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The Journal of Neuroscience, October 1, 1999, 19(19):8696-8703
Neurotoxic Basolateral Amygdala Lesions Impair Learning and
Memory But Not the Performance of Conditional Fear in Rats
Stephen
Maren
Department of Psychology and Neuroscience Program, University of
Michigan, Ann Arbor, Michigan 48109-1109
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ABSTRACT |
We examined the influence of extensive overtraining (75 trials) on
the impact of neurotoxic basolateral amygdala (BLA) lesions on
Pavlovian fear conditioning in rats. As we have shown
previously, pretraining BLA lesions yielded
severe deficits in the acquisition of conditional freezing in rats
trained with either 1 or 25 conditioning trials. However, extensive
overtraining (50 or 75 trials) mitigated deficits in conditional
freezing. Under these conditions the rats with BLA lesions expressed
normal and robust freezing behavior, although they required at least 10 times as much training as control rats to reach this level of
performance. The ability of rats with BLA lesions to acquire and
express conditional freezing after extensive overtraining was
modality-specific; conditional freezing in individual rats was acquired
to contextual, but not acoustic, conditional stimuli. These results
suggest that neural circuitry outside of the amygdala can mediate
contextual fear conditioning under some conditions. In contrast to
pretraining lesions, post-training BLA lesions
eradicated the memory for Pavlovian fear in rats trained with either 1 or 75 trials; this deficit was not modality-specific. Together, these
results reveal that impairments in the acquisition and expression of
conditional fear in rats with BLA lesions are not attributable to
deficits in the performance of the freezing response but are
attributable to disruptions in the learning and memory of Pavlovian
fear conditioning.
Key words:
amygdala; NMDA; lesion; overtraining; learning; memory; conditioning; freezing; fear
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INTRODUCTION |
Considerable progress has been made
in elucidating the neural substrates of emotional learning and memory
in mammals (Lavond et al., 1993 ; Fanselow, 1994; Maren, 1996; McGaugh
et al., 1996; Davis, 1997; LeDoux, 1998). One form of aversive learning
that has served as the primary model for studying the neural substrates of emotional learning and memory is Pavlovian fear conditioning in
rats. Several investigators have demonstrated that both the acquisition
and expression of conditional fear require neurons in the basolateral
amygdala (BLA; Sananes and Davis, 1992; Campeau and Davis, 1995; Lee et
al., 1996; Cousens and Otto, 1998). For example, we have shown that
neurotoxic lesions of the BLA abolish conditional freezing (immobility
except for breathing) when the lesions are made either 1 week before or
up to 1 month after training (Maren et al., 1996a) and even when they
are made after moderate overtraining (Maren, 1998). Moreover,
reversible inactivation of the BLA (Helmstetter and Bellgowan, 1994;
Muller et al., 1997) or intra-BLA infusion of NMDA receptor antagonists
(Miserendino et al., 1990; Fanselow and Kim, 1994; Maren et al., 1996b;
Lee and Kim, 1998) prevents the acquisition of conditional fear.
Although these results are consistent with a role for the BLA in
associative processes in fear conditioning (i.e., encoding and storing
fear memories; Maren and Fanselow, 1996; Fanselow and LeDoux, 1999),
they nonetheless are open to alternative interpretations. For example,
McGaugh and colleagues have argued that the BLA is not essential for
encoding and storing fear memories but, rather, is critically involved
in the performance of fear responses, such as freezing
(Cahill and McGaugh, 1998; Cahill et al., 1999). In support of this
view, they recently have reported that rats with neurotoxic BLA lesions
learn to avoid a compartment in which footshock was delivered, despite
exhibiting robust deficits in conditional freezing (Vazdarjanova and
McGaugh, 1998). Thus, although associative models of BLA function do
not rest solely on studies examining freezing behavior (Fanselow and
LeDoux, 1999), they must contend with the fact that freezing behavior
has yet to be observed in rats with BLA lesions (Maren et al.,
1996a).
A key question, then, is whether or not rats with neurotoxic BLA lesion
are ever capable of exhibiting freezing behavior. Recently, we reported
that moderate overtraining (25 trials) generates low levels of
conditional freezing (30-40%) in rats with pretraining BLA lesions
(Maren, 1998). This result is interesting because it suggests that more
extensive overtraining might generate normal levels of conditional
freezing in rats with BLA lesions. Such a finding would bolster
associative models of BLA function in fear conditioning and temper the
claim that freezing impairments in rats with BLA lesions are merely
attributable to performance deficits. To address this issue, the
present experiments examined whether extensive overtraining
(75 trials) would yield conditional freezing in rats with pretraining
neurotoxic BLA lesions and, if so, whether this level of training also
would immunize rats against the normally deleterious effects of
post-training BLA lesions. Both contextual and auditory fear
conditioning were examined.
