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 Previous Article
The Journal of Neuroscience, March 15, 2001, 21(6):2186-2193
Cellular Imaging of zif268 Expression in the
Hippocampus and Amygdala during Contextual and Cued Fear Memory
Retrieval: Selective Activation of Hippocampal CA1 Neurons during the
Recall of Contextual Memories
Jeremy
Hall,
Kerrie L.
Thomas, and
Barry J.
Everitt
Department of Experimental Psychology, University of Cambridge,
Cambridge, CB2 3EB United Kingdom
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ABSTRACT |
The neuroanatomical and molecular basis of fear memory retrieval
was studied by analyzing the expression of the plasticity-associated immediate early gene zif268. Cellular
quantitative in situ hybridization revealed that
zif268 is expressed within specific regions of the hippocampus and amygdala during fear memory retrieval. Within the
hippocampus, increased expression of zif268 was observed
within CA1 neurons, but not dentate gyrus neurons, during the retrieval of contextual, but not cued, fear associations. In contrast,
zif268 expression was increased within neurons of the
amygdala (lateral, basal, and central nuclei) during the retrieval of
both contextual and cued fear memories. These results demonstrate
activation of hippocampal CA1 neurons in contextual fear memory
retrieval that was not merely a correlate of the behavioral expression
of fear itself, because it was limited to the retrieval of contextual, and not cued, fear memories. Further studies revealed that the selective increase in hippocampal CA1 zif268 expression
seen after contextual fear memory retrieval was limited to the
retrieval of recent (24 hr) but not older (28 d) memories. These
experiments represent the first demonstration that
zif268 expression in specific neuronal populations is
associated with memory retrieval and suggest that this gene may
contribute to plasticity and reconsolidation accompanying the retrieval process.
Key words:
zif268; gene expression; fear conditioning; memory retrieval; hippocampus; amygdala
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INTRODUCTION |
The hippocampus and amygdala form
part of a neural system required for fear memory (Selden et al., 1991 ;
Aggleton, 1992; Davis, 1992; Phillips and LeDoux, 1992; Rogan and
LeDoux, 1996; Fendt and Fanselow, 1999; Hamann et al., 1999). A widely
held view is that the hippocampus is required for the formation and
retrieval of context-fear associations, whereas the amygdala is
required for conditioning and recall of associations to contextual and discrete cues (Maren and Fanselow, 1996; Rogan and LeDoux, 1996). Recent investigations have revealed that fear memory recall induces a
reconsolidation of memories requiring new protein synthesis (Nader et
al., 2000). Significant questions, however, remain concerning both the
neuroanatomical and molecular substrates of fear memory retrieval.
First, several studies have questioned the involvement of the
hippocampus in the retrieval of aversive associations (Gewirtz et al.,
2000). Lesions of the hippocampus disrupt contextual fear memory
retrieval when measured by conditioned freezing (Kim and Fanselow,
1992; Maren et al., 1997; Fanselow, 2000), but not necessarily when
assessed by other behavioral measures (McNish et al., 1997; Gisquet-Verrier et al., 1999; Gewirtz et al., 2000). Furthermore, whereas some studies of post-training hippocampal lesions suggest a
time-limited role for the hippocampus in fear memory retrieval (Kim and
Fanselow, 1992; Anagnostaras et al., 1999), other reports have
suggested that the amnesic effect of hippocampal lesions may extend to
older memories (Nadel and Moscovitch, 1997).
Second, although the amygdala plays a critical role in fear memory
retrieval (Liang et al., 1982; Kim and Davis, 1993; Lee et al., 1996;
Maren et al., 1996; Muller et al., 1997), the exact nature of its
involvement remains controversial. Some authors have argued that the
basolateral amygdala (BLA) is the central locus of all fear
conditioning (Fanselow and LeDoux, 1999). However, certain forms of
discrete and contextual fear conditioning persist despite lesions to
the BLA (Selden et al., 1991; Killcross et al., 1997; Vazdarjanova and
McGaugh, 1998; Cahill et al., 1999; Maren, 1999), reflecting
either the involvement of other amygdaloid nuclei in fear memory recall
(Killcross et al., 1997) or a more limited involvement of the amygdala
in the acquisition, but not the storage, of fear memories (McGaugh et
al., 1996; Cahill and McGaugh, 1998).
