus and
control lesions in the mPFC) groups were combined into one control
group, CT, because of a lack of significant difference between the two groups (p > 0.5)]. The deficit in performance
in both groups, however, recovered to control levels by the second
block. An ANOVA with a repeated-measures design showed a significant
effect of groups (F(2,19) = 20.5;
p < 0.001). There were also significant effects of
blocks (F(1,19) = 35.8;
p < 0.001) and the interaction between groups and
blocks (F(2,19) = 5.8;
p < 0.05). A post hoc analysis [Tukey's
honestly significant difference (HSD)] demonstrated that, only
in block 1, both the HP/LES+mPFC/PBS and the HP/PBS+mPFC/LES groups
were significantly impaired in performance compared with the CT group
(p values of <0.001) with no significant difference between the two groups (p values of >0.1). The time
spent on the study arm (i.e., study-arm duration) was recorded. The
latency to obtain the reward at the end of the choice arm (i.e., choice latency) was also measured. Those activity measures (i.e., study-arm duration and choice latency) (Fig. 2b) showed no significant
difference among the groups (p values of >0.1 for
both measures).
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Figure 2.
Postsurgery performance in a short-term spatial
water maze task. a, Choice accuracy for two
blocks with PBS injections into either the dorsal hippocampus or mPFC
after surgery (1 block is 2 d of 8 trials per day). Note the
initial deficit in both lesion groups (but more severely in the
mPFC/LES group) in block 1 yet with improvement in block 2. b, Average activity levels of different lesion groups
during postsurgery performance in the spatial working memory task
(Study arm duration, the time spent on a study arm;
Choice latency, the latency to reach the end of a choice
arm from the center platform). There were no significant differences
among the groups. CT, Control group;
HP/LES, the group with dorsal hippocampal lesions and
PBS injections into mPFC; mPFC/LES, the group with mPFC
lesions and PBS injections into the dorsal hippocampus.
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Spatial memory with intermediate-term delays
To test the time-dependent functional relationship between mPFC
and the dorsal hippocampus, four intermediate-delay (i.e., 5 min)
trials were randomly intermixed with four original short-delay (i.e.,
10 sec) trials, thus forming a block of eight trials of variable delays
per day. All of the groups were first injected with PBS during two
blocks of testing (i.e., 4 d). Then, they were tested with MUS
injections for two more blocks. A dynamic interaction between mPFC and
the dorsal hippocampus was observed as a result (Fig.
3). The hippocampal control lesion group
(HP/CT) exhibited no difference in choice accuracy between the PBS and MUS injections into mPFC (Fig. 3a). The mPFC control lesion
group (mPFC/CT) showed lower choice accuracy only in 5 min delay trials when MUS was injected into the dorsal hippocampus compared with PBS
injections (Fig. 3b). Compared with PBS injections, the
hippocampal lesion group (HP/LES) showed a marked deficit in choice
accuracy only in 10 sec delay trials with MUS injections into mPFC,
whereas both PBS and MUS injections disrupted performance in 5 min
delay trials with hippocampal lesions (Fig. 3c). The mPFC
lesion group (mPFC/LES) was impaired in both delay conditions (i.e., 10 sec and 5 min) when MUS was injected into the dorsal hippocampus
compared with PBS injections (Fig. 3d). An ANOVA performed
with groups as a between-subject variable and both drugs and delays as
two within-subject variables revealed significant effects of groups (F(3,18) = 106.2; p < 0.001), drugs (F(1,18) = 272.1;
p < 0.001), and delays
(F(1,18) = 269.7; p < 0.001). There were significant interaction effects between groups and
within-subjects variables: groups × drugs,
F(3,18) = 44.5, p < 0.001; groups × delays, F(3,18) = 9.4 , p < 0.001); and groups × drugs × delays, F(3,18) = 32.1, p < 0.001).
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Figure 3.
