 |
 Previous Article | Next Article 
The Journal of Neuroscience, January 1, 2003, 23(1):17-22
BRIEF COMMUNICATION
The Hippocampus Plays an Important Role in Eyeblink Conditioning
with a Short Trace Interval in Glutamate Receptor Subunit  2 Mutant
Mice
Kanako
Takatsuki1,
Shigenori
Kawahara1, 3,
Sadaharu
Kotani1,
Satoshi
Fukunaga1,
Hisashi
Mori2,
Masayoshi
Mishina2, and
Yutaka
Kirino1
1 Laboratory of Neurobiophysics, School of
Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan, 2 Department of Molecular Neurobiology and
Pharmacology, Graduate School of Medicine, The University of Tokyo, and
Solution Oriented Research for Science and Technology, Japan Science
and Technology Corporation, Tokyo 113-0033, Japan, and
3 Core Research for Evolutional Science and Technology,
Japan Science and Technology Corporation, Saitama 332-0012, Japan
 |
ABSTRACT |
Mutant mice lacking the glutamate receptor subunit  2 exhibit
changes in the structure and function of the cerebellar cortex. The
most prominent functional feature is a deficiency in the long-term depression (LTD) at parallel fiber-Purkinje cell synapses. These mutant mice exhibit severe impairment during delay eyeblink
conditioning but learn normally during trace eyeblink conditioning
without the cerebellar LTD, even with a 0 trace interval. We
investigated the hippocampal contribution to this cerebellar
LTD-independent "0 trace interval" learning. The mutant mice whose
dorsal hippocampi were aspirated exhibited severe impairment in
learning, whereas those that received post-training hippocampal lesions
retained the memory. The wild-type mice showed no impairment in either case. These results suggest that the hippocampal component of the
eyeblink conditioning task becomes dominant when cerebellar LTD is impaired.
Key words:
classical conditioning; eyeblink; hippocampus; cerebellum; long-term depression; mouse
| |
Introduction |
The hippocampus is involved in
various kinds of learning (Morris et al., 1982 ; Barnes, 1988). Although
its role could be interpreted in terms of behavioral function, the
exact mechanism to execute that function remains to be elucidated. To
achieve this understanding, knowledge about the neural network, with
which the hippocampus interacts, is critical. Classical eyeblink
conditioning is one of candidates from which such knowledge could be
obtained. In this learning, the essential neural circuit has been
studied extensively with a delay paradigm, in which the unconditioned
stimulus (US) is delayed and coterminates with the conditioned stimulus
(CS). Thompson and colleagues have indicated that the locus of the
memory trace is in the cerebellum; they stress the importance for
memory function of long-term depression (LTD) at parallel fiber
(PF)-Purkinje cell (PC) synapses, as well as the presumptive
plasticity in the interpositus nucleus (Kim and Thompson, 1997).
The contribution of the hippocampus to eyeblink conditioning has been
shown to differ across conditioning paradigms. For example, an intact
hippocampus is required for successful learning in trace conditioning
(Solomon et al., 1986; Moyer et al., 1990) and discrimination reversal conditioning (Berger and Orr, 1983) but not in delay conditioning (Solomon et al., 1986).
We investigated previously classical eyeblink conditioning in mutant
mice lacking the glutamate receptor subunit 2 (GluR2). These
mutant mice exhibit a selective dysfunction of the cerebellar cortex,
impaired cerebellar LTD (Kashiwabuchi et al., 1995), a decrease in the
number of PF-PC synapses (Kurihara et al., 1997), and multiple
innervation of PCs by climbing fibers (Kashiwabuchi et al., 1995).
Consistent with the hypothesis that cerebellar LTD plays a critical
role in eyeblink conditioning (Ito, 1989; Thompson and Kim, 1996),
GluR2 / mice exhibited severe
impairment in learning when a delay paradigm was used (Kishimoto et
al., 2001a). However, GluR2/ mice
learned normally in the trace paradigm, in which a stimulus-free trace
interval intervenes between the CS and US (Kishimoto et al., 2001a),
and even in a "trace 0 paradigm," in which the US starts just after
the CS ends (Kishimoto et al., 2001c). These results suggest that
another learning mechanism, one that does not require cerebellar LTD,
underlies the ability of GluR2/
mice to learn in eyeblink conditioning paradigms in which
the US does not overlap with the CS. Results in another cerebellar LTD-deficient mouse lacking the phospholipase C 4 subunit also support this hypothesis (Kishimoto et al., 2001b).