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MATERIALS AND METHODS |
Subjects. The subjects were 204 adult male
Long-Evans rats (200-224 gm) obtained from a commercial supplier
(Harlan Sprague Dawley, Indianapolis, IN). After arrival, the rats were
housed individually in standard stainless-steel hanging cages on a
14/10 hr light/dark cycle (lights on at 7:00 A.M.) and were provided free access to food and tap water. After being housed, the rats were
handled daily (10-20 sec per rat) for 5 d to acclimate them to
the experimenter.
Behavioral apparatus. Eight identical observation chambers
(30 × 24 × 21 cm; MED Associates, Burlington, VT) were used
for both conditioning and contextual fear testing. The chambers were constructed from aluminum (side walls) and Plexiglas (rear wall, ceiling, and hinged front door) and were situated in sound-attenuating cabinets located in a brightly lit and isolated room. The floor of each
chamber consisted of 19 stainless steel rods (4 mm diameter) spaced 1.5 cm apart (center-to-center). The rods were wired to a shock source and
solid-state grid scrambler (MED Associates) for the delivery of
footshock unconditional stimuli (USs). A speaker mounted outside a
grating in one wall of the chamber was used for the delivery of
acoustic conditional stimuli (CSs). The chambers were cleaned with a
5% ammonium hydroxide solution, and stainless steel pans containing a
thin film of the same solution were placed underneath the grid floors
before the rats were placed inside. Ventilation fans in each chest
supplied background noise (65 dB, A scale).
Each conditioning chamber rested on a load-cell platform that was used
to record chamber displacement in response to each rat's motor
activity. To ensure interchamber reliability, we calibrated each
load-cell amplifier to a fixed chamber displacement. The output of the
load cell of each chamber was set to a gain (Vernier dial = 8)
that was optimized for detecting freezing behavior. Load-cell amplifier
output ( 10 to +10 V) from each chamber was digitized and acquired
on-line, using Threshold Activity software (MED Associates). The
absolute values of the load-cell voltages were computed, and these
absolute values were multiplied by 10 to yield a load-cell activity
scale that ranged from 0 to 100.
During both the conditioning and extinction sessions each rat's
activity was monitored continuously, using the data acquisition system
described above. For each chamber the load-cell activity was digitized
at 5 Hz, yielding one observation per rat every 200 msec (300 observations per rat per minute). In all experiments, freezing was
quantified by computing the number of observations for each rat that
had a value less than the freezing threshold (load-cell activity = 5; animals exhibit freezing when the load-cell activity is at or below
this value; see Maren, 1998). To avoid counting momentary inactivity as
freezing, we scored an observation as freezing only if it fell within a
contiguous group of at least five observations that were all less than
the freezing threshold. Thus, freezing was scored only if the rat was
immobile for at least 1 sec. For each session the freezing observations
were transformed to a percentage of total observations. In addition to
freezing, motor activity was quantified during the preshock period on
the conditioning day by using the raw load-cell output.
Surgery. Rats were treated with atropine methyl nitrate (0.4 mg/kg body weight), anesthetized with an intraperitoneal injection of
Nembutal (sodium pentobarbital, 65 mg/kg body weight), and mounted in a
stereotaxic apparatus (David Kopf Instruments, Tujunga, CA). The scalp
was incised and retracted, and the head position was adjusted to place
Bregma and lambda in the same horizontal plane. Small burr holes (2 mm
diameter) were drilled bilaterally in the skull for the placement of
28-gauge cannula in the basolateral amygdala (3.3 mm posterior to
Bregma; 5.0 mm lateral to the midline). A 10 µl Hamilton syringe was
mounted in an infusion pump (Harvard Apparatus, South Natick, MA) and
connected to the injection cannula with polyethylene tubing. NMDA (20 µg/µl; Sigma, St. Louis, MO) in 100 mM PBS, pH 7.4, was
infused (0.1 µl/min) 8.0 mm ventral to brain surface (0.2 µl) and
7.5 mm ventral to brain surface (0.1 µl) for each penetration. After
each infusion 5 min were allowed for diffusion of the drug. After
surgery the incision was closed with stainless steel wound clips, and
the rats were allowed to recover on a heating pad before returning to
their home cage.