Choice accuracy in different lesion groups after
the injection of PBS or MUS in 10 sec or 5 min delay trials.
a, The hippocampal control lesion group
(HP/CT) exhibited no difference in choice
accuracy between the conditions with MUS and PBS injections into mPFC.
b, The mPFC control lesion group
(mPFC/CT) showed lower choice accuracy only in 5 min delay trials with MUS injection into the dorsal hippocampus
compared with PBS injection. c, Compared with PBS
injection, the hippocampal lesion group (HP/LES) showed
a marked deficit in choice accuracy only in 10 sec delay trials with
MUS injection into mPFC. Both PBS and MUS injections disrupted
performance in 5 min delay trials in the hippocampal lesion group.
d, The mPFC lesion group (mPFC/LES) was
impaired in both delay conditions (i.e., 10 sec and 5 min) when MUS was
injected into the dorsal hippocampus compared with PBS injection.
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An additional post hoc analysis (Tukey's HSD)
demonstrated that the HP/LES+mPFC/PBS group (Fig. 3c) was
significantly different in choice accuracy in 5 min delay trials from
the other PBS-injected groups (i.e., HP/CT+mPFC/PBS,
HP/PBS+mPFC/CT, and HP/PBS+mPFC/LES) (p values
of <0.001). Both double-inactivation groups for the dorsal hippocampus
and mPFC (i.e., the HP/LES+mPFC/MUS and the HP/MUS+mPFC/LES in Fig. 3,
c and d, respectively) were significantly different in 10 sec delay trials from both single-inactivation groups
with sham lesions (i.e., the HP/CT+mPFC/MUS and the HP/MUS+mPFC/CT) in
choice accuracy (p values of <0.001). In 5 min delay
trials, the HP/CT+mPFC/MUS group (Fig. 3a) showed
significantly higher choice accuracy compared with the HP/MUS+mPFC/CT
group (p < 0.01) and the other two hippocampal
inactivation groups (i.e., HP/LES+mPFC/MUS and HP/MUS+mPFC/LES;
p values of <0.001). The activity measures showed no
significant difference among the groups in the MUS-injection conditions
(p values of >0.1 in both measures) (Fig.
4). The results showed that short-term
memory (i.e., 10 sec) was intact only when either the dorsal
hippocampus or mPFC was allowed to function normally. Intermediate-term
memory (i.e., 5 min), however, was severely impaired whenever the
dorsal hippocampus was inactivated, regardless of mPFC
inactivation.
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Figure 4.
Average activity levels for different groups
during 10 sec and 5 min delay trials (Study arm
duration, the time spent on a study arm; Choice
latency, the latency to reach the end of a choice arm from the
center platform). No significant differences were found among the
groups when MUS was injected.
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Discussion |
Our results showed that inactivating either mPFC or the dorsal
hippocampus produced an initial deficit in short-term (i.e., 10 sec)
spatial working memory, which eventually improved over time to a normal
level of performance. This suggests that inactivating one of these
structures initially affected the short-term working memory system, but
a compensatory adjustment was made to achieve normal performance.