Furthermore, we found recently that scopolamine impairs cerebellar
LTD-independent learning in GluR2/
mice (Takatsuki et al., 2002). This suggests that the hippocampus contributes to LTD-independent learning, because scopolamine slows delay eyeblink conditioning primarily through its effect on the hippocampus (Solomon et al., 1983) via the septum (Solomon and Gottfried, 1981); scopolamine also impairs trace eyeblink conditioning, which we know requires an intact hippocampus (Kaneko and Thompson, 1997). To examine the hippocampal contribution to cerebellar
LTD-independent learning, we investigated the effect of hippocampal
lesions on learning using a trace 0 paradigm with
GluR2/ mice.
| |
Materials and Methods |
Subjects and surgery. We used
GluR2/ mice with a 99.99% C57BL/6
genetic background (Kishimoto et al., 2001a) and wild-type C57BL/6 mice
(Japan SLC, Hamamatsu, Shizuoka, Japan). The animals were kept on a 12 hr light/dark cycle with ad libitum access to food and
water. All experiments were performed in accordance with the guidelines
established by the Institutional Animal Investigation Committee at the
University of Tokyo and the National Institutes of Health Guide
for the Care and Use of Laboratory Animals. Before surgery, the
animals were anesthetized with ketamine (80 mg/kg, i.p.; Sankyo, Tokyo,
Japan) and xylazine (20 mg/kg, i.p.; Bayer, Tokyo, Japan). A bilateral
aspiration of the dorsal hippocampus and overlying neocortex was
performed on the hippocampal lesion group. The control group received
only bilateral aspiration of the neocortex. Four Teflon-coated
stainless steel wires (#7910; A-M Systems, Carlsborg, WA) were
implanted to record electromyographic (EMG) activity and to deliver a
periorbital shock, as described in our previous report (Kishimoto et
al., 2001a).
Behavioral training. At least 3 d after implanting the
electrodes, the animals were given 2 d to adapt to the
experimental apparatus, during which EMGs were recorded to calculate
spontaneous eyeblink frequency. The conditioning began the next day.
Daily conditioning consisted of 90 CS-US paired trials and 10 CS-alone trials on every 10th trial, with a pseudorandomized intertrial interval
of 20-40 sec. In the paired trials, a 352 msec tone CS (1 kHz, 90 dB)
was followed by a 100 msec periorbital shock US (100 Hz square pulses).
The US intensity was carefully calibrated to elicit an
eyeblink-head-turn response and adjusted daily for each animal;
it ranged from 8 to 17 V (Kishimoto et al., 2001a). The
interstimulus interval was set at 352 msec so that the trace interval
was 0 msec.
Data analysis. The conditioned response (CR) was monitored
through eyelid EMG activity, and the analysis of that activity was
performed as described previously (Kishimoto et al., 2001a). In brief,
mean + SD of the amplitudes of the EMG activity for 300 msec before CS
onset in 100 trials was defined as the threshold, which was then used
in the analysis below. In each trial, average values of EMG amplitude
above the threshold were calculated for 300 msec before CS onset
(pre-value), 30 msec after CS onset (startle-value), and 202 msec
before US onset (CR-value). If both the pre-value and startle-value
were <10% of threshold, the trial was regarded as a valid trial.
Among the valid trials, a trial was assumed to contain the CR if the CR
value was larger than 1% of threshold and it exceeded two times the
pre-value. For the CS-alone trials, the period for CR-value calculation
was extended to the CS end. To evaluate the effect on the startle
response, we calculated the frequency of trials in which the
startle-value exceeded 10% of threshold. The frequency of CRs in the
valid trials (CR%) was expressed as mean ± SEM. Statistical
significance was determined by a two-way ANOVA and a three-way
repeated-measures ANOVA using SPSS (Chicago, IL) statistical
software. p < 0.05 was considered significant in this study.