Experiment 1: Pretraining BLA lesions and contextual fear
conditioning. Rats (n = 128) were assigned
randomly to a 2 × 4 factorial design with factors of surgery
(sham or BLA lesion) and training trials (1, 25, 50, or 75 trials).
Fourteen rats were excluded from the experiment because of misplaced
lesions. This yielded the following groups: SH-1 (n = 16), BL-1 (n = 13), SH-25 (n = 16),
BL-25 (n = 12), SH-50 (n = 16), BL-50
(n = 12), SH-75 (n = 16), and BL-75
(n = 13). All rats received either sham surgery or
neurotoxic BLA lesions 1 week before fear conditioning. On the
conditioning day the rats were transported to the laboratory in squads
of eight and placed in the conditioning chambers; the chamber position
was counterbalanced for each squad and group. The rats received
unsignaled footshock (2 sec, 1.0 mA; 60 sec intertrial interval; 1, 25, 50, or 75 trials) 3 min after being placed in the chambers. At 60 sec
after the final shock the rats were returned to their home cages. Then
24 hr after training, fear conditioning to the context of the
conditioning chamber was assessed by returning the rats to the
conditioning chambers and measuring freezing behavior (somatomotor
immobility except that necessitated by breathing) during an 8 min
extinction test.
Experiment 2: Post-training BLA lesions and contextual fear
conditioning. Rats (n = 46) were assigned randomly
to a 2 × 2 factorial design with factors of surgery (sham or BLA
lesion) and training trials (1 or 75 trials). Four subjects were
excluded because of death or misplaced lesions, yielding the following groups: SH-1 (n = 11), BL-1 (n = 11),
SH-75 (n = 10), and BL-75 (n = 10). On
the conditioning day the rats were transported to the laboratory in
squads of eight and placed in the conditioning chambers; the chamber
position was counterbalanced for each squad and group. The rats
received unsignaled footshock (2 sec, 1.0 mA; 60 sec intertrial
interval; 1 or 75 trials) 3 min after being placed in the chambers. At
60 sec after the final shock the rats were returned to their home
cages. The rats received either sham surgery or BLA lesions 1 d
after fear conditioning. Then 1 week after their recovery from surgery,
fear conditioning to the context of the conditioning chamber was
assessed by returning the rats to the conditioning chambers and
measuring freezing behavior during an 8 min extinction test.
Experiment 3: Pre- or post-training lesions and auditory fear
conditioning. Rats (n = 30) were assigned randomly
to a 2 × 2 factorial design with factors of surgery (sham or BLA
lesion) and time-of-lesion (pretraining or post-training). This
assignment yielded four groups: SH-Pre (n = 6), BL-Pre
(n = 8), SH-Post (n = 8), and BL-Post
(n = 8). Rats received sham surgery or BLA lesions either 1 week before or 1 d after fear conditioning, which
consisted of 75 signaled footshock trials. On the conditioning day the
rats were transported to the laboratory in squads of eight and placed in the conditioning chambers; the chamber position was counterbalanced for each squad and group. The rats received 75 tone (90 dB, 10 sec, 2 kHz) footshock (2 sec, 1.0 mA; 70 sec intertrial interval) trials 3 min
after being placed in the chambers. At 60 sec after the final shock the
rats were returned to their home cages. Then 1 week after training (to
allow for recovery from surgery in the post-training groups), fear
conditioning to the context of the conditioning chamber was assessed by
returning the rats to the conditioning chambers and measuring freezing
behavior during an 8 min extinction test. At 24 hr after the context
extinction test, fear to the tone CS was measured by placing the rats
in a novel context and presenting a 6 min tone 2 min after placement in
the context. The tone testing was performed in the chambers described above, except that the room housing the chambers was darkened (illumination in the room was provided by a 40 W red light), the doors
on the sound-attenuating cabinets were closed, the ventilation fans
were turned off, and the chambers were cleaned with a 1% acetic acid solution.
Histology. Histological verification of lesion location was
performed after behavioral testing. Rats were perfused across the heart
with 0.9% saline, followed by 10% formalin. After extraction from the
skull, the brains were post-fixed in 10% formalin for 2 d and
10% formalin/30% sucrose until sectioning. Coronal sections (50 µM thick, taken every 200 µM) were cut on a
cryostat (16°C) and wet-mounted on glass microscope slides with
70% ethanol. After being dried, the sections were stained with 0.25%
thionin to visualize the neuronal cell bodies. Lesions were verified by
reconstructing the damage on stereotaxic atlas templates.