Finally, little is known about the molecular events underlying synaptic
plasticity accompanying fear memory retrieval. A role for protein
synthesis in memory reconsolidation at retrieval has been demonstrated
(Nader et al., 2000), however, the specific genes involved have yet to
be identified. One candidate is the immediate early gene (IEG)
zif268 (or EGR-1, krox-24, TIS-8). The
expression of zif268 has been closely correlated with the induction of hippocampal long-term potentiation (LTP) (Cole et al.,
1989; Wisden et al., 1990; Worley et al., 1993), a major form of
protein synthesis-dependent plasticity in the adult brain, as well as
the predominant cellular model of learning (Bliss and Collingridge,
1993). The involvement of zif268 in memory retrieval has not
previously been investigated.
In the present study we demonstrate that expression of
zif268 accompanies Pavlovian fear memory retrieval, and we
use the quantification of zif268 expression to define
differential regional activation within the hippocampus and amygdala
during the retrieval of both cued and contextual fear associations.
This approach using cellular imaging may help to resolve discrepancies
in the literature concerning the involvement of the amygdala and
hippocampus in fear memory after its acquisition.
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MATERIALS AND METHODS |
Animals. A total of 82 male hooded Lister rats (Olac,
Bicester, UK) weighing between 280 and 320 gm were used. The animals were housed in pairs and kept in a holding room at 21°C under reverse
light conditions (lights off at 8:30 A.M.). Animals were allowed
ad libitum access to food and water and were handled on 3 consecutive days for 1 min before the experiments.
Cued and contextual fear conditioning and retrieval.
Animals were differentially conditioned to associate either an auditory cue or an experimental context with a footshock using a novel version
of the conditioned freezing procedure. Animals were first pre-exposed
for 3 d to two experimental chambers (contexts) for 20 min/d.
These contexts were designed to differ in a number of features
including size, spatial location, odor, and lighting. In addition, to
further the distinguish the contexts, each animal was only exposed to
each chamber at a distinct time of day. After this pre-exposure period
rats were given one 25 min training trial in one of the environments to
associate either a discrete 10 sec cue [4 Hz, 80 dB clicker, the
conditioned stimulus (CS)] or the experimental context itself with a
footshock [0.5 sec, 0.45 mA shock, the unconditioned stimulus (US)].
Animals in the cued training condition received five cue presentations
(interstimulus interval 5 ± 1 min) that terminated in the
delivery of the footshock (cued group), whereas animals in the
contextual training condition received an equivalent number of CS and
US presentations in pseudorandom order (context group). Freezing
behavior served as a measure of conditioned fear to the discrete cue at
a retrieval test 48 hr after conditioning in which the rats were placed
in the nontraining context and exposed to an 8 min presentation of the
clicker cue. The next day all the rats were tested for conditioning to
contextual stimuli, as assessed by conditioned freezing during an 8 min
retrieval test in the training context. Freezing behavior was
video-recorded and quantified by an observer blind to the experimental
group. One unit of freezing was defined as a continuous absence of
movement other than that required for respiration for 5 sec, and
behavior was expressed as a percentage of units spent freezing.
For in situ hybridization experiments, animals in the
cued and context training groups were trained as described above and killed 30 min after exposure to either the conditioned context (first experiment) or auditory cue (second experiment) 3 d after conditioning. Two additional control groups were also included in the
in situ hybridization experiments. The first of these
(control group) received shock training as described but were killed
without testing 3 d after training. The second, box group, were
trained, tested, and killed with the cue and context groups, but
received neither footshock nor cue presentations.
Retrieval of old versus recent fear associations. Animals
were randomly allocated to two experimental groups: control and conditioned. All animals were extensively handled before the onset of
the experiment. On the first experimental day (training day) rats from
the control and conditioned groups were placed individually in the
training box for 10 min. During this time animals in the conditioned
group but not in the control group received 5 × 1 sec 0.45 mA
footshocks spaced pseudorandomly across the 10 min session. In all
cases the first shock presentation occurred at least 1 min after the
introduction of the rats to the chamber. Rats in the control group were
allowed to explore the novel context for 10 min without receiving any
stimulus presentations. All rats were returned to their home cages
after training.