Experimental protocols. In acquisition experiments, mice
first received the lesion, electrodes were implanted after a recovery period of 10 d, and then conditioning occurred for 7 d for CR acquisition. In the retention experiments, the order was electrode implanting, acquisition sessions, and then lesion. Mice for which CR%
reached the criteria described below were divided randomly into two
groups and received a cortical lesion or a hippocampal lesion on the
next day. After a recovery period of 2 weeks, all mice underwent 7 d of retention testing (CS-US paired session). In retention experiment
1, mice underwent 7 d of acquisition session. We used only
those mice whose CR% exceeded 50% on the seventh day of the
acquisition session. In retention experiment 2, mice were conditioned
until their CR% exceeded 70%. The mice that did not reach this
criterion after 14 d of acquisition session were excluded from
additional study.
Histology. After completing all behavioral experiments, the
mice were overdosed with sodium pentobarbital and perfused
transcardially with 0.9% saline, followed by 10% Formalin. Brains
were removed and placed in 10% Formalin. Before sectioning, brains
were placed in a 30% sucrose solution overnight. Frozen sections (40 µm thick) were made using a cryostat and stained with cresyl violet.
The largest and smallest lesioned areas were reconstructed from the sections according to the stereotaxic atlas of the mouse brain (Paxinos
and Franklin, 2001).
| |
Results |
Histology
To confirm the extent of each lesion, coronal sections (40 µm
thick) were made through the length of the hippocampus after conclusion
of the behavioral experiments. We completely removed the dorsal
hippocampus in all mice in the hippocampal-lesion group (Fig.
1B). Although some of
them retained the posteroventral portion of the hippocampus, the
fimbria was bilaterally transected so that the remaining ventral
hippocampus was isolated from the fornix. There was no damage to
surrounding structures, such as the amygdala, thalamus, or entorhinal
cortex, except the overlying neocortex. The results of the histological
analysis are summarized in Figure 1, C and D.
View larger version (53K):
[in this window]
[in a new window]
|
Figure 1.
Extent of hippocampal lesion. A,
B, Typical brain sections from the control group
(A) and the hippocampal-lesion group
(B). Sections of 40 µm were stained with cresyl
violet. Scale bars, 1 mm. C, D,
Histological reconstruction of the control group
(C) and the hippocampal-lesion group
(D). The filled and
shaded areas indicate the least and the most extensive
lesions, respectively. Numbers on the
left indicate stereotaxic coordinates (in
millimeters) relative to bregma.
|
|
Acquisition of the CR depends primarily on the hippocampus
in GluR2 mutant mice
When conditioned using a trace 0 paradigm, the
hippocampal-lesioned GluR2/ mice
exhibited severe learning impairment compared with the
cortical-lesioned GluR2/ mice (Fig.
2B). In contrast, the
hippocampal-lesioned wild-type mice learned as normally as the control
wild-type mice did (Fig. 2A). A three-way
repeated-measures ANOVA revealed that there was a significant effect
for lesion type (F(1,203) = 14.645;
p < 0.001) and for genotype
(F(1,203) = 4.891; p < 0.05), indicating that the learning impairment attributable
to a hippocampal lesion differed between wild-type and
GluR2/ mice. There was no
significant effect of interactions between sessions and lesion type
(F(6,203) = 0.089; p > 0.9) or between sessions and genotype
(F(6,203) = 0.708; p > 0.6).
View larger version (30K):
[in this window]
[in a new window]
|
Figure 2.
