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The Journal of Neuroscience, 2001, 21:RC162:1-5
RAPID COMMUNICATION
Mitogen-Activated Protein Kinase Cascade in the Basolateral
Nucleus of Amygdala Is Involved in Extinction of Fear-Potentiated
Startle
Kwok-Tung
Lu,
David L.
Walker, and
Michael
Davis
Department of Psychiatry and Behavioral Science, Emory University,
Atlanta, Georgia 30322
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ABSTRACT |
Previous results indicate that intra-amygdala infusions of
NMDA receptor antagonists block the extinction of conditioned
fear. Mitogen-activated protein kinase (MAPK) can be activated by NMDA receptor stimulation and is involved in excitatory fear conditioning. Here, we evaluate the role of MAPK within the basolateral amygdala in
the extinction of conditioned fear.
Rats received 10 light-shock pairings. After 24 hr, fear was
assessed by eliciting the acoustic startle reflex in the presence of
the conditioned stimulus (CS) (CS-noise trials) and also in its
absence (noise-alone trials). Rats subsequently received an intra-amygdala or intrahippocampal infusion of either 20% DMSO or the
MAPK inhibitor PD98059 (500 ng/side) followed 10 min later by 30 presentations of the light CS without shock (extinction training).
After 24 hr, they were again tested for fear-potentiated startle.
PD98059 infusions into the basolateral amygdala but not the hippocampus
significantly reduced extinction, which was otherwise evident in
DMSO-infused rats. Control experiments indicated that the effect of
intra-amygdala PD98059 could not be attributed to lasting damage to the
amygdala or to state dependency. These results suggest that a
MAPK-dependent signaling cascade within or very near the basolateral
amygdala plays an important role in the extinction of conditioned fear.
Key words:
amygdala; hippocampus; extinction; fear conditioning; fear-potentiated startle; mitogen-activated protein kinase
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INTRODUCTION |
Mitogen-activated
protein kinase (MAPK) is a serine-threonine kinase that is widely
expressed in cell bodies and dendrites of postmitotic neurons (Boulton
et al., 1991 ; Fiore et al., 1993). Although a role for MAPK in cell
growth and proliferation has been known for some time (cf. Neary,
1997), recent evidence has pointed to an additional involvement of MAPK
in the neuroplasticity that underlies learning (cf. Impey et al.,
1999). For example, Schafe et al. (1999) reported that pretraining
intraventricular infusions of the MAPK inhibitor PD98059 markedly
impaired contextual fear conditioning and also impaired, albeit to a
lesser degree, discrete cue conditioning to an auditory conditioned
stimulus (CS). The same inhibitor has also been found to disrupt
long-term potentiation (LTP) in the hippocampal formation (English and
Sweatt, 1997; S. Davis et al., 2000) and in the lateral nucleus
of the amygdala (Huang et al., 2000). Also, Brambilla et al. (1997)
reported that knock-out mice lacking Ras guanine nucleotide exchange
factor, an MAPK activator, show a profound disruption not only of
avoidance learning and of cued and contextual fear conditioning but
also of amygdala LTP.
From the standpoint of fear conditioning, evidence for an involvement
of MAPK in amygdala plasticity is particularly interesting. It has long
been recognized that the amygdala is involved in emotional processes,
and considerable evidence points to the basolateral complex of the
amygdala as an important site of plasticity for both the development
and extinction of fear memories (cf. Aggleton, 2000). With respect to
the latter, Falls et al. (1992) reported that intra-amygdala infusion
of the NMDA receptor antagonist AP-5 made just before extinction
training (i.e., nonreinforced cue presentations) prevented extinction
as assessed with fear-potentiated startle. Lee and Kim (1998) reported
that intra-amygdala administration of AP-5 also blocked extinction when
freezing was used as a measure of fear and when auditory, visual, or
contextual CSs were used as conditioned fear stimuli.
