 |
 Previous Article | Next Article 
The Journal of Neuroscience, March 1, 2003, 23(5):1574
BRIEF COMMUNICATION
Identification of Calcineurin as a Key Signal in the Extinction
of Fear Memory
Chih-Hung
Lin1,
Shiu-Hwa
Yeh1,
Tzeng-Horng
Leu1,
Wen-Chang
Chang1,
Shan-Tair
Wang2, and
Po-Wu
Gean1
Departments of 1 Pharmacology and 2 Public
Health, College of Medicine, National Cheng-Kung University, Tainan
City, Taiwan 701
 |
ABSTRACT |
Memory extinction refers to a gradual decrease of the previously
acquired response when exposed to conditional stimulus without pairing
with unconditional stimulus. Here we show for the first time
that fear training-induced phosphorylation of specific substrates in
the rat amygdala is reduced after extinction trials and is accompanied
by an increase in the protein level and enzymatic activity of
calcineurin. In parallel, calcineurin inhibitors prevented extinction-induced protein dephosphorylation as well as extinction of
fear memory. Thus, extinction training increased phosphatase activity
likely via an expression of calcineurin. Calcineurin then created a
negative-feedback loop and directly or indirectly dephosphorylated
specific substrates, which, in their phosphorylated state, were
required for memory consolidation. Accordingly, in our experimental
condition, extinction could be ascribed at least in part to a weakening
of the original signaling.
Key words:
learning and memory; amygdala; calcineurin; synaptic plasticity; fear conditioning; fear-potentiated startle
| |
Introduction |
It is a general observation in
animals that a cue [conditioned stimulus (CS)] comes to induce fear
response when it is repeatedly paired with a noxious stimulus
[unconditioned stimulus (US)], such as footshock (Davis, 2000 ;
LeDoux, 2000). However, it is also known for some time that, if animals
are exposed only to the CS without pairing with US, the previously
acquired responses will gradually decrease, a phenomenon referred to as
fear extinction (Rescorla, 2001). Converging evidence indicate that the
amygdala plays an important role in both formation and extinction of
fear memory (Falls et al., 1992; Maren, 1999; Nader et al., 2000; Lu et
al., 2001). Experiments performed by various laboratories using different animal models indicated that long-term memory formation involved activation of the protein kinases such as calcium/calmodulin kinase II, cAMP-dependent protein kinase (PKA), and mitogen-activated protein kinase (MAPK) (Impey et al., 1998; Schafe et al., 2000; Josselyn et al., 2001). Once stimulated, these kinases could
translocate to the nucleus and subsequently activate transcription
factors to promote gene transcription and new protein synthesis. Much less is known about the cellular mechanisms leading to memory extinction. Previous studies have shown that experimental extinction was blocked by NMDA receptor antagonists and MAPK kinase (MEK) inhibitors (Falls et al., 1992; Lu et al., 2001) and facilitated by
D-cycloserine, a partial NMDA agonist (Walker et al.,
2002). Recently, it was found that extinction of fear conditioning was impaired in cannabinoid receptor 1-deficient (Marsicano et al., 2002)
or protein phosphatase 1-inhibited (Genoux et al., 2002) mice.
This laboratory showed recently that acquisition of fear was associated
with an activation of phosphatidylinositol 3-kinase (PI-3 kinase) and
its downstream target Akt in the rat amygdala. PI-3 kinase and Akt were
also activated in response to long-term potentiation (LTP)-inducing
tetanic stimulation (TS). In parallel, PI-3 kinase inhibitors
interfered with TS-induced LTP as well as long-term fear memory
formation (Lin et al., 2001). Therefore, it is of particular interest
to see whether extinction trials affect phosphorylated state of this
protein kinase. Here we show for the first time that fear
training-induced phosphorylation of Akt in the rat amygdala is reduced
after extinction training and is accompanied by an increase in the
protein level and enzymatic activity of calcineurin.
| |
Materials and Methods |
Surgery
Rats, anesthetized with sodium pentobarbital (50 mg/kg, i.p.),
were mounted on a stereotaxic apparatus and two cannulas made of
22 gauge stainless steel tubing (C313G; Plastic Products) were implanted bilaterally into the lateral amygdala (LA) or basolateral amygdala (BLA). The coordinates were as follows (according to Paxinos
and Watson, 1986): anteroposterior,  2.3 mm; mediolateral, ±4.5 mm;
dorsoventral, 7.0 mm. Only rats with cannula tips within the
boundaries of LA and BLA were included in the data analysis. Rats were
monitored and handled daily and were given 7 d to recover. Calcineurin inhibitor FK-506 was dissolved in DMSO, and
cypermethrin was dissolved in 95% ethanol. The drugs were administered
bilaterally in a volume of 0.8 µl at a rate of 0.5 µl/min.