Effect of hippocampal lesions made before
conditioning. A, B, CR% in wild-type
(A) and GluR2/
(B) mice. These mice received a bilateral
aspiration of the dorsal hippocampus and the overlying neocortex
(hippocampal-lesion; filled circles;
n = 7 for wild-type mice and n = 8 for mutant mice) or only the overlying neocortex (cortical-lesion;
open circles; n = 8 for wild-type
mice and n = 9 for mutant mice). C,
CR% of the individual mice in the hippocampal-lesioned
GluR2/ sample. Each line
represents the CR% of the individual mice. D, Temporal
pattern of the CR in GluR2/ mice. The EMG
amplitude data in the last session were averaged and normalized by the
activities before the CS in GluR2/ mice. The
thin, thick, and dotted
traces represent the control group, learned
hippocampal-lesioned group, and nonlearned hippocampal-lesioned group,
respectively. The horizontal lines at the
bottom indicate the timing of the CS.
|
|
Although most of the hippocampal-lesioned
GluR2/ mice exhibited severe
learning impairment, two of them learned well, resulting in a smaller
increase of CR% on average. The CR% reached ~90% in one mouse and
50% in another mouse by the end of training and stayed almost at
spontaneous levels in the remaining six mice (Fig. 2C). The
extent of the hippocampal lesion in these two learned mice was
intermediate, showing no correlation with their CR%. To investigate
the temporal pattern of the EMG activities of these mice, the amplitude
data of the valid trials in the last session were averaged in each
mouse and then over the mice. Therefore, the pattern does not depend on
the criterion used for CR detection. Consistent with their CR%, the
amplitude of the average EMG activities of the six nonlearned
hippocampal-lesioned GluR2/ mice
was small, whereas that of the two learned mice was similar to that of
the control mice (Fig. 2D). The temporal pattern of the EMG activities was not noticeably changed in either groups, which
is consistent with the previous results with this line of mutant mice
(Kishimoto et al., 2001a,c).
Retention experiment 1: the hippocampus is not essential for
retention of the CR in GluR2 mutant mice
Next, we tested whether the hippocampus was required for retention
of the CR. In this experiment, mice received the lesion after 7 d
of acquisition sessions. Eighteen of 28 wild-type mice and 20 of 31 GluR2/ mice reached the criterion
(see Materials and Methods). Their CR% at the last acquisition session
was 73.4 ± 3.9 and 73.6 ± 4.2%, respectively. Even after
removing the hippocampus and the overlying cortex, the CR remained at
the same level as before, in both wild-type mice (Fig.
3A) and
GluR2/ mice (Fig. 3B). A
three-way repeated-measures ANOVA revealed that the CR% of the
postlesion sessions was not significantly influenced by lesion type
(F(1,196) = 3.103; p > 0.05) or by genotype (F(1,196) = 0.131; p > 0.7), indicating that the hippocampus is not necessary for retention of the CR in either
GluR2/ mice or the wild-type mice.
Figure 3C shows the retention index of the CR,
calculated by dividing the CR% in the first postlesion session by the
CR% in the last prelesion session. A two-way ANOVA revealed that there
was no significant effect for either lesion type
(F(1,27) = 0.477; p > 0.4) or genotype (F(1,27) = 0.793; p > 0.3). The average temporal pattern of the EMG
activities in the first postlesion session of the hippocampal-lesioned
GluR2/ mice was also almost the
same as that of the control mutant mice (Fig. 3D).
View larger version (17K):
[in this window]
[in a new window]
|
Figure 3.
Effect of hippocampal lesions made after 7 d
of conditioning. A, B, CR% in wild-type
(A) and GluR2/
(B) mice. Mice were conditioned using a trace 0 paradigm for 7 d (1-7) and then on the next
day received a hippocampal lesion (filled
circles; n = 8 for wild-type mice and
n = 7 for mutant mice) or a cortical lesion
(open circles; n = 8 for wild-type
mice and n = 8 for mutant mice). After 2 weeks of
recovery, the mice were conditioned again for an additional 7 d
(p1-p7). C, Retention
index of the CR after the lesion. The ratio of the CR% in the first
postlesion session to that in the last prelesion session was calculated
for wild-type mice (wt) and for mutant mice
(d2). c and h refer to
cortical lesion and hippocampal lesion, respectively. D,
The temporal pattern of the CR in the first postlesion session of
GluR2/ mice. The thin and
thick traces represent the control group and
hippocampal-lesioned group, respectively.
|
|
Retention experiment 2: the hippocampus is partially involved for
retention or expression of the CR right after reaching asymptotic
level
The retention experiment 1 indicated that the hippocampus is not
essential for retention of the CR a few days after reaching asymptotic
level. In this experiment, we examined the contribution of the
hippocampus in an early phase of the asymptotic state of memory. Mice
received the lesion on the next day after their CR% exceeded 70%.