Data analysis. For each session the freezing data were
transformed to a percentage of total observations, a probability
estimate that is amenable to analysis with parametric statistics. These probability estimates of freezing were analyzed by ANOVA.
Post hoc comparisons in the form of Fisher Protected Least
Significant Difference tests were performed after a significant omnibus
F ratio. All data are represented as the means ± SEMs.
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RESULTS |
Histology
Neurotoxic BLA lesions were comparable in all three experiments
and similar to those described in previous reports (Maren et al.,
1996a; Maren, 1998). Figure 1 displays a
photomicrograph of a representative lesion, and Figure
2 illustrates the maximum and minimum
extent of the lesions. There was extensive damage to the basolateral
complex of the amygdala, including the lateral, basolateral, and
basomedial nuclei. The central amygdaloid nucleus was spared, although
there was minimal damage to its most caudal aspect in some cases. There
was damage to the posterior amygdala, the amygdalo-hippocampal area,
and the entorhinal cortex in some cases; the perirhinal cortex was
intact in all cases. Rats with mainly unilateral or partial BLA
bilateral lesions were excluded from the statistical analyses (see
group assignments above).
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Figure 1.
Photomicrographs of thionin-stained brain sections
at low and high magnifications from representative rats receiving
either sham surgery or a neurotoxic BLA lesion. The lesion (indicated
by arrows) was confined to the basolateral amygdaloid
complex. BL, basolateral; CE, central
nuclei of the amygdala; LA, lateral nuclei of the
amygdala.
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Figure 2.
Schematic diagram illustrating the maximum
(light gray) and minimum (dark gray)
extents of lesions in the amygdala. In general, the lesions were
confined to the lateral (LA), basolateral
(BL), and basomedial (BM)
nuclei.
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Behavior
The first experiment examined the impact of extensive overtraining
on the acquisition of contextual freezing in rats with pretraining neurotoxic BLA lesions. Figure
3 shows freezing in rats with neurotoxic
BLA lesions (BL) and sham (SH) rats during an 8 min context extinction
test that was conducted 24 hr after various amounts of training (1, 25, 50, or 75 trials). It is apparent that the amount of training (the
number of training trials) determined the severity of freezing deficits
in rats with pretraining BLA lesions. That is, rats with BLA lesions
exhibited severe impairments in freezing during the 8 min extinction
test after receiving either 1 or 25 conditioning trials, but they
exhibited normal and high levels of freezing after receiving 50 or 75 conditioning trials. These impressions were confirmed by a two-way
ANOVA with variables of group (lesion or sham) and trials (1, 25, 50, or 75 trials). The ANOVA revealed a significant main effect of group
[F(1,106) = 52.1; p < 0.0001] and trial [F(3,106) = 24.8; p < 0.0001] and a significant Group × Trial interaction [F(3,106) = 6.1;
p < 0.001]. Thus, rats with BLA lesions exhibit
normal freezing behavior after extensive overtraining (75 trials),
although the rate at which they reach this behavioral asymptote was
severely retarded as compared with rats receiving sham surgery.
Nonetheless, rats with BLA lesions did acquire conditional freezing
after 75 trials, and this implies that there is a second neural
substrate capable of mediating fear conditioning during extensive
overtraining.
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Figure 3.
Mean ± SEM percentage of freezing during an
8 min extinction test in rats receiving sham surgery
(SH) or neurotoxic basolateral amygdala lesions
(BL) 1 week before training with either 1, 25, 50, or 75 unsignaled shocks. The extinction test was conducted 24 hr after
training. Pretraining BLA lesions severely retarded the acquisition of
contextual freezing, although normal asymptotic performance was
achieved after 75 conditioning trials.
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Unconditional freezing to the context of the conditioning chamber
(i.e., freezing elicited by the novelty of the chamber) before
footshock delivery was not affected by neurotoxic BLA lesions (mean ± SEM; SH, 9.0 ± 1.5%; BL, 8.6 ± 2.0%;
F < 1). This suggests that unconditional freezing in
rats with BLA lesions is intact, at least at the very low levels of
freezing that are associated with exposure to a novel context.