Behavioral apparatus and procedures
Fear conditioning was measured using potentiated startle
paradigm adapted and modified from Lu et al. (2001). Rats were trained and tested in a stabilimeter device. A piezoelectric device mounted below stabilimeter detects and transduces the motion of the cylinder produced by the whole-body startle response of the rat (San Diego Instruments, San Diego, CA). The whole setup was enclosed in a ventilated, sound-attenuating cabinet (length of 38 cm, width of 38 cm,
and height of 55 cm). The acoustic startle stimulus was a 50 msec white
noise at the intensity of 95 dB. The visual CS was a 3.7 sec light
produced by an 8 W fluorescent bulb attached to the back of
stabilimeter. The US was a 0.6 mA footshock with a duration of 0.5 sec.
Acclimation. On 3 consecutive days, rats were placed in the
startle test boxes for 10 min and returned to their home cages.
Matching. On 2 consecutive days, rats were placed in the
startle box and, 3 min later, presented with 10 startle stimuli at a 2 min intertrial interval (ITI). On the basis of their mean startle
amplitudes in the second of these two sessions, rats were matched into
groups with similar response levels.
Training. Rats were placed in the startle boxes and received
10 light-footshock pairings with an ITI of 2 min. Unpaired controls received the same number of light and footshock presentation but in a
pseudorandom manner in which the US could occur at anytime except at
the 3.2 sec after the CS.
Preextinction test. Twenty-four hours after training, rats
were tested for fear-potentiated startle. This involved 10 startle-eliciting noise bursts presented alone (noise-alone trial) and
10 noise bursts presented 3.2 sec after onset of the 3.7 sec light
(light-noise trials). The two trial types were presented in a balanced
mixed order (ITI, 30 sec). The percentage of fear-potentiated startle was computed as follows: [(startle amplitude on CS-noise minus noise-alone trials)/(noise-alone trials)] × 100.
Extinction training. Ten minutes after the pretests, rats
were returned to the stabilimeter and given three sessions of 10 presentations of the 3.7 sec light in the absence of either shock or
the startle-elicited noise burst (light-alone trials). Each session was
separated by 10 min with an ITI of 1 min. The context control group
remained in the stabilimeter for an equivalent period of time without
receiving any stimulation.
Postextinction training. Immediately after extinction
training, rats were tested for fear-potentiated startle in a procedure identical to pretests.
Western blot analysis
Rats were killed by decapitation, and the lateral and
basolateral subregions of the amygdala were sonicated briefly in
ice-cold buffer [50 mM Tris-HCl, pH 7.5, 0.3 M
sucrose, 5 mM EDTA, 2 mM sodium pyrophosphate,
1 mM sodium orthovanadate, 1 mM
phenylmethylsulfonyl fluoride (PMSF), 20 µg/ml leupeptin, and 4 µg/ml aprotinin]. After sonication, the samples were centrifuged at
7500 rpm for 15 min, and the supernatant was obtained after pelleting
the crude membrane fraction by centrifugation at 50,000 rpm for 1 hr at
4°C. Equivalent amounts of protein for each sample were resolved in
8.5% SDS-polyacrylamide gels, blotted electrophoretically to
Immobilon, and blocked overnight in TBS buffer (50 mM
Tris-HCl, pH 7.5, and 150 mM NaCl) containing 3% bovine
serum albumin. For detection of the phosphorylated forms of Akt or the
protein level of calcineurin, blots were incubated with
anti-phospho-Akt (1:1000; New England Biolabs, Beverly,
MA) and anti-calcineurin (1:2000; BD Transduction
Laboratories, Los Angeles, CA) antibodies, respectively. To
assess for change in the activation of PI-3 kinase, total kinase levels
were first normalized to total protein levels for each sample. Results
were expressed by the ratio of activated kinase levels to total kinase levels. However, in some experiments, activated kinase levels in
trained animals were normalized to total kinase levels and then were
expressed as a percentage of those in unpaired controls.
Calcineurin activity assay
Light-alone trained rats were killed by decapitation immediately
after trials. The LA and BLA were microdissected and frozen on dry ice.
Phosphatase assay was performed according to the instructions of the
calcineurin assay kit (Promega, Madison, WI). Pooled LA and BLA areas were homogenized in ice-cold buffer (50 mM
Tris-HCl, pH 7.5, 50 mM NaCl, 10 mM EGTA, 5 mM EDTA, 1 mM sodium orthovanadate, 1 mM PMSF, 20 µg/ml leupeptin, and 4 µg/ml aprotinin) and
centrifuged at 100,000 rpm for 1 hr to remove particular matter.