Therefore, it seems that the dorsal hippocampus and mPFC normally
process short-term spatial working memory in parallel, which may
explain the null effect of hippocampal damage on short-term or
immediate memory in the previous literature (Scoville and Milner, 1957;
Mishkin, 1978; Kesner and Novak, 1982; Kesner and Adelstein, 1989;
Winocur, 1992; Jarrard, 1993; Alvarez et al., 1994; Eichenbaum et al.,
1994; Holdstock et al., 1995; Steele and Morris, 1999; Eichenbaum,
2000; Porter et al., 2000; Clark et al., 2001; Kesner and Hopkins,
2001). The data also support, based on computational models, a proposed
role for the dorsal hippocampus in short-term memory (Granger et al.,
1996; Wiebe et al., 1997; Kesner and Rolls, 2001). After the system
becomes stabilized, presumably as a result of a compensatory mechanism in the absence of one structure, this compensatory structure might be
sufficient for normal performance when information needs to be stored
for only seconds (Fig. 2a). Inactivating both regions at the
same time, however, resulted in a severe impairment of short-term
spatial working memory, suggesting that one of the structures needs to
function properly for intact processing of short-term spatial working
memory. Importantly, the dorsal hippocampus became a necessary
structure for spatial working memory after an intermediate-term delay
(i.e., 5 min), whereas mPFC failed to show compensation for this time
window (Fig. 3), suggesting a unique function for the dorsal
hippocampus in the time range longer than short term (Scoville and
Milner, 1957; Mishkin, 1978; Kesner and Novak, 1982; Kesner and
Adelstein, 1989; Winocur, 1992; Jarrard, 1993; Alvarez et al., 1994;
Eichenbaum et al., 1994; Holdstock et al., 1995; Steele and Morris,
1999; Eichenbaum, 2000; Porter et al., 2000; Clark et al., 2001; Kesner
and Hopkins, 2001).
Memory appears to be the product of dynamic interactions among multiple
systems in the brain, and the interaction between the hippocampal and
neocortical systems has turned into a topic of importance in studying
hippocampal function in memory (Mishkin and Appenzeller, 1987; Squire,
1992; Eichenbaum et al., 1994; Nadel, 1995; Eichenbaum, 2000; Maguire
et al., 2000). Although the concept of interaction among multiple brain
systems has well been accepted (Nadel et al., 2000; Kim and Baxter,
2001), the mnemonic constraints that control the nature of interaction
among those systems are primarily unknown. The current results
suggest that the time window of memory (i.e., intermediate-term delay) is a critical factor in dissociating the function of the dorsal hippocampus from that of mPFC in a delayed choice task. The initial deficits exhibited in both HP/LES+mPFC/PBS and HP/PBS+mPFC/LES groups
suggest that normally there is parallel processing between the dorsal
hippocampus and mPFC for spatial working memory that operates within a
short-term range. However, the dorsal hippocampus becomes more
essential once the critical time window entails spatial working memory
for a period exceeding a short-term range. There are several
possibilities that may explain this delay-dependent function toward the
dorsal hippocampus for spatial working memory. That is, mPFC may not
have a suitable neural architecture to hold spatial items for more than
several seconds. The recurrent networks within the dorsal hippocampus
(e.g., CA3), with the aid of the hippocampal-parahippocampal loop, may
be better suited to circulate spatial information for a longer time
period compared with mPFC. Therefore, the dorsal hippocampus and mPFC
might process spatial working memory in parallel initially for a
short-term period, but as soon as the system detects that the delay
period is prolonged from short-term to intermediate-term (or
long-term), hippocampal memory may become essential, demonstrating more
persistence than mPFC memory. Alternatively, mPFC per se may not
maintain spatial items (Rowe et al., 2000) but has access to multiple
brain regions. The rats with hippocampal lesions might still be able to
perform well on short-term delay trials, because other associational
sensory cortices than the dorsal hippocampus could still provide
information on sensory cues to mPFC for a short-term delay period.
However, this information access hypothesis for mPFC does not seem to
be universally applicable, because an mPFC inactivation alone spares short-term working memory (Dias and Aggleton, 2000; Izaki et al., 2001), as well as in our case, intermediate-term spatial working memory.