Seventeen of 20 wild-type mice and 18 of 22 GluR2/ mice reached the criterion.
Their CR% in the last session and the number of days conditioned were
84.9 ± 2.2% and 3.4 ± 0.5 d in the wild-type mice and
85.4 ± 2.5% and 5.1 ± 0.9 d in the GluR2/ mice. They were assigned
randomly to the lesion groups.
In the wild-type mice, the hippocampal-lesion group retained the memory
as well as the control group (Fig.
4A). In
GluR2/ mice, the hippocampal-lesion
group exhibited moderate impairment in retention of the CR compared
with the cortical-lesion group (Fig. 4B). Among the
eight hippocampal-lesioned GluR2/
mice, five mice retained the CR well, whereas the other three mice
showed severe impairment, although two of the latter three mice showed
an increase in CR% during the subsequent conditioning (Fig.
4D). Among seven cortical-lesioned
GluR2/ mice, five mice retained the
CR well, whereas the other two mice showed impairment (Fig.
4C). A two-way ANOVA on the retention index (Fig.
4E) revealed that there was no significant effect for
lesion type (F(1,28) = 0.772;
p > 0.3) or genotype
(F(1,28) = 1.335; p > 0.2), suggesting that the effect of the hippocampal lesion in
GluR2/ mice was limited. The
average temporal pattern of the EMG activity in the first postlesion
session of the hippocampal-lesioned
GluR2/ mice also was similar to
that of the control mutant mice (Fig. 4F). During the
postlesion sessions, the CR% of the hippocampal-lesioned GluR2/ mice (Fig.
4D) was unstable compared with the cortical-lesioned mice (Fig. 4C). A three-way repeated-measures ANOVA revealed
that there was significant effect for both lesion type
(F(1,203) = 9.007; p < 0.01) and genotype (F(1,203) = 23.539; p < 0.001).
View larger version (23K):
[in this window]
[in a new window]
|
Figure 4.
Effect of hippocampal lesions made
immediately after conditioning. A, B,
CR% in wild-type (A) and
GluR2/ (B) mice. Mice
were conditioned until their CR% exceeded 70% and on the next day
received a hippocampal lesion (filled circle;
n = 9 for wild-type mice and n = 8 for mutant mice) or a cortical lesion (open circle;
n = 8 for wild-type mice and n = 7 for mutant mice).  1 and p1-p7
represent the last prelesion session and the postlesion sessions,
respectively. C, D, CR% of the
individual mice in the cortical-lesioned
GluR2/ mice (C) and
hippocampal-lesioned GluR2/ mice
(D). Each line represents the CR%
of the individual mice. E, Retention index (see Fig.
3C) of the CR after the lesion. c and
h refer to cortical lesion and hippocampal lesion,
respectively. F, The temporal pattern of the CR in the
first postlesion session of GluR2/ mice. The
thin and thick traces represent the
control group and hippocampal-lesioned group, respectively.
|
|
The basic sensory and motor performances are normal
To check for any possible effects of these lesions on the basic
sensory or motor performance involved in eyeblink conditioning, we also
looked at spontaneous eyeblink and startle responses to a tone.
Spontaneous eyeblink frequency was not influenced by hippocampal destruction in either wild-type mice or
GluR2/ mice (Fig. 2). A two-way
ANOVA indicated no significant interaction effects between genotype and
lesion type (F(1,28) = 0.005;
p > 0.9) and no significant effects for genotype
(F(1,28) = 0.856; p > 0.3) or lesion type (F(1,28) = 2.885;
p = 0.1). The frequency of the startle responses during
conditioning was 5.5 ± 0.6% (n = 8) and 5.7 ± 0.6% (n = 7) for the cortical- and
hippocampal-lesioned wild-type mice, respectively, and 5.7 ± 0.5% (n = 9) and 5.0 ± 0.6% (n = 8) for the cortical- and hippocampal-lesioned
GluR2/ mice, respectively. The mean
startle response of the hippocampal-lesion group was almost the same as
that of the control group and did not increase during conditioning.