Supernatants were added to the reaction buffer from the kit, and
the reaction was incubated at 30°C for 10 min. The reaction buffer
contains 50 mM imidazole, pH 7.2, 0.2 mM EGTA,
10 mM MgCl2, 1 mM
NiCl2, 50 µg/ml calmodulin, and 0.02%
 -mercaptoethanol. FK-506 (1 µM) in the supernatant
completely blocked inorganic phosphate (Pi) release, indicating that
the measured phosphatase activity reflects calcineurin function. The
enzyme activity was expressed in nanomoles of Pi released per minute
per milligram of protein from the substrate. The calcineurin substrate
sequence is RRA(pT)VA.
| |
Results |
Rats were given 10 pairings of light (CS) and footshock (US) and
tested 24 hr later (pretest). After initial training, animals exhibited
fear of the light manifesting as an increase in acoustic startle
(195.9 ± 6.8% of potentiation; n = 54;
p < 0.001). They were subsequently divided into three
groups: light alone, context control, and light plus shock
groups. The rats in the light-alone group were given three sessions of
10 presentations of light in the absence of either shock or
startle-elicited noise burst. Group context control was placed in the
testing apparatus for an equivalent amount of time without stimulation,
and group light plus shock was given three sessions of light-shock
pairs (Fig. 1A). As
shown in Figure 1B, rats in the light-alone group
displayed a significant reduction in startle amplitude relative to
their preextinction levels. A two-way ANOVA with treatment (light-alone
presentations vs context control) and sessions as between-subjects
factors indicated a significant treatment effect
(F(1,30) = 190.4; p < 0.0001) and also a significant treatment × sessions interaction
(F(2,30) = 3.88; p < 0.05). As expected, rats in the light-shock group showed a slight
increase after three sessions of training
(t(5) = 2.82; p < 0.05). Together, these results indicate that fear extinction is
attributable to repeated presentations of light in the absence of shock rather than to the exposure of experimental context or the
desensitization to conditioning stimuli. It is important to note that,
when presenting the light-alone protocol to unpaired rats that were
exposed to the light and footshock in an unpaired, pseudorandom manner,
startle responses were not decreased to below the baseline level. This
result suggests a selective effect of extinction training on the
learned association between CS and US but not on the startle reflex
itself.
View larger version (37K):
[in this window]
[in a new window]
|
Figure 1.
Effect of extinction training on the
fear-potentiated startle. A, Timeline of behavioral
procedures for experiments B. B, Percentage of startle
potentiation before (pre-test), during, and after
three sessions of extinction training, context exposure, or
light-shock (post-test). The degree of
potentiation was significantly reduced only in the light-alone group.
It is noted that unpaired controls did not exhibit a decrease in
startle responses. *p < 0.05, **p < 0.01, and ***p < 0.001 versus pretests.
|
|
We next examined whether the activated state of PI-3 kinase induced by
fear conditioning is affected after extinction trials. Rats were
exposed to the light repeatedly paired with footshock, and behavioral
tests were performed 24 hr later (Fig.
2A). Figure 2B shows that conditioned rats exhibited an increase
in Akt phosphorylation after test compared with those of naive and
unpaired controls. The increase was transient and significant from 60 to 120 min after testing but not at other time points
(F(6,35) = 24.32; p < 0.001). Post hoc comparisons (Newman-Keuls) revealed the
differences between control and 60, 90, and 120 min time points
(p < 0.01). No change was observed when blotted
membrane was reprobed with an antibody that recognized Akt
independently of its phosphorylated state. To determine whether the
higher level of Akt phosphorylation in conditioned animals shown here
is indicative of induction after behavioral tests or a persistent
posttraining increase, we measured the level of Akt phosphorylation 24 hr after training but before test. Figure 2B also
shows that the level of Akt phosphorylation in conditioned rats 24 hr
after training is not significantly different from those of naive and
unpaired controls. Thus, behavioral tests caused reactivation of
protein kinase.
View larger version (39K):
[in this window]
[in a new window]
|
Figure 2.