On the retrieval testing day, either 24 hr or 28 d after training,
both groups of rats were returned to the training box for 8 min, during
which time their behavior was recorded on video. These videos were
later screened for freezing behavior as described above. For in
situ hybridization experiments, rats were killed 30 min after testing.
Tissue preparation. Rats were killed by
CO2 exposure and decapitation 30 min after the
end of behavioral testing, and whole brains were rapidly removed and
frozen on dry ice. The brains were stored at  70°C until sectioned.
Sections (14 µm) were cut at 20°C on a freezing microtome (Leica,
Nussloch, Germany) and thaw-mounted onto
poly-L-lysine (hydrobromide; molecular mass >300,000; Sigma, Poole, UK)-coated glass slides (0.02 mg/ml diethyl pyrocarbonate-treated water). The sections were air-dried for not <30
min, fixed in 4% paraformaldehyde in 0.1 M
PBS, pH 7.4, for 5 min, rinsed in PBS for 1 min, delipidated in
70% ethanol for 4 min, and stored in 95% ethanol at 4°C.
In situ hybridization. A cDNA antisense probe complementary
to nucleotides 460-505 of the zif268 gene (Milbrandt, 1987)
was synthesized on an Applied Biosystems (Foster City, CA) DNA
Synthesizer. This oligonucleotide was 3' end-labeled with
[ -35S]dATP (1200 Ci/mmol; NEN,
Hounslow, UK) in a 30:1 molar ratio of radiolabeled ATP:oligonucleotide
using terminal deoxynucleotidyl transferase (Promega, Southampton, UK)
as described previously (Wisden and Morris, 1994). Specific
activity of the 35S-labeled probe was
between 2.0 × 105 and 8.0 × 105 dpm/µl probe.
Hybridizations were performed essentially as described by Wisden and
Morris (1994). To define nonspecific hybridization,
adjacent slide-mounted sections were incubated with radiolabeled
oligonucleotide in the presence of an excess (100×) concentration of
unlabeled oligonucleotide probe. After hybridization sections were
opposed to Eastman Kodak (Rochester, NY) BioMax x-ray film for 1-2
weeks. After obtaining appropriate x-ray film exposures, sections were dipped in K5 photographic emulsion (Ilford). Sections were exposed for
5-10 weeks at 4°C, before development and counterstaining with
0.01% thionin.
Silver grain density was assessed in discrete neuronal populations
using OpenLab imaging software (ImproVision Coventry, UK) [CA1
pyramidal neurons and dentate gyrus (DG) granule cells, bregma 3.3
mm; basal amygdala (B) neurons, bregma 3.0 mm; lateral amygdala (LA)
neurons, bregma 3.0 mm; accessory basal nucleus of the amygdala (AB)
neurons, bregma 3.5 mm, and central nucleus of the amygdala (CeN)
neurons, bregma 2.0 mm]. Grains (total and nonspecific) were counted
over sufficient randomly selected neurons from each region for each
animal such that the SE of the counts for any region was <10% of the
population mean (typically 20 cells). In each case cells were selected
from at least three separate sections. A specific grain count was then
calculated for each region by subtracting total and nonspecific counts.
The mean silver grain count in each region for each animal was then
divided by the mean count in that region for the control group to give
a standardized grain count for each group. Standardized results were
analyzed by ANOVA, and individual post hoc comparisons were
made using Sidak's test (corrected pairwise comparisons).
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RESULTS |
Differential Pavlovian fear conditioning to discrete or
contextual stimuli
Conditioning of the cued and context groups to the CS
(discrete auditory cue) and to the experimental context as measured by
conditioned freezing during the retrieval tests is shown in Figure
1. Analysis of the total amount of
freezing in each group (cued or context) by ANOVA revealed a group × stimulus interaction (F(1,18) = 100.2; p < 0.001). This effect was characterized by greater freezing to the discrete CS in the cued group compared with
context group (F(1,18) = 129.0;
p < 0.001), and greater freezing to the contextual
cues in the context group compared with the cued group
(F(1,18) = 8.2; p = 0.01). Thus, animals in the cued and context groups, despite receiving
the same total number of stimulus presentations, showed a double
dissociation in their conditioning to the CS and the context,
respectively.
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Figure 1.