There were no significant effects for genotype
(F(1,203) = 0.108; p > 0.7), lesion type (F(1,203) = 0.240; p > 0.6), or session
(F(6,203) = 0.525; p > 0.7).
| |
Discussion |
In the present study, we demonstrated that ablation of the dorsal
hippocampus severely impairs the acquisition of a CR in GluR2/ mice. This result clearly
indicates that eyeblink conditioning with a short trace interval in
GluR2/ mice depends primarily on
the hippocampus and mirrors the effect of scopolamine in
GluR2/ mice (Takatsuki et al.,
2002), thus supporting the idea that the functional hippocampus is
important to cerebellar LTD-independent learning to occur.
Previous studies using rabbits and rats have indicated that the
hippocampus is required for eyeblink conditioning with a long trace
interval but not with a shorter trace interval (Solomon et al., 1986;
Moyer et al., 1990; Weiss et al., 1999) and therefore have paid no
attention to the role of the hippocampus in short trace-interval
conditioning. The present study has revealed that the
hippocampal-lesioned GluR2/ mice
have severe impairment in learning the trace 0 paradigm, but the
hippocampal-lesioned wild-type mice do not. Thus, the contribution of
the hippocampus to short trace interval conditioning becomes greater in
GluR2/ mice than that in the
wild-type mice, suggesting that cerebellar LTD-independent learning
occurs efficiently with a contribution of the hippocampus. Because
GluR2/ mice exhibit severe learning
impairment with a delay paradigm (Kishimoto et al., 2001a,c), this kind
of hippocampal function does not work well during delay conditioning.
When considering the role of the hippocampus in
GluR2/ mice, it is important to ask
whether it is required for retention of the acquired memory. Because
the acquired CR was retained fairly well after a hippocampal lesion, we
conclude that the hippocampus is not required for retention and recall
of the memory. In eyeblink conditioning with a long trace interval, the
contribution of the hippocampus appears to be time limited: hippocampal
ablation 1 d after learning impairs retention of a trace eyeblink
CR, but ablation has no effect if it occurs 4 weeks after learning in rabbits (Kim et al., 1995) and mice (Takehara et al., 2002). Consistent with these lesion studies, excitability increases in hippocampal pyramidal neurons remain for a limited period of time after learning (Moyer et al., 1996; Thompson et al., 1996). In the present study, the
hippocampal lesion affected the preacquired CR in
GluR2/ mice in a time-dependent
manner; it did not impair the retention at all if made a few days after
asymptotic level of learning but moderately impaired the acquired CR if
made right after asymptotic level of learning. This is consistent with
the previous reports (Kim et al., 1995; Takehara et al., 2002) in the
sense that the role of hippocampus in retention or expression of the
memory diminishes as time elapses. However, because the CR remained to
some extent even if the lesion were made right after learning, there is
a possibility that the role of the hippocampus in eyeblink conditioning with a short trace interval is a little different from that in long
trace interval conditioning. Additional experiments using wild-type
animals will be needed to test this hypothesis.
In conclusion, the present study has demonstrated that the hippocampus
is important for the acquisition, but not for the
retention, of a motor memory in
GluR2/ mice, which have
deficiencies selective to the cerebellar cortex, including cerebellar
LTD. These results suggest that the hippocampal component of the
eyeblink conditioning task becomes dominant in the cerebellar
LTD-independent learning. It remains to be clarified where that memory
trace is formed and stored and what the role of the hippocampus is in
cerebellar LTD-independent learning. Answering these questions should
lead to a better understanding of the role of the hippocampus in
eyeblink conditioning and may provide valuable information concerning
the general mechanism of hippocampus-dependent learning.
| |
FOOTNOTES |
Received April 16, 2002; revised Sept. 3, 2002; accepted Oct. 9, 2002.
This work was supported by Ministry of Education, Culture, Sports,
Science and Technology of Japan Grants-in-Aid 13210036 and 13680734 and
a grant from the Core Research for Evolution Science and Technology of
Japan Science and Technology Corporation.