Effect of extinction training on
conditioning-induced Akt phosphorylation. A, Behavioral
procedure used in experiment B. B, Time course of PI-3
kinase activation in paired as opposed to those of unpaired and naive
rats. Shown are the representative blots and mean ± SE ratios of
P-Akt/Akt immunoreactivities from rats decapitated at 30, 60, 90, 120, 150, and 180 min (n = 6 rats in each time point)
after pretests. The 10 min time point represents the level of Akt
phosphorylation 24 hr after training but before test, whereas the 0 min
time point is the value taken from naive rats. *p < 0.01 versus unpaired control. C, Behavioral procedure
used in experiment D. D, Rats received fear training in
a paired or unpaired manner and were tested 24 hr later (pretest).
Shown are the representative blots and mean ± SE percentage of
P-Akt immunoreactivities from unpaired (lane 1) and
paired (lane 2) rats decapitated at 60 min after
pretest. Ten minutes after pretest, paired rats were given light-alone
trials (lane 3) or exposed to the context (lane
4), and the amygdala was removed for biochemical assay.
The degree of Akt phosphorylation was significantly reduced in the
light-alone group. Bilateral infusion of FK-506 (10 µg dissolved in
1.6 µl of DMSO, 0.8 µl per side) before light-alone trials blocked
dephosphorylation (lane 5). *p < 0.01 versus pretest.
|
|
After been conditioned, rats were divided into two groups: light-alone
and context control. Immunoblotting for phosphorylated Akt
(P-Akt) was performed immediately after extinction training (Fig. 2C). Figure 2D indicates that the
degree of Akt phosphorylation was significantly reduced in the
light-alone group (t(10) = 3.75; p < 0.01). In contrast, Akt phosphorylation in the
context control group was comparable with and not significantly
different from the preextinction test
(t(10) = 0.32; p = 0.75). These results suggest that memory testing-induced Akt
phosphorylation was abrogated after light-alone trials. Given that
synaptic plasticity may be governed by the balance between protein
kinase and phosphatase activity (O'Dell and Kandel, 1994; Winder and
Sweatt, 2001), a decrease in the phosphorylated state of Akt after
extinction trials led us consider the possible involvement of
calcium-dependent phosphatase calcineurin. We determined the
involvement of calcineurin by infusing FK-506, a calcineurin inhibitor,
bilaterally into the amygdala before extinction training. As shown in
Figure 2D, FK-506 treatment reversed
extinction-induced dephosphorylation.
We tested whether calcineurin inhibitors affected experimental
extinction by giving cyclosporin A intravenously into the rats before
light-alone trials. This drug, which inhibits calcineurin by forming
complex with cyclophilin (Liu et al., 1991), dose-dependently blocked
extinction (F(1,10) = 255.5;
p < 0.001) (Fig. 3).
Conversely, rats that received vehicle showed a normal decrease in the
startle after extinction trials
(F(2,15) = 82.8; p < 0.001). Additional support for an involvement of calcineurin came from
the observation that direct injection of two other calcineurin
inhibitors FK-506 (10 µg dissolved in 1.6 µl of DMSO, 0.8 µl per
side) or cypermethrin (3 µg dissolved in 1.6 µl of ethanol, 0.8 µl per side) into the amygdala blocked extinction. Startle responses
after light-alone trials in FK-506-treated
(t(5) = 0.19; p = 0.85) or cypermethrin-treated (t(5) = 0.39; p = 0.71) rats were comparable with their
pretests. These results suggest that FK-506 blocked memory extinction
at the same dose that inhibited P-Akt dephosphorylation. However, the
effects of FK-506 could reflect an enhancement of fear-potentiated startle rather than a blockade of extinction (e.g., FK-506 elevated the
level of startle potentiation regardless of the extinction protocol).
To differentiate these possibilities, additional rats were matched into
four groups. Two groups (one group of vehicle-injected rats and one
group of FK-506-injected rats) received fear training, whereas two
other groups (one group of vehicle-injected rats and one group of
FK-506-injected rats) were exposed to the CS and US in an unpaired,
pseudorandom manner. We found that FK-506 did not affect startle
potentiation in either the unpaired
(t(10) = 0.48; p = 0.64) or paired (t(10) = 0.34;
p = 0.74) groups because there was no difference in the
degree of potentiation between vehicle- and FK-506 treated rats in both
groups. In parallel to the startle results, FK-506 did not affect Akt
phosphorylation. In both paired (t(10) = 0.15; p = 0.88) and unpaired
(t(10) = 0.59; p = 0.57) rats, Akt phosphorylation in vehicle group was not different from
that of FK-506 group.
View larger version (32K):
[in this window]
[in a new window]
|
Figure 3.