Freezing in response to presentation of discrete
or contextually conditioned cues. Freezing (percentage 8 min after cue)
in response to presentation of discrete CS (clicker) and contextual
cues in rats trained with either clicker-shock pairings (cued;
n = 10) or pseudorandom presentations of clicker
and shock (context; n = 10). There was greater
freezing to the discrete CS in the cued compared with context group and
greater freezing to the contextual cues in the context compared with
cued group. All results are presented as mean ± SEM values.
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Expression of zif268 after the retrieval of
contextual fear associations
We used in situ hybridization to investigate
whether the plasticity-associated IEG zif268 is expressed in
neurons of the hippocampus and amygdala after the retrieval of
contextual fear associations. Animals were trained in the cued,
context, box, and control conditions described above and were killed 30 min after testing of retrieval responses to the context. There was a
significant effect of group on freezing behavior
(F(2,15) = 9.6; p < 0.01) derived from a greater level of freezing in the context group
than in either the cued (p < 0.05) or box
(p < 0.01) groups (Fig.
2a). Analysis of the
expression of zif268 in hippocampal CA1 neurons and in the
DG after the context retrieval test revealed an effect of group on
zif268 expression in CA1
(F(3,20) = 21.8; p < 0.001) but not in the DG (F(3,20) = 2.0; p = NS) (Fig. 2b-e). The effect of
group on zif268 expression in CA1 was shown by post
hoc tests to derive from a higher level of expression of
zif268 in the context group than in either the cued
(p < 0.01), box (p < 0.001), or control (p < 0.001) groups. In
addition the cued group, although expressing significantly less
zif268 in CA1 than the context group, also showed increased
expression relative to the control group (p < 0.01). No differences in zif268 expression were seen between the box and control groups.
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Figure 2.
Expression of zif268 after the
retrieval of contextual fear associations. a, Freezing
of rats in the box (exposure to context only during training and
testing; n = 6), cued (n = 6),
and context (n = 6) groups in response to
re-exposure to contextual stimuli at the retrieval test. Animals in the
control group (n = 6) were given shock and cue
presentations on the training day but were not tested later.
b-i, Zif268 expression 30 min after
re-exposure to contextual stimuli. b, c,
Zif268 expression in neurons in the hippocampus: CA1
(b), DG (c). d, e,
Photomicrographs (100×) of small dark silver grains associated with
CA1 pyramidal cells from an individual rat from the control
(d) and context (e) groups.
f, i, Zif268 expression in neurons in the
amygdala: B (f), LA (g),
CeN (h), and AB (i). All
results are presented as mean ± SEM values.
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There was also increased zif268 expression in several
nuclei of the amygdala in the context group. Analysis demonstrated a significant effect of group on zif268 expression in neurons
in the B (F(3,20) = 9.5;
p < 0.001), LA
(F(3,20) = 8.0; p = 0.001), and CeN (F(3,20) = 17.9;
p < 0.001), but not the AB
(F(3,20) = 2.8; p = NS). Further post hoc comparisons confirmed that the significant effect of group in the B, LA, and CeN was attributable to
increased zif268 expression in the context group relative to cued, box, and control groups in the B and CeN and in the context group
relative to the cued and control groups in the LA (Fig. 2f-i).
In summary these results show that animals from the context group
showed significantly greater contextual conditioning, as assessed by
conditioned freezing, than animals from the cued or box training
conditions. In response to the context retrieval test a large increase
in zif268 expression was seen in CA1 but not in the DG of
animals from the context group, and this increase was greater than that
seen in the cued group. In addition, animals in the context group, but
not in the cued group, showed higher levels of zif268
expression in the B, LA, and CeN nuclei of the amygdala than control
animals when exposed to a fear-conditioned context.
Expression of zif268 after the retrieval of cued
fear associations
We next investigated the expression of zif268 in the
hippocampus and amygdala during the retrieval of a cued, rather than contextual, fear association. This allowed us to investigate whether a
common system is recruited during the retrieval of fear-related memories or if instead certain structures are selectively required for
the retrieval of cued or contextual associations.
Animals were trained in the cued and context groups described above and
were killed 30 min after testing of retrieval responses to the CS.
Because no differences were observed between the control and box groups
in the previous experiment, only a single control group was used in the
second experiment (control condition).