Given evidence that (1) amygdala NMDA receptors are involved in the
extinction of conditioned fear, (2) MAPK is activated by NMDA receptor
stimulation (English and Sweatt, 1996; Xia et al., 1996), and (3)
amygdala MAPK is involved in both excitatory fear conditioning and
amygdala LTP, we evaluated the role of amygdala MAPK in the extinction
of conditioned fear. To do this, the MAPK inhibitor PD98059 was infused
directly into the amygdala just before extinction training (experiment
1). As an anatomical control, and in view of evidence implicating the
hippocampus in extinction for some tasks but not others (cf. M. Davis et al., 2000), PD90059 was also infused into the
hippocampus (experiment 2). In experiment 3, we controlled for
state-dependent drug effects by infusing PD98059 before both extinction
training and extinction testing.
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MATERIALS AND METHODS |
Animals
Male Sprague Dawley rats (300-400 gm; Charles River, Raleigh,
NC) were housed in groups of four before surgery and housed singly
after surgery. Food and water were available ad libitum. The
vivarium was kept on a 12 hr light/dark cycle with lights on at 07:00
A.M. Behavioral procedures took place during the animal's light cycle.
Apparatus
Animals were trained and tested in 8 × 15 × 15 cm
Plexiglas and wire-mesh cages. The cage floor consisted of four
6.0-mm-diameter stainless steel bars spaced 18 mm apart. Each cage was
suspended between compression springs within a steel frame and located
within a custom-designed 90 × 70 × 70 cm ventilated
sound-attenuating chamber. Background noise (60 dB wide-band) was
provided by a General Radio Type 1390-B noise generator (Concord, MA)
and delivered through high-frequency speakers (Radio Shack
Supertweeter; Tandy, Fort Worth, TX) located 5 cm from the front of
each cage.
Startle responses were evoked by 50 msec, 95 dB white-noise bursts (5 msec rise-decay) generated by a Macintosh G3 computer soundfile (0-22
kHz), amplified by a Radio Shack amplifier (100 W; model MPA-200;
Tandy), and delivered through the same speakers used to provide
background noise. Sound pressure levels were measured using a
Bruel & Kjaer (Marlborough, MA) model 2235 sound-level meter (A scale;
random input) with the microphone (type 4176) held 7 cm from the
speaker (approximating the distance of the rat's ear from the speaker).
An accelerometer (model U321AO2; PCB Piezotronics, Depew, NY) affixed
to the bottom of each cage produced a voltage output proportional to
the velocity of cage movement. This output was amplified (model 483B21;
PCB Piezotronics) and digitized on a scale of 0-2500 U by an InstruNET
device (model 100B; GW Instruments, Somerville, MA) interfaced to a
Macintosh G3 computer. Startle amplitude was defined as the maximal
peak-to-peak voltage that occurred during the first 200 msec after
onset of the startle-eliciting stimulus.
The CS was a 3.7 sec light produced by an 8 W fluorescent bulb (100 µsec rise time) located 10 cm behind each cage. Light intensity at
the center of the test cage was 82 lux as measured with a VWR light
meter (VWR Scientific, Atlanta, GA). The unconditioned stimulus (a 0.5 sec, 0.4 mA floorbar shock) was produced by a LeHigh Valley shock
generator (SGS-004; LeHigh Valley, Beltsville, MD). Shock intensity was
measured as described by Cassella and Davis (1986).
Surgery
Rats were anesthetized with Nembutal (sodium pentobarbital, 50 mg/kg, i.p.) and placed in a Kopf stereotaxic instrument (David Kopf
Instruments, Tujunga, CA). We then implanted 22 gauge guide cannulas
(model C313G; Plastic Products, Roanoke, VA) into the basolateral
nucleus of the amygdala [anteroposterior (AP),  2.8; dorsoventral
(DV), 9.0; mediolateral (ML), ±5.0 from bregma] or dorsal
hippocampus (AP, 4.6; DV, ±4.0; ML, ±3.2). Size 0 insect pins
(Carolina Biological Supply, Burlington, NC) were inserted into each
cannula to prevent clogging. Screws were anchored to the skull and the
assembly was cemented in place using dental cement (Plastic Products).