Extinction training-induced reduction of fear
memory is blocked by calcineurin inhibitors. Percentage of startle
potentiation before (pretest) and after three sessions of extinction
training in conditioned rats given intravenous administration of
cyclosporin A (5 or 20 mg/kg), bilateral amygdala infusion of FK-506
(10 µg dissolved in 1.6 µl of DMSO, 0.8 µl per side), or
cypermethrin (3 µg dissolved in 1.6 µl of ethanol, 0.8 µl per
side) before light-alone trials. *p < 0.01 and
**p < 0.001 versus pretests.
|
|
If calcineurin is involved in the extinction, then one might expect its
activity to be regulated by extinction training. We assayed calcineurin
activity by measuring the released Pi from the phosphopeptide substrate
that was insensitive to okadaic acid but could be blocked by FK-506. In
the first series of experiments, rats were assigned into three groups
(naive, unpaired, and paired), and each individual group was trained
according to its own protocol. Subsequently, the release of Pi from LA
and BLA was measured in each group. There was no difference among these
three groups. Next, conditioned rats were subjected to light-alone
trials, and calcineurin activity was measured after training. Figure
4A shows that, after
extinction training, Pi release was enhanced from 5.0 ± 0.4 nmol
Pi/min/mg (n = 6 rats) to 10.1 ± 0.3 nmol
Pi/min/mg (n = 6; p < 0.001). Because
it is possible that the observed increase may be attributable to some
unrelated factors in the experimental procedure not specifically
related to extinction, we repeated the experiments in the naive and
unpaired animals. The results indicated that calcineurin activity was
not altered in these animals (Fig. 4A).
View larger version (27K):
[in this window]
[in a new window]
|
Figure 4.
Increase in the enzymatic activity and protein
expression of calcineurin after extinction training. A,
Rats were assigned into three groups (naive, unpaired, and paired; 12 rats in each group), and each group was trained according to its own
protocol. After training, six rats in each group were killed, and the
release of Pi from LA and BLA was measured. Next, the remaining six
rats in each group were subjected to extinction training, and
calcineurin activity was measured after training. After extinction
training, the release of Pi was enhanced only in the paired rats.
***p < 0.001 versus naive or unpaired groups.
B, Time course of calcineurin expression induced by
light-alone trials in cytosolic fraction. Shown are representative
blots and mean ± SE of calcineurin immunoreactivities from rats
decapitated at various time points (n = 6 rats in
each time point) after extinction training ( -actin was used as
internal control). **p < 0.01 and
***p < 0.001 versus paired.
|
|
We determined calcineurin protein levels after extinction training.
Fear conditioning did not affect the cytosolic level of calcineurin
(90.1 ± 6.8%; n = 6 rats; p > 0.1). However, after light-alone trials, calcineurin was significantly
increased, which peaked at 10 min after training and subsided within 60 min (F(3,20) = 16.25;
p < 0.001) (Fig. 4B). Newman-Keuls
t tests revealed that differences existed between control
and 10 and 30 min time points (p < 0.001 and
p < 0.01, respectively). As a control, the
immunoreactivity for -actin was checked and found unchanged.
| |
Discussion |
Previous studies have shown that infusion of anisomycin shortly
after testing produced amnesia. This has led to the hypothesis that
memory, when reactivated, became vulnerable and sensitive to disruption
by protein synthesis inhibitors (Nader et al., 2000; Sara, 2000). In
the present study, we found that behavioral tests (light plus noise)
caused reactivation of kinase. The reactivation of kinase may lead to
new protein synthesis that is crucial for memory reconsolidation. This
could explain why memory became labile when retrieved. Conversely,
extinction training (light-alone) resulted in dephosphorylation of Akt.
It is suggested that acquisition and extinction may share some
common mechanisms (Corcoran and Maren, 2001; Vianna et
al., 2001). For example, NMDA receptor and MEK inhibitors that blocked the acquisition of fear (Miserendino et al., 1990; Schafe et al., 2000)
also blocked the extinction of conditioned fear (Falls et al., 1992; Lu
et al., 2001). Consistent with these results, we found that wortmannin
produced comparable effects on both acquisition and extinction of fear
memory (Lin et al., 2001; our unpublished data). Furthermore,
anisomycin, a protein synthesis inhibitor known to block acquisition of
many memory tasks (Davis and Squire, 1984), also blocked extinction of
an inhibitory avoidance task and the conditioned taste aversion
(Berman and Dudai, 2001; Vianna et al., 2001) (but see
Lattal and Abel, 2001). Thus, it is possible that extinction
training initiates calcium influx through NMDA receptors in the
amygdala. The increase in intracellular calcium results in the
activation protein kinases such as PI-3 kinase and MAPK. Once
stimulated, MAPK can translocate to the nucleus, in which they activate
cAMP response element-binding protein (CREB) and unidentified
transcriptional factors to reactivate original memory on one hand and
promote calcineurin synthesis on the other hand. Calcineurin creates a
negative-feedback loop to suppress phosphorylation and weakens the
original memory. Thus, inhibition of protein synthesis during or
immediately after retrieval can result in either enhancement or
extinction of a learned response that is region or task dependent and
also depends on the balance between protein kinase and phosphatase
activity. When calcineurin activity induced by extinction protocol
exceeds the activity of protein kinase, inhibition of protein synthesis
would block extinction and thus strengthen memory. In contrast, if
protein kinase activity dominates, then anisomycin produces amnesia
after memory reactivation.