The freezing responses of animals from the cued and context groups
during the CS retrieval test are shown in Figure
3a. Analysis of the time spent
freezing during the CS presentation revealed a significant effect of
group (F(1,14) = 51.7;
p < 0.001) resulting from a greater freezing response
to the CS in the cued group than in the context group.
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Figure 3.
Expression of zif268 after the
retrieval of discrete CS fear associations. a, Freezing
of rats in the cued (n = 8) and context
(n = 8) groups in response to re-exposure to the
discrete cue at retrieval testing. Animals in the control group
(n = 8) were given shock and cue presentations on
the training day but were not tested later. b-i,
Zif268 expression 30 min after re-exposure to the cue
stimulus stimuli. b, c, Zif268 expression
in neurons in the hippocampus: CA1 (b), DG
(c). d, e, Photomicrographs
(100×) of small dark silver grains associated with LA pyramidal cells
from an individual rat from the control (d) and
cued (e) groups. f, i, Zif268
expression in neurons in the amygdala: B (f), LA
(g), CeN (h), and AB
(i). All results are presented as mean ± SEM values.
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Analysis of zif268 expression in the hippocampus of animals
retrieving the cued fear association revealed a different pattern from
that seen after the retrieval of a contextual fear association. There
was a significant overall effect of group on zif268
expression in pyramidal neurons in the CA1
(F(2,21) = 4.5; p < 0.05) (Fig. 3b). Post hoc tests revealed that
there was a significant increase in CA1 zif268 expression in
the context group relative to the control group. However, because there
were no differences in zif268 expression between the
cued and control (p > 0.07) or between the cued
and context groups (p > 0.9), the increase over
basal expression of zif268 in the context group was not
related to conditioning to the discrete cue. There was no effect of
group on zif268 expression within the DG
(F(2,21) = 1.35; p = NS; Fig. 3c).
In contrast, zif268 expression in the amygdala of animals
retrieving a cued fear association showed a similar pattern to that seen after the retrieval of a contextual fear association. Thus, there
was a significant effect of group on zif268 expression in neurons in the B (F(2,21) = 29.7;
p < 0.001), LA
(F(2,21) = 11.5; p < 0.001), and CeN (F(2,21) = 14.9;
p < 0.001), but not in the AB
(F(2,21) = 0.2; p = NS). Furthermore post hoc analysis revealed that the
significant effect of group on zif268 expression within the
B, LA, and CeN derived in all cases from increased expression in the
conditioned (cued) group relative to the context and control groups
(Fig. 3d-i).
In summary therefore, rats from the cued group showed selective
conditioning to the CS compared with the animals in the context group,
as shown by their freezing response during CS presentation in the cued
retrieval test. Retrieval of a discrete fear association however
produced no difference between the cued and context groups in terms of
zif268 expression in the CA1 pyramidal neurons of the
hippocampus. However, retrieval of the cued fear association did
selectively increase zif268 expression in the cued group in the B, LA, and CeN, but not the AB, of the amygdala. This pattern of
zif268 activation within the amygdala was therefore common to the retrieval of both cued and contextual fear associations.
Hippocampal zif268 expression during the retrieval
of recent versus old contextual fear associations
The previous experiments demonstrated a selective activation of
zif268 expression in CA1 after contextual memory retrieval, which was hence a consequence of contextual memory retrieval itself rather than the expression of fear. We therefore further investigated the activation of the hippocampal CA1 neurons during memory retrieval by comparing zif268 expression in the hippocampus of animals
retrieving either recent (24 hr) or old (28 d) contextual fear associations.
In a first experiment zif268 expression in the hippocampus
was measured after the retrieval of a contextual fear association acquired 24 hr previously. Contextual fear responding measured at
retrieval testing confirmed significantly greater conditioned freezing
in the conditioned than in the control group
(F(1,10) = 56.9; p < 0.001). Analysis of zif268 expression within CA1 by ANOVA
also revealed a significant increase in zif268 expression in
animals in the conditioned group relative to the control group after
the 24 hr retrieval test (F(1,10) = 24.2; p = 0.001; Fig. 4b). In contrast, there was no
effect of retrieval on expression in the DG
(F(1,10) = 0.9; p = NS; Fig. 4c). These results therefore confirmed our earlier
finding of CA1 zif268 expression during contextual fear
memory retrieval using a second contextual conditioning procedure.