A previous disconnection experiment (Floresco et al., 1997) showed that
the interaction between the hippocampus and mPFC was necessary for rats
to perform a spatial working memory task with a 30 min delay. However,
our results demonstrates that mPFC might not be necessary for an
intermediate- or long-term delayed response when only a simple rule
(i.e., win shift) is applied to a very small number of trial-unique
items (i.e., two different arms per trial in our task). Once a task
requires prospective coding (Rainer et al., 1998) of a sequence of
several spatial items during an intermediate-term delay [i.e., 30 min
(Floresco et al., 1997)], based on memory of previously coded items
(i.e., during sample phase), the interactive communication between the
hippocampus and mPFC might become intensified (Floresco et al., 1997),
thus resulting in a performance deficit with even one of the
communicating partners disabled (Ragozzino et al., 1998). That is, the
interaction between the "past" (hippocampus) and the "future"
(PFC) may need the intimate PFC-hippocampal interaction especially
when those items need to be organized sequentially with a significant
amount of delay. Such prospective coding based on retroactive search in
memory might be very difficult in our task, because the animals had no
prediction, during a delay period, on which side's adjacent arm to a
study arm would be chosen as a test arm. Therefore, additional investigation is needed to determine whether the hippocampal-PFC interaction is critical primarily when proactively guidance and/or temporal integration of sequential responses are required (Seamans et
al., 1995; Miller, 2000; Fuster, 2001). Furthermore, the relatively long period of delay (i.e., 30 min) combined with removal of the rats
from the behavioral context, thus necessitating the reinstatement of
the context at the time of testing (Redish, 2001), may further recruit
the active PFC-hippocampal interaction in the study (Floresco et al.,
1997).
Our study provides an essential bridge between the two memory systems
that have been emphasized as important in supporting short-term memory
(Mishkin, 1978; Kesner and Novak, 1982; Kesner and Adelstein, 1989;
Winocur, 1992; Shaw and Aggleton, 1993; Alvarez et al., 1994; Holdstock
et al.,1995; Delatour and Gisquet-Verrier, 1996; Granger et al., 1996;
Floresco et al., 1997; Wiebe et al., 1997; Rainer et al., 1998; Steele
and Morris, 1999; Porter et al., 2000; Clark et al., 2001;
Constantinidis et al., 2001; Fuster, 2001; Izaki et al., 2001; Kesner
and Hopkins, 2001; Kesner and Rolls, 2001). The current results provide
compelling evidence indicating that a mnemonic time window is a
critical factor in dissociating the function of the hippocampal system
from that of mPFC in a delayed choice task. That is, the dorsal
hippocampus and mPFC appear to process spatial memory in parallel
within a short-term range, whereas the dorsal hippocampal function
becomes more essential once the critical time window requires spatial memory for a time period exceeding that range.
Given the previously suggested executive and integrative role of PFC
(Miller, 2000; Fuster, 2001; Tanji and Hoshi, 2001), our results
suggest that PFC may have similar interactions with other brain regions
[e.g., inferior temporal cortex (Fuster, 2001; Rolls and Deco,
2002)]. That is, PFC may possess the capability of monitoring
virtually the same information processed in other brain regions (e.g.,
spatial information in the dorsal hippocampus or object-identity
information in the inferior temporal cortex) mainly to strategically
coordinate multiple systems to achieve a goal. Although the current
study showed that the length of delay was one of the critical factors
in dissociating parallel coding between the dorsal hippocampus and PFC,
what other factors [e.g., familiarity vs novelty (Dolan and Fletcher,
1997; Parkin, 1997; Stern et al., 2001) or prospective vs retrospective
coding (Kesner, 1989; Floresco et al., 1997)] also contribute to the
interaction between the dorsal hippocampus and PFC (as well as other
neocortical structures) needs additional investigation. Because PFC is
the brain region that has presumably the most dynamic and richest interactions with other brain regions, it is suggested that
understanding the nature of PFC in the context of function of other
brain regions is essential (Fuster, 2001).
| |
FOOTNOTES |
Received Sept. 9, 2002; revised Nov. 13, 2002; accepted Nov. 22, 2002.
The work was supported by Human Frontiers Science Program Grant
RG0110/1998B and National Science Foundation Grant IBN 9817583.
Correspondence should be addressed to Raymond P. Kesner, Department of
Psychology, University of Utah, 380S 1530E Room 502, Salt Lake City, UT
84112. E-mail: rpkesner{at}behsci.utah.edu.
| |
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TOP
ABSTRACT
Introduction