Correspondence should be addressed to Shigenori Kawahara, Laboratory of
Neurobiophysics, School of Pharmaceutical Sciences, The University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail:
kawahara{at}mol.f.u-tokyo.ac.jp.
| |
References |
-
Barnes CA
(1988)
Spatial learning and memory process: the search for their neurobiological mechanisms in the rat.
Trends Neurosci
11:163-169[ISI][Medline].
-
Berger TW,
Orr WB
(1983)
Hippocampectomy selectively disrupts discrimination reversal conditioning of the rabbit nictitating membrane response.
Behav Brain Res
8:49-68[ISI][Medline].
-
Ito M
(1989)
Long-term depression.
Annu Rev Neurosci
12:85-102[ISI][Medline].
-
Kaneko T,
Thompson RF
(1997)
Disruption of trace conditioning of the nictitating membrane response in rabbits by central cholinergic blockade.
Psychopharmacology
131:161-166[Medline].
-
Kashiwabuchi N,
Ikeda K,
Araki K,
Hirano T,
Shibuki K,
Takayama C,
Inoue Y,
Kutsuwada T,
Yagi T,
Kang Y,
Aizawa S,
Mishina M
(1995)
Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR2 mutant mice.
Cell
81:245-252[ISI][Medline].
-
Kim JJ,
Thompson RF
(1997)
Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning.
Trends Neurosci
20:177-181[ISI][Medline].
-
Kim JJ,
Clark RE,
Thompson RF
(1995)
Hippocampectomy impairs the memory of recently, but not remotely, acquired trace eyeblink conditioned responses.
Behav Neurosci
109:195-203[ISI][Medline].
-
Kishimoto Y,
Kawahara S,
Suzuki M,
Mori H,
Mishina M,
Kirino Y
(2001a)
Classical eyeblink conditioning in glutamate receptor subunit 2 mutant mice is impaired in the delay paradigm but not in the trace paradigm.
Eur J Neurosci
13:1249-1253[ISI][Medline].
-
Kishimoto Y,
Hirono M,
Sugiyama T,
Kawahara S,
Nakao K,
Kishio M,
Katsuki M,
Yoshioka T,
Kirino Y
(2001b)
Impaired delay but normal trace eyeblink conditioning in PLC4 mutant mice.
NeuroReport
12:2919-2922[ISI][Medline].
-
Kishimoto Y,
Kawahara S,
Fujimichi R,
Mori H,
Mishina M,
Kirino Y
(2001c)
Impairment of eyeblink conditioning in GluR2 mutant mice depends on the temporal overlap between conditioned and unconditioned stimuli.
Eur J Neurosci
14:1515-1521[ISI][Medline].
-
Kurihara H,
Hashimoto K,
Kano M,
Takayama C,
Sakimura K,
Mishina M,
Inoue Y,
Watanabe M
(1997)
Impaired parallel fiber
 Purkinje cell synapse stabilization during cerebellar development of mutant mice lacking the glutamate receptor 2 subunit.
J Neurosci
17:9613-9623[Abstract/Free Full Text]. -
Morris RG,
Garrud P,
Rawlins JN,
O'Keefe J
(1982)
Place navigation impaired in rats with hippocampal lesion.
Nature
297:681-683[Medline].
-
Moyer Jr JR,
Deyo RA,
Disterhoft JF
(1990)
Hippocampectomy disrupts trace eye-blink conditioning in rabbits.
Behav Neurosci
104:243-252[ISI][Medline].
-
Moyer Jr JR,
Thompson LT,
Disterhoft JF
(1996)
Trace eyeblink conditioning increases CA1 excitability in a transient and learning-specific manner.
J Neurosci
16:5536-5546[Abstract/Free Full Text].
-
Paxinos G,
Franklin KBJ
(2001)
In: The mouse brain in stereotaxic coordinates. San Diego: Academic.
-
Solomon PR,
Gottfried KE
(1981)
The septohippocampal cholinergic system and classical conditioning of the rabbit's nictitating membrane response.
J Comp Physiol Psychol
95:322-330[ISI][Medline].