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Figure 4.
Expression of zif268 after the
retrieval of recent versus old contextual-fear associations.
a, Freezing of rats in the control and context groups in
response to re-exposure to training context 24 hr after training.
Expression of zif268 in neurons of the CA1
(b) and DG (c) after memory
retrieval at 24 hr. d, Freezing of rats in the control
and context groups in response to re-exposure to training context
28 d after training. Expression of zif268 in
neurons of the CA1 (e) and DG
(f) after memory retrieval at 28 d. All
results are presented as mean ± SEM values.
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We next sought to confirm that the expression of zif268 in
the CA1 region after the 24 hr retrieval test was not a residual effect
of the conditioning procedure itself. Rats from the control and context
groups were killed 24 hr after training directly from their home cages
without testing retrieval. Analysis of the results of in
situ hybridization for zif268 mRNA in the hippocampi of these rats showed that there was no difference between the groups in
the expression of zif268 in CA1 [grain density (% control) ± SEM: control group, 1.00 ± 0.09; context group,
1.14 ± 0.15, F(1,10) = 0.08, p > 0.78].
Finally, we investigated the expression of zif268 in the
hippocampus of animals retrieving older (28 d) contextual fear
associations. Animals in the context group still showed robust
retrieval of the contextual fear association at this time point, as
confirmed by a significant effect of group on conditioned freezing
during the retrieval test (F(1,10) = 73.3, p < 0.001; Fig. 4d). Furthermore, there was no decrease in conditioned freezing during retrieval at
28 d compared with 24 hr (freezing scores, 24 hr, 60.6 + 7.2%; 28 d 73.9 + 1.3%). However, after retrieval at 28 d there
was no difference in zif268 expression between the context
conditioned and control groups in CA1
(F(1,10) = 1.2; p = NS; Fig. 4e), in contrast to the effect seen at 24 hr. There
was also no difference between groups in terms of zif268
expression within the DG at this time point
(F(1,10) = 0.05; p = NS; Fig. 4f).
In summary, the results of these experiments show that rats aversively
conditioned to a novel context showed increased expression of
zif268 mRNA in CA1 after the retrieval of the contextual
association 24 hr, but not 28 d, after training. No changes in
zif268 expression were seen at either time point in the DG.
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DISCUSSION |
In the present study we have shown that the plasticity associated
IEG zif268 is expressed in specific regions of the
hippocampus and amygdala during the retrieval of fear-related memories.
Training was conducted using a procedure in which rats were
differentially conditioned to either cued or contextual stimuli,
despite receiving the same total number of stimulus presentations, by
altering the contingency between the CS and US, thereby providing a
rigorous control for stimulus exposure. Expression of zif268
in the B, LA, and CeN of the amygdala accompanied the retrieval of both contextual and cued fear associations, indicating a role for these nuclei in the retrieval of fear-related memories. However, expression of zif268 in the CA1 region of the hippocampus was
selectively increased during the retrieval of contextual, but not cued,
fear-related memories. Hippocampal CA1 zif268 expression was
therefore specifically related to contextual memory retrieval and could
not be explained as a more general correlate of the production of a
fear-related response. Further investigation of the time course of CA1
zif268 expression during fear memory retrieval revealed a
selective increase during the recall of recent (24 hr), but not old (28 d) contextual memories, supporting a time-limited role of hippocampal
CA1 neurons in memory consolidation and retrieval.
Hippocampal zif268 expression during the retrieval
of contextual fear memories
The specific activation of CA1 neurons during the retrieval of
contextual, but not cued, fear associations provides strong evidence
for a mnemonic role of the hippocampus in the recall of contextual
information and complements the results of studies of hippocampal
lesions (Selden et al., 1991; Phillips and LeDoux, 1992; Kim and
Fanselow 1992) and reversible inactivation of the hippocampus
(Bellgowan and Helmstetter, 1995; Holt and Maren, 1999). This contrasts
with suggestions that deficits in contextual freezing seen in animals
with hippocampal lesions derive solely from lesion-induced locomotor
hyperactivity (Good and Honey 1997; McNish et al., 1997; but see
Maren et al., 1998), and provides strong support for an involvement of
the hippocampus in this form of conditioning. However, as some studies
have demonstrated different forms of contextual fear conditioning in
hippocampal lesioned subjects, it remains possible that not all forms
of contextual conditioning require hippocampal integrity (Gewirtz et
al., 2000).