Calcineurin has long been implicated in the synaptic plasticity. In the
hippocampus, calcineurin is involved in both long-term depression
(Mulkey et al., 1994) and depotentiation (Zhuo et al., 1999) and
negatively regulates the transition between early and late phases of
LTP (Winder et al., 1998). Developmental shift of NMDA
receptor-dependent dephosphorylation of CREB is mediated by calcineurin
(Sala et al., 2000). Calcineurin also directly modulates AMPA (Banke et
al., 2000), NMDA (Shi et al., 2000), as well as
GABAA receptor-channel kinetics (Jones and
Westbrook, 1997). In combination with behavioral and biochemical
experiments, we show here that activation of calcineurin contributes to
the extinction of fear memory. The identification of calcineurin as a
molecular signal in memory liability suggests a potential new target
for the treatment of anxiety and posttraumatic stress disorders.
| |
FOOTNOTES |
Received July 16, 2002; revised Dec. 9, 2002; accepted Dec. 11, 2002.
This work was supported by National Science Council Grant
NSC89-2320-B006-011 and Academic Excellence Program of the Ministry of
Education of Taiwan Grant 89-B-FA08-1-4.
Correspondence should be addressed to Dr. Po-Wu Gean, Department of
Pharmacology, College of Medicine, National Cheng-Kung University,
Tainan, Taiwan 701. E-mail: powu{at}mail.ncku.edu.tw.
| |
References |
-
Banke TG,
Bowie D,
Lee HK,
Huganir RL,
Schousboe A,
Traynelis SF
(2000)
Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase.
J Neurosci
20:89-102[Abstract/Free Full Text].
-
Berman DE,
Dudai Y
(2000)
Memory extinction, learning anew, and learning the new: dissociation in the molecular machinery of learning in cortex.
Science
291:2417-2419[Abstract/Free Full Text].
-
Corcoran KA,
Maren S
(2001)
Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction.
J Neurosci
21:1720-1726[Abstract/Free Full Text].
-
Davis HP,
Squire LR
(1984)
Protein synthesis and memory: a review.
Psychol Bull
96:518-559[ISI][Medline].
-
Davis M
(2000)
The role of the amygdala in conditioned and unconditioned fear and anxiety.
In: The amygdala: a functional analysis (Aggleton JP,
ed), pp 213-287. New York: Oxford UP.
-
Falls WA,
Miserendino JD,
Davis M
(1992)
Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala.
J Neurosci
12:854-863[Abstract].
-
Genoux D,
Haditsch U,
Knobloch M,
Michalon A,
Storm D,
Mansuy IM
(2002)
Protein phosphatase 1 is a molecular constraint on learning and memory.
Nature
418:970-975[Medline].
-
Impey S,
Smith DM,
Obrietan K,
Donahue R,
Wade C,
Storm DR
(1998)
Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning.
Nat Neurosci
1:595-601[ISI][Medline].
-
Jones MV,
Westbrook GL
(1997)
Shaping of IPSCs by endogenous calcineurin activity.
J Neurosci
17:7626-7633[Abstract/Free Full Text].
-
Josselyn SA,
Shi C,
Carlezon WA,
Neve Jr RL,
Nestler EJ,
Davis M
(2001)
Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala.
J Neurosci
21:2404-2412[Abstract/Free Full Text].
-
Lattal KM,
Abel T
(2001)
Different requirements for protein synthesis in acquisition and extinction of spatial preferences and context-evoked fear.
J Neurosci
21:5773-5780[Abstract/Free Full Text].
-
LeDoux JE
(2000)
Emotion circuits in the brain.
Annu Rev Neurosci
23:155-184[ISI][Medline].
-
Lin CH,
Yeh SH,
Lin CH,
Lu KT,
Leu TH,
Chang WC,
Gean PW
(2001)
A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala.
Neuron
31:841-851[ISI][Medline].
-
Liu J,
Farmker JD,
Lane WS,
Friedman J,
Weissman I,
Schreiber SL
(1991)
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.