-
Solomon PR,
Solomon SD,
Vander Schaaf E,
Perry HE
(1983)
Altered activity in the hippocampus is more detrimental to classical conditioning than removing the structure.
Science
220:329-331[Abstract/Free Full Text].
-
Solomon PR,
Vander Schaaf ER,
Thompson RF,
Weisz DJ
(1986)
Hippocampus and trace conditioning of the rabbit's classically conditioned nictitating membrane response.
Behav Neurosci
100:729-744[ISI][Medline].
-
Takatsuki K,
Kawahara S,
Mori H,
Mishina M,
Kirino Y
(2002)
Scopolamine impairs eyeblink conditioning in cerebellar LTD-deficient mice.
NeuroReport
13:159-162[Medline].
-
Takehara K,
Kawahara S,
Takatsuki K,
Kirino Y
(2002)
Time-limited role of the hippocampus in the memory for trace eyeblink conditioning in mice.
Brain Res
951:183-190[Medline].
-
Thompson LT,
Moyer Jr JR,
Disterhoft JF
(1996)
Transient changes in excitability of rabbit CA3 neurons with a time course appropriate to support memory consolidation.
J Neurophysiol
76:1836-1849[Abstract/Free Full Text].
-
Thompson RF,
Kim JJ
(1996)
Memory systems in the brain and localization of a memory.
Proc Natl Acad Sci USA
93:13438-13444[Abstract/Free Full Text].
-
Weiss C,
Bouwmeester H,
Power JM,
Disterhoft JF
(1999)
Hippocampal lesions prevent trace eyeblink conditioning in the freely moving rat.
Behav Brain Res
99:123-132[ISI][Medline].
Copyright © 2003 Society for Neuroscience 0270-6474/03/23117-06$05.00/0
This article has been cited by other articles:
|
|
|
|
 
C. Gil-Sanz, J. M. Delgado-Garcia, A. Fairen, and A. Gruart
Involvement of the mGluR1 Receptor in Hippocampal Synaptic Plasticity and Associative Learning in Behaving Mice
Cereb Cortex,
July 1, 2008;
18(7):
1653 - 1663.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Sahun, J. M. Delgado-Garcia, A. Amador-Arjona, A. Giralt, J. Alberch, M. Dierssen, and A. Gruart
Dissociation between CA3-CA1 Synaptic Plasticity and Associative Learning in TgNTRK3 Transgenic Mice
J. Neurosci.,
February 28, 2007;
27(9):
2253 - 2260.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Gruart, C. Sciarretta, M. Valenzuela-Harrington, J. M. Delgado-Garcia, and L. Minichiello
Mutation at the TrkB PLC{gamma}-docking site affects hippocampal LTP and associative learning in conscious mice
Learn. Mem.,
January 1, 2007;
14(1-2):
54 - 62.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Gruart, M. D. Munoz, and J. M. Delgado-Garcia
Involvement of the CA3-CA1 Synapse in the Acquisition of Associative Learning in Behaving Mice
J. Neurosci.,
January 25, 2006;
26(4):
1077 - 1087.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Fontan-Lozano, J. Troncoso, A. Munera, A. M. Carrion, and J. M. Delgado-Garcia
Cholinergic septo-hippocampal innervation is required for trace eyeblink classical conditioning
Learn. Mem.,
November 1, 2005;
12(6):
557 - 563.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Sacchetti, B. Scelfo, and P. Strata
The Cerebellum: Synaptic Changes and Fear Conditioning
Neuroscientist,
June 1, 2005;
11(3):
217 - 227.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. C. Inda, J. M. Delgado-Garcia, and A. M. Carrion
Acquisition, Consolidation, Reconsolidation, and Extinction of Eyelid Conditioning Responses Require De Novo Protein Synthesis
J. Neurosci.,
February 23, 2005;
25(8):
2070 - 2080.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Lee and J. J. Kim
Differential Effects of Cerebellar, Amygdalar, and Hippocampal Lesions on Classical Eyeblink Conditioning in Rats
J. Neurosci.,
March 31, 2004;
24(13):
3242 - 3250.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
Introduction