Drug infusion
PD98059 (500 ng in 1 µl of 20% DMSO; Calbiochem, La Jolla,
CA) or 20% DMSO was infused (0.25 µl/min) through 28 gauge
injection cannulas (model C313I; Plastic Products) 10 min before
extinction training. This dose was chosen on the basis of pilot data
and Western blot analyses performed by Blum et al. (1999) showing that
intrahippocampal infusions of a slightly higher dose (2 µg) disrupt
MAPK phosphorylation without noticeably influencing the phosphorylation
of several other kinases (e.g., protein kinase A, protein kinase C, and
calcium-calmodulin-dependent protein kinase).
Behavioral procedures
The behavioral procedure consisted of the following phases:
acclimation, initial startle test, fear conditioning, pre-extinction test, nonreinforced cue exposure (i.e., extinction training), and
post-extinction test (also see Fig. 1 timelines).
Acclimation. On 3 consecutive days, rats were placed in the
startle test boxes and returned to their home cage after 10 min.
Initial startle test. On 2 consecutive days, animals were
placed in the startle cages and presented with 30 startle stimuli using
an intertrial interval (ITI) of 30 sec.
Training. Rats were returned to the startle cages and 5 min
later received the first of 10 light-shock pairings. Shocks were delivered during the last 0.5 sec of the 3.7 sec CS. The average ITI
was 4 min (range, 3-5 min).
Pre-extinction test. Rats were placed in the startle cages
and, after 5 min, presented with 30 startle-eliciting noise bursts. These initial startle stimuli (hereafter referred to as "leaders") were used to habituate the startle response to a stable baseline. Thirty seconds after the final leader stimulus, each animal received 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 CS
(CS-noise trials). The two trial types were presented in a balanced
mixed order (ITI, 30 sec). For each rat, the percentage of
fear-potentiated startle was computed as follows: [(startle amplitude
on CS-noise minus noise-alone trials)/(noise-alone trials)] × 100. Using these scores, rats were assigned to two groups such that each
group had equivalent mean levels of fear-potentiated startle.
Extinction training (nonreinforced cue exposure). Rats were
returned to the startle cages and given 30 presentations of the CS
without shock 5 min later (ITI, 30 sec). This extinction procedure was
repeated 24 h later.
Post-extinction test. Rats were placed in the startle cages
and presented 5 min later with 18 leader stimuli followed by 30 noise-alone and 30 CS-noise trials (presented in a balanced irregular order with a 30 sec ITI). The larger number of CS trials was used here,
compared with the pre-extinction test, for two reasons. First, the
fear-potentiated startle test is itself an extinction procedure (i.e.,
nonreinforced CS presentations), and we wanted to minimize, in the
pre-extinction test, any incidental extinction that might occur.
Second, the primary statistical comparison of interest is between drug-
and vehicle-infused rats after extinction. The greater number of test
trials on the post-extinction test allows for a more sensitive
statistical analysis of this comparison. This also provides a greater
opportunity for within-session extinction. However, the statistical
impact of this is minimal insofar as both groups are equally
susceptible, on noninfusion test days, to within-session extinction.
Test for toxicity. If extinction was disrupted by PD98059
(and the corresponding control group), rats were given two additional extinction training sessions without drug, followed 24 h later by
a second post-extinction test. A finding that extinction could still
occur would suggest that the previously observed disruption of
extinction was not attributable to amygdala toxicity.