One key observation in the present study was that zif268
expression was induced only in CA1 neurons and not in DG neurons during
contextual memory recall. Both DG and CA1 neurons are known to support
associative plasticity (Bliss and Collingridge 1993). Moreover,
increased expression of zif268 can be induced in the DG
after electrical stimulation of the perforant path (Cole et al., 1989;
Wisden et al., 1990). However, increasing evidence suggests that CA1
neurons may be especially involved in the encoding and retrieval of
contextual memories. These neurons have reciprocal connections with
subcortical regions, including the B/LA, as well as cortical areas that
are independent of the DG (van Groen and Wyss, 1990) and previous
studies have also demonstrated CA1 neuronal activation despite
inactivation of inputs from the DG (Mizumori et al., 1989). In
addition, contextual conditioning has been shown to activate both the
cAMP-calcium response element transcriptional pathway and
expression of BDNF in CA1 neurons but not in the DG (Impey
et al., 1998; Hall et al., 2000), and the IEG Arc is also expressed in CA1 neurons selectively after learning about a novel environment (Guzowski et al., 1999). Hippocampal CA1 neurons and their
cortical and subcortical connections may therefore be particularly involved in both the acquisition and recall of contextual memories.
Time-limited role of the hippocampus in memory retrieval
Induction of zif268 expression was seen in CA1 neurons
after the retrieval of recent, but not older, contextual fear
associations. This finding could not be explained by a decrease in
memory for the fearful event itself, because animals showed equivalent
levels of freezing to the conditioned context at both 24 hr and 28 d after conditioning. This time-limited activation of zif268
expression in hippocampal CA1 neurons is consistent with results of
animal and human studies demonstrating a temporal gradient in the
impact of hippocampal lesions on fear memory recall, with sparing of older memories (Zola-Morgan et al., 1986; Kim and Fanselow, 1992; Rempel-Clower et al., 1996; Anagnostaras et al., 1999; Teng and Squire
1999). One explanation for this observation may be that memory traces
become consolidated in extrahippocampal cortical areas over time with
their recall becoming independent of the hippocampus (Bontempi et al.,
1999; Teng and Squire, 1999 Alternatively, memories may become broadly
distributed across multiple corticohippocampal circuits with increasing
time from acquisition (Nadel and Moscovitch, 1997). Although the
results of the present study more parsimoniously support the former
view, an investigation of integrated cellular activation across all
hippocampal regions, including the analysis of a number of genes, would
be required to exclude the possibility that traces become more broadly
distributed within the hippocampus over time or, indeed, that the
memory remains within the hippocampus but no longer engages or requires
further plasticity-related processes for its continued maintenance
after retrieval.
Amygdala activation during the retrieval of
fear-associated memories
The present results demonstrate increased zif268
expression within the amygdala during the retrieval of both cued and
contextual fear memories and are therefore consistent with suggestions
that the amygdala is a critical element of fear processing in general (Davis et al., 1994; Maren and Fanselow, 1996; Fanselow and LeDoux, 1999). Although a recent lesion study showed that the acquisition of
cued freezing responses is dependent on the LA but not the B
(Amorapanth et al., 2000), the present results demonstrate that the LA
and B are recruited in concert during the retrieval of both cued and
contextual aversive memories. The CeN, which receives extensive
connections from the LA and B (Pitkanen et al., 1997) and projects to
brainstem regions, including those involved in the generation of
freezing responses (Price and Amaral, 1981; LeDoux et al., 1988), was
also found to be activated in both cued and contextual fear retrieval,
consistent with the involvement of this nucleus in the generation of
the freezing response (Davis, 1992; Maren and Fanselow, 1996; Fanselow
and LeDoux, 1999). However the AB, which represents a major site of
input of hippocampal afferents (Canteras and Swanson, 1992;
Amaral and Witter, 1995; Maren and Fanselow, 1996) and has been
implicated in contextual fear conditioning in some lesion studies
(Majidishad et al., 1996), did not show increased zif268
expression during the retrieval of contextual fear memories in the
present study.