Cell
66:807-815[ISI][Medline].
-
Lu KT,
Walker DL,
Davis M
(2001)
Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle.
J Neurosci
21:RC162[Abstract/Free Full Text](1-5).
-
Maren S
(1999)
Long-term potentiation in the amygdala: a mechanism for emotional learning and memory.
Trends Neurosci
22:561-567[ISI][Medline].
-
Marsicano G,
Wotjak CT,
Azad SC,
Bisogno T,
Rammes G,
Cascio MG,
Hermann H,
Tang J,
Hofmann C,
Zieglgansberger W,
Di Marzo V,
Lutz B
(2002)
The endogenous cannabinoid system controls extinction of aversive memories.
Nature
418:530-534[Medline].
-
Miserendino MJ,
Sananes CB,
Melia KR,
Davis M
(1990)
Blocking of acquisition but not expression on conditioned fear-potentiated startle by NMDA antagonists in the amygdala.
Nature
345:716-718[Medline].
-
Mulkey RM,
Endo S,
Shenolikar S,
Malenka RC
(1994)
Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression.
Nature
369:486-488[Medline].
-
Nader K,
Schafe GE,
LeDoux JE
(2000)
Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval.
Nature
406:722-726[Medline].
-
O'Dell T,
Kandel E
(1994)
Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases.
Learn Mem
1:129-139[Abstract/Free Full Text].
-
Paxinos G,
Watson C
(1986)
In: The rat brain in stereotaxic coordinates. New York: Academic.
-
Rescorla RA
(2001)
Experimental extinction.
In: Handbook of contemporary learning theories (Mowrer RR,
Klein S,
eds), pp 119-154. Mahwah, NJ: Erlbaum.
-
Sala C,
Rudolph-Correia S,
Sheng M
(2000)
Developmentally regulated NMDA receptor-dependent dephosphorylation of cAMP response element-binding protein (CREB) in hippocampal neurons.
J Neurosci
20:3529-3536[Abstract/Free Full Text].
-
Sara SJ
(2000)
Retrieval and reconsolidation: toward a neurobiology of remembering.
Learn Mem
7:73-84[Free Full Text].
-
Schafe GE,
Atkins CM,
Swank MW,
Bauer EP,
Sweatt JD,
LeDoux JE
(2000)
Activation of ERK/MAPK kinase in the amygdala is required for memory consolidation of Pavlovian fear conditioning.
J Neurosci
20:8177-8187[Abstract/Free Full Text].
-
Shi J,
Townsend M,
Constantine-Paton M
(2000)
Activity-dependent induction of tonic calcineurin activity mediates a rapid developmental downregulation of NMDA receptor currents.
Neuron
28:103-114[ISI][Medline].
-
Vianna MRM,
Szapiro G,
McGaugh JL,
Medina JH,
Izquierdo I
(2001)
Retrieval of memory for fear-motivated training initiates extinction requiring protein synthesis in the rat hippocampus.
Proc Natl Acad Sci USA
98:12251-12254[Abstract/Free Full Text].
-
Walker DL,
Ressler KJ,
Lu KT,
Davis M
(2002)
Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats.
J Neurosci
22:2343-2351[Abstract/Free Full Text].
-
Winder DG,
Sweatt JD
(2001)
Roles of serine/threonine phosphatases in hippocampal synaptic plasticity.
Nat Rev Neurosci
2:461-474[ISI][Medline].
-
Winder DG,
Mansuy IM,
Osman M,
Moallem TM,
Kandel ER
(1998)
Genetic and pharmacological evidence for a novel, intermediate phase of long-term potentiation suppressed by calcineurin.
Cell
92:25-37[ISI][Medline].
-
Zhuo M,
Zhang W,
Son H,
Mansuy I,
Sobel RA,
Seidman J,
Kandel ER
(1999)
A selective role of calcineurin A in synaptic depotentiation in hippocampus.
Proc Natl Acad Sci USA
96:4650-4655[Abstract/Free Full Text].