Test for state dependency. Because pharmacological
disruption of extinction has sometimes been attributed to
state-dependent learning (Bouton et al., 1990), it is possible that
rats infused with PD98059 during extinction training would not show
evidence of extinction when subsequently tested without drug. To
evaluate this possibility, additional rats were trained and tested as
described previously. However, 24 h after post-extinction test 1, rats received a second infusion of the same compound that they had
received during extinction training (i.e., either DMSO or PD98059) and were tested again 10 min later for fear-potentiated startle (i.e., post-extinction test 2).
Histology
Rats were overdosed with chloral hydrate and perfused
intracardially with 0.9% saline followed by 10% formalin. The brains were removed and immersed in a 30% sucrose-formalin solution for at
least 3 d. Coronal sections (30 µm) were cut through the area of
interest, stained with cresyl violet, and examined under light microscope for cannula placement.
Statistics
The mean startle amplitude on noise-alone and CS-noise trials
was calculated for each animal. The percentage of fear-potentiated startle was computed as [(startle amplitude on CS-noise minus noise-alone trials)/(noise-alone trials)] × 100. Between-group comparisons were made using t tests for independent samples.
Within-group comparisons (e.g., pre-extinction vs post-extinction) were
evaluated using t tests for paired samples. In experiment 3, ANOVA was used to evaluate the effect of session (post-extinction test
1 vs post-extinction test 2) and treatment (DMSO vs PD98059). The
criterion for significance for all comparisons was p < 0.05 (two-tailed t test).
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RESULTS |
Histology
Behavioral data from 10 animals were excluded from the statistical
analyses of experiments 1 and 3 because of missed placements (defined
as  0.5 mm from the basolateral complex of the amygdala) or because of
complications with the drug infusion. Placements for the remaining
animals are shown in Figure 1.
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Figure 1.
For each panel, an experimental
timeline is shown at the top, experimental data are
shown at the bottom, and cannula tip locations
[transcribed onto atlas plates modified from Paxinos and Watson
(1997)] are shown to the right. In experiment 1 (A), animals were tested for fear-potentiated
startle before (Pre-extinction test) and after
(Post-extinction test 1) nonreinforced cue exposure
(extinction training). Before extinction training, rats received
intra-amygdala infusions of either PD98095 or the DMSO vehicle. PD98059
blocked extinction learning. These same animals showed normal
extinction after nonreinforced cue exposure without drug
(Post-extinction test 2). The effects were anatomically
specific. PD98059 did not block extinction learning when infused into
the dorsal hippocampus (experiment 2; B). The disruptive
effect of amygdala MAPK inhibition could not be readily attributed to
state dependence. In experiment 3 (C), rats
received extinction training after intra-amygdala infusions of DMSO or
PD98095. As expected, PD98095 blocked extinction learning
(Post-extinction test 1). When retested
(Post-extinction test 2) after an infusion of the same
compound that they had received during extinction training,
PD98095-infused rats continued to show significantly higher levels of
fear-potentiated startle than vehicle-infused rats.
*p < 0.05.
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Intra-amygdala infusion of the MAPK inhibitor PD98059 blocks the
extinction of fear conditioning
Behavioral data for animals that received intra-amygdala infusions
are shown in Figure 1A. For rats infused with DMSO
(n = 8), fear-potentiated startle was significantly
lower during the post-extinction test compared with the pre-extinction
test (t(7) = 2.364; p < 0.05). In contrast, fear-potentiated startle in animals infused with
PD98059 (n = 8) was comparable with and not
significantly different from their pre-extinction level
(t(7) = 0.23; p = 0.82). The level of fear-potentiated startle after nonreinforced cue exposure was significantly lower in the DMSO group versus the PD98059
group (t(14) = 2.51; p < 0.05). In short, intra-amygdala infusions of PD98059 blocked extinction.