Overall our findings support a role for specific nuclei of the amygdala
during the retrieval of fearful memories. This perhaps contrasting with
suggestions that the amygdala may function only to reinforce the
learning of emotionally salient associations in other brain regions
(Cahill et al., 1999) but supporting previous studies
demonstrating that post-training lesions (Lee et al., 1996; Maren et
al., 1996) or pretraining, but not immediate post-training, inactivation of the amygdala prevents conditioned freezing to either
cued or contextual stimuli tested subsequently (Muller et al., 1997;
Wilensky et al. 2000).
Zif268 expression during memory retrieval
Although there is an apparently close association of
zif268 expression with hippocampal LTP, particularly in the
DG (Cole et al., 1989; Wisden et al., 1990; Worley et al., 1993),
studies have failed to find an association between zif268
induction in the hippocampus and learning in hippocampal-dependent
tasks (Wisden et al., 1990; Richter-Levin et al., 1998). Furthermore,
we have recently shown that expression of zif268 within the
hippocampus and amygdala is not selectively induced during the
acquisition of contextual fear conditioning (Hall et al., 2000).
Increased zif268 expression in the LA after contextual
conditioning compared with that measured in naive rats has been
reported (Rosen et al., 1998), but, this induction of zif268
may have been in part because of the nonspecific effects of the
training procedure used, because the increased expression was not
different from noncontextually conditioned rats that had experienced
footshock presentations in the training context.
In contrast to the lack of correlation of zif268 expression
with the acquisition of contextual fear conditioning, we demonstrate in
the present study that zif268 expression is associated with memory retrieval. Synaptic plasticity during retrieval may
contribute to the reorganization of hippocampal or amygdala memory
traces over time. Importantly, a requirement for protein synthesis in the amygdala for the reconsolidation of cued fear memories after retrieval has been demonstrated, confirming that plasticity accompanies the retrieval process (Nader et al., 2000). Although the molecular processes underlying this plasticity have not yet been elucidated, the
present results suggest that zif268, which is selectively expressed during memory retrieval, may contribute to the encoding and
recoding of the memory trace during retrieval.
Conclusion
This study has shown that the plasticity-associated IEG
zif268 is expressed in specific neuronal populations in the
hippocampus and amygdala during the retrieval of fear-associated
memories. Expression of zif268 was increased in hippocampal
CA1 neurons after the retrieval of contextual, but not cued, fear
memories. CA1 neurons were also found to express zif268 only
during the retrieval of recently formed contextual memories, but not
after the retrieval of older memories, suggesting that this cell
population may form part of a corticohippocampal network mediating the
temporal consolidation of contextual fear memories. In addition,
neurons within the B, LA, and CeN nuclei of the amygdala, but not
within the AB nucleus, showed increased zif268 expression
during the retrieval of both cued and contextual fear-associated
memories, supporting a role for these nuclei in the retrieval, as well
as in the acquisition of fear-related memories. The selective
expression of zif268 in neuronal populations required for
fear memory retrieval suggests that this gene may play a role in the
plastic reconsolidation of memories accompanying the retrieval process.
| |
FOOTNOTES |
Received Nov. 8, 2000; revised Dec. 20, 2000; accepted Jan. 5, 2001.
This work was supported by a Medical Research Council (MRC)
Program Grant G9537855 and an MRC Cooperative in Brain, Behavior, and
Neuropsychiatry. J.H. was supported by Trinity College (Cambridge, UK)
under the Cambridge Clinical School MB/PhD program. We thank Trevor
Robbins for helpful discussions and Caroline Morrison for technical assistance.
Correspondence should be addressed to Dr. Kerrie L. Thomas, Department
of Experimental Psychology, University of Cambridge, Downing Street,
Cambridge, CB2 3EB UK. E-mail: klt25{at}cus.cam.ac.uk.
| |
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T. Maviel, T. P. Durkin, F. Menzaghi, and B. Bontempi
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P. W. Frankland, B. Bontempi, L. E. Talton, L. Kaczmarek, and A. J. Silva
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J. B. Rosen
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M. I. Anderson and K. J. Jeffery
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A. Kelly, S. Laroche, and S. Davis
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J. F. Guzowski, B. Setlow, E. K. Wagner, and J. L. McGaugh
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TOP
ABSTRACT
INTRODUCTION