Copyright © 2003 Society for Neuroscience 0270-6474/03/2351574-06$05.00/0
This article has been cited by other articles:
|
|
|
|
 
K. Hefner, N. Whittle, J. Juhasz, M. Norcross, R.-M. Karlsson, L. M. Saksida, T. J. Bussey, N. Singewald, and A. Holmes
Impaired Fear Extinction Learning and Cortico-Amygdala Circuit Abnormalities in a Common Genetic Mouse Strain
J. Neurosci.,
August 6, 2008;
28(32):
8074 - 8085.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Schiller, C. K. Cain, N. G. Curley, J. S. Schwartz, S. A. Stern, J. E. LeDoux, and E. A. Phelps
Evidence for recovery of fear following immediate extinction in rats and humans
Learn. Mem.,
May 28, 2008;
15(6):
394 - 402.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Santini, G. J. Quirk, and J. T. Porter
Fear Conditioning and Extinction Differentially Modify the Intrinsic Excitability of Infralimbic Neurons
J. Neurosci.,
April 9, 2008;
28(15):
4028 - 4036.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. J. Sajdyk, P. L. Johnson, R. J. Leitermann, S. D. Fitz, A. Dietrich, M. Morin, D. R. Gehlert, J. H. Urban, and A. Shekhar
Neuropeptide Y in the Amygdala Induces Long-Term Resilience to Stress-Induced Reductions in Social Responses But Not Hypothalamic-Adrenal-Pituitary Axis Activity or Hyperthermia
J. Neurosci.,
January 23, 2008;
28(4):
893 - 903.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Kim, S. Lee, K. Park, I. Hong, B. Song, G. Son, H. Park, W. R. Kim, E. Park, H. K. Choe, et al.
Amygdala depotentiation and fear extinction
PNAS,
December 26, 2007;
104(52):
20955 - 20960.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Isiegas, A. Park, E. R. Kandel, T. Abel, and K. M. Lattal
Transgenic Inhibition of Neuronal Protein Kinase A Activity Facilitates Fear Extinction
J. Neurosci.,
December 6, 2006;
26(49):
12700 - 12707.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Maren and C.-h. Chang
Recent fear is resistant to extinction
PNAS,
November 21, 2006;
103(47):
18020 - 18025.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Havekes, I. M. Nijholt, P. G.M. Luiten, and E. A. Van der Zee
Differential involvement of hippocampal calcineurin during learning and reversal learning in a Y-maze task
Learn. Mem.,
November 1, 2006;
13(6):
753 - 759.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kamprath, G. Marsicano, J. Tang, K. Monory, T. Bisogno, V. D. Marzo, B. Lutz, and C. T. Wotjak
Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes.
J. Neurosci.,
June 21, 2006;
26(25):
6677 - 6686.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Barad
Is extinction of fear erasure or inhibition? Why both, of course.
Learn. Mem.,
March 1, 2006;
13(2):
108 - 109.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. M. Myers, K. J. Ressler, and M. Davis
Different mechanisms of fear extinction dependent on length of time since fear acquisition.
Learn. Mem.,
March 1, 2006;
13(2):
216 - 223.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. C.-K. Chan, S. Tonegawa, and D. R. Storm
Hippocampal Neurons Express a Calcineurin-Activated Adenylyl Cyclase
J. Neurosci.,
October 26, 2005;
25(43):
9913 - 9918.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. K. Cain, B. P. Godsil, S. Jami, and M. Barad
The L-type calcium channel blocker nifedipine impairs extinction, but not reduced contingency effects, in mice
Learn. Mem.,
May 1, 2005;
12(3):
277 - 284.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Chhatwal, K. M. Myers, K. J. Ressler, and M. Davis
Regulation of Gephyrin and GABAA Receptor Binding within the Amygdala after Fear Acquisition and Extinction
J. Neurosci.,
January 12, 2005;
25(2):
502 - 506.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Cao, F. Kambe, L. C. Moeller, S. Refetoff, and H. Seo
Thyroid Hormone Induces Rapid Activation of Akt/Protein Kinase B-Mammalian Target of Rapamycin-p70S6K Cascade through Phosphatidylinositol 3-Kinase in Human Fibroblasts
Mol. Endocrinol.,
January 1, 2005;
19(1):
102 - 112.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-L. Su, C.-H. Chen, H.-Y. Lu, and P.-W. Gean
The Involvement of PTEN in Sleep Deprivation-Induced Memory Impairment in Rats
Mol. Pharmacol.,
November 1, 2004;
66(5):
1340 - 1348.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Cannich, C. T. Wotjak, K. Kamprath, H. Hermann, B. Lutz, and G. Marsicano
CB1 Cannabinoid Receptors Modulate Kinase and Phosphatase Activity During Extinction of Conditioned Fear in Mice
Learn. Mem.,
September 1, 2004;
11(5):
625 - 632.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-H. Lin, S.-H. Yeh, H.-Y. Lu, and P.-W. Gean
The Similarities and Diversities of Signal Pathways Leading to Consolidation of Conditioning and Consolidation of Extinction of Fear Memory
J. Neurosci.,
September 10, 2003;
23(23):
8310 - 8317.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
Introduction