To test for toxicity, all animals received an additional 2 d of
drug-free extinction training and were retested 24 h later. Under
these conditions, animals previously infused with PD98059 did show a
significant reduction of fear-potentiated startle from post-extinction
test 1 to post-extinction test 2 (t(7) = 2.518; p < 0.05) (Fig. 1A). Thus,
the blockade of extinction observed during post-extinction test 1 appeared to result from an acute drug effect rather than from a more
permanent, perhaps toxic action of PD98059, especially because previous
studies have shown that lesions of the basolateral amygdala block
fear-potentiated startle (Sananes and Davis, 1992; Campeau and Davis,
1995), an outcome opposite in direction from that obtained with PD98059 infusions.
Intrahippocampal infusions of PD98059 do not block extinction of
fear conditioning
Behavioral data for animals that received intrahippocampal
infusions are shown in Figure 1B. Fear-potentiated
startle in the DMSO versus PD98059 groups did not significantly differ
from one another either before or after cue exposure. In both groups,
fear-potentiated startle was significantly lower during the
post-extinction test than during the pre-extinction test
(t(6) = 2.78; p < 0.05 and t(7) = 2.58;
p < 0.05 for the DMSO and PD98098 groups,
respectively). Thus, PD98059 did not disrupt extinction when infused
into the dorsal hippocampus.
The disruptive effect of intra-amygdala PD98059 infusions is not
attributable to state dependency
To evaluate the possible contribution of state-dependent drug
effects to the results obtained in experiment 1, additional amygdala-cannulated rats were tested for extinction in a drug-free state and subsequently after receiving the same compound that they had
received during extinction training. These results are shown in Figure
1C. For control rats (n = 8),
fear-potentiated startle was significantly lower during post-extinction
test 1 compared with the pre-extinction test
(t(7) = 2.364; p < 0.05). In contrast, the level of fear-potentiated startle in animals infused with PD98059 (n = 8) was comparable with and
not significantly different from their pre-extinction level. In
addition, the level of fear-potentiated startle after cue exposure was
significantly lower in the control group versus the PD98059 group
(t(14) = 2.179; p < 0.05). Thus, these results replicate the principal finding of
experiment 1.
Rats infused with PD98095 before post-extinction test 2 showed a loss
of fear-potentiated startle from post-extinction test 1 to
post-extinction test 2. Vehicle-infused rats showed a comparable loss.
Statistically, an ANOVA using session and treatment as within- and
between-subject factors, respectively, indicated significant session
(F(1,14) = 17.232; p < 0.01) and treatment (F(1,14) = 20.087; p < 0.01) effects but not a significant
interaction. The loss of fear-potentiated startle in both groups
probably reflects incidental extinction produced by the 30 nonreinforced CS presentations of post-extinction test 1. The failure
of rats infused with the MAPK inhibitor before testing to show a loss
of fear-potentiated startle beyond that which could be attributed to
this incidental extinction suggests that state dependency is not a
major factor in accounting for the previously described effects of PD98095.
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DISCUSSION |
Previous findings have shown that MAPK inhibitors retard
acquisition in a variety of learning paradigms. In addition to
previously mentioned effects on discrete cue and contextual fear
conditioning (Schafe et al., 1999) after intraventricular
administration, MAPK inhibitors have been shown to disrupt taste
aversion learning when infused into the insular cortex (Berman et al.,
1998), avoidance learning when infused into the amygdala, hippocampus,
entorhinal, or parietal cortices (Walz et al., 1999a,b, 2000), and
spatial learning with the Morris water maze after either systemic or
intrahippocampal administration (Blum et al., 1999; Selcher et al.,
1999).
Here we show that the MAPK pathway is also involved in extinction.
Specifically, intra-amygdala infusion of the MAPK inhibitor PD98059
blocked the extinction of conditioned fear as assessed with
fear-potentiated startle. This could not be attributed either to
lasting damage to the amygdala (because conditioned fear did extinguish
in animals previously given PD98059 when the extinction procedure was
repeated without drug) or to state-dependent drug effects. Moreover,
the effects were anatomically specific. Intrahippocampal infusions did
not disrupt extinction.
These results are compatible with an emerging appreciation for the role
of the amygdala in the extinction of conditioned fear. As noted
previously, Falls et al. (1992) reported that intra-amygdala infusions
of the NMDA receptor antagonist AP-5 blocked extinction as assessed
with fear-potentiated startle, and Lee and Kim (1998) reported similar
results using freezing as a measure of fear. Using functional magnetic
resonance imaging, LaBar et al. (1998) noted amygdala activation during
both the acquisition and extinction phase of discriminative fear
conditioning in humans.
These results are also compatible with the view that fear acquisition
and fear extinction are forms of learning with at least partially
similar neuroanatomical substrates and pharmacologies. As with
extinction, fear acquisition can also be disrupted by MAPK inhibitors
(Schafe et al., 1999; our current results) (although see Berman and
Dudai, 2001) and by intra-amygdala infusion of NMDA receptor
antagonists (Miserendino et al., 1990). In fact, evidence that MAPK is
activated by NMDA receptor stimulation suggests that these two sets of
observations may be causally linked. In particular, extinction training
may activate amygdala NMDA receptors, which in turn may activate MAPK,
which in turn is required for extinction. It is alternatively possible
that intra-amygdala PD98059 infusions decrease tonic MAPK activity
levels below a critical threshold required for extinction. However,
evidence that MAPK activity increases after behavioral training and
also after LTP induction (Atkins et al., 1998; Berman et al., 1998;
Blum et al., 1999; S. Davis et al., 2000), and that this
activation is NMDA receptor-dependant (Cammarota et al., 2000), is
perhaps more consistent with the former possibility.
The exact role that amygdala MAPK plays in extinction is unclear. In
general, the prominent role of this kinase in genomic regulation (Seger
and Krebs, 1995; Impey et al., 1999; S. Davis et al., 2000)
suggests that the MAPK pathway participates in the synthesis of
proteins important for the long-term stabilization and storage of fear
memories. Consistent with this possibility, treatments that interfere
with MAPK function have been found to have their greatest effects on
long- but not short-term retention in behavioral studies (Brambilla et
al., 1997; Martin et al., 1997; Blum et al., 1999; Schafe et al., 1999;
Walz et al., 1999b) and on late-stage but not early-stage potentiation
in electrophysiological studies (Brambilla et al., 1997; Huang et al.,
2000). However, differential effects of MAPK and other treatments on
short- versus long-term memory, although often attributed to selective
effects on different phases of memory storage, may sometimes be
attributed to parametric differences in the strength of the conditioned
response and therefore its susceptibility to disruption at short-
versus long-train test intervals (Walker and Davis, 2000). Additional experiments will be necessary to resolve this issue with respect to
MAPK and the extinction of conditioned fear.
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FOOTNOTES |
Received April 9, 2001; revised June 11, 2001; accepted June 11, 2001.
This work was supported by National Institute of Mental Health Grants
MH 47840, MH 57250, MH 58922, MH 52384, and MH 59906, by the Woodruff
Foundation, and by the Science and Technology Centers program
(The Center for Behavioral Neuroscience) of the National Science
Foundation under Agreement No. IBN-9876754.
Correspondence should be addressed to Dr. Michael Davis, Department of
Psychiatry and Behavioral Science, Emory University School of Medicine,
Woodruff Memorial Building Suite 4000, 1639 Pierce Drive, Atlanta, GA
30322. E-mail: mdavis4{at}emory.edu.
This article is published in
The Journal of Neuroscience, Rapid Communications Section,
which publishes brief, peer-reviewed papers online, not in print. Rapid
Communications are posted online approximately one month earlier than
they would appear if printed. They are listed in the Table of Contents
of the next open issue of JNeurosci. Cite this article as:
JNeurosci, 2001, 21:RC162 (1-5). The
publication date is the date of posting online at
www.jneurosci.org.
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TOP
ABSTRACT
INTRODUCTION
Compound via MeSH