The first experiment reveals that extensive overtraining mitigates the
effects of pretraining neurotoxic BLA lesions on the acquisition of
contextual fear conditioning. The second experiment was conducted to
ascertain whether extensive overtraining would protect or immunize rats
against the normally deleterious effects of post-training
neurotoxic BLA lesions on contextual freezing. Figure
4A shows freezing
during an 8 min context extinction test in rats that received
neurotoxic BLA lesions or sham surgery 1 d after training with
either 1 or 75 conditioning trials. As shown, the rats receiving
post-training BLA lesions exhibited massive impairments in the
expression of contextual freezing independent of the amount of
presurgical training. These impressions were confirmed by a two-way
ANOVA with variables of group (lesion or sham) and trials (1 or 75 trials). The ANOVA revealed a significant main effect of group
[F(1,38) = 129.3; p < 0.0001] and a nonsignificant main effect of trial and a
nonsignificant Group × Trial interaction (F
values < 1). Thus, extensive overtraining (75 trials) did not immunize rats against the deleterious effects of neurotoxic BLA lesions. This confirms and extends our earlier report in which we found
that moderate overtraining (25 trials) did not mitigate the effects of
post-training BLA lesions (Maren, 1998). However, both of these results
stand in contrast to those in instrumental escape tasks in which
overtraining has been reported to mitigate the effects of post-training
amygdala lesions (Brady et al., 1954; Parent et al., 1992, 1994;
Thatcher and Kimble, 1966) (for a discussion of this issue, see
Maren, 1998).
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Figure 4.
A, Mean ± SEM percentage of
freezing during an 8 min extinction test in rats receiving sham surgery
(SH) or neurotoxic basolateral amygdala lesions
(BL) 1 d after training with either 1 or 75 unsignaled shocks. The extinction test was conducted 1 week after
training. Extensive overtraining did not mitigate the deleterious
effects of post-training BLA lesions. B, Mean ± SEM percentage of freezing during 4 min extinction tests in rats
receiving sham surgery (SH) or neurotoxic
basolateral amygdala lesions (BL). The data from Test 1 represent the first 4 min of the 8 min data shown in A.
Tests 2 and 3 represent 4 min extinction tests conducted after
reacquisition sessions, which consisted of 25 unsignaled footshocks
(indicated by arrowheads). A single reacquisition
session was interposed between Tests 1 and 2 and Tests 2 and 3. The
rate of reacquisition of conditional freezing in rats with BLA lesions
was independent of the amount of original training; there were no
savings in rats with post-training BLA lesions.
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The results of Experiment 2 suggest that the neural system that is
engaged by extensive overtraining in rats with BLA lesions (Experiment
1) normally is not engaged by extensive overtraining in intact rats.
Otherwise, extensive overtraining in Experiment 2 should have mitigated
the effects of post-training BLA lesions. To explore this possibility
further, we examined reacquisition of contextual freezing in the same
rats used in Experiment 2 by administering two additional conditioning
sessions (25 trials per session). As shown in Figure
4B and consistent with Experiment 1, both groups of
BLA rats slowly reacquired the conditional freezing response after
additional training. Importantly, however, the rate at which the BLA
rats reacquired contextual freezing was independent of the level of
original training. That is, BLA rats trained with 75 trials before
surgery reacquired at the same rate as BLA rats trained with one trial.
Thus, there were no behavioral savings for original acquisition in the
BLA rats that had received 75 original training trials. Moreover, the
presentation of footshock during reacquisition, which may have served
as a reminder for original training (Spear, 1973), did not rapidly
instate performance in rats with BLA lesions. This suggests that fear
memories in intact rats are formed and stored (at least 1 d after
training) in the BLA and are therefore exquisitely sensitive to
disruption by post-training BLA lesions. It is also important to note
that these data reveal an important within-subjects demonstration of the associative deficits in rats with BLA lesions. That is, individual BLA rats exhibited normal (and high) levels of freezing after reacquisition training despite exhibiting severely impaired freezing during their first context extinction test. Thus, it cannot be argued
that freezing deficits obtained in the initial context extinction test
were attributable to a performance failure clearly, the rats were
capable of exhibiting the freezing response when given subsequent
extensive overtraining.
It is well known that the training-to-test interval (i.e., the
retention interval) can interact with the level of initial training to
affect the performance of some aversive memories (Schulenberg et al.,
1971; Spear, 1973). In our experiments the retention interval ranges
from 1 to 7 d. To examine whether the conditional freezing we
established in rats with BLA lesions survives a longer retention interval, we administered a second extinction test to a subset of the
Experiment 2 rats 24 d after their last reacquisition session. This test revealed that conditional freezing was retained in rats with
BLA lesions and that there was no forgetting in either the rats with
BLA lesions or the sham controls (data not shown). This indicates that
fear memories in rats with BLA lesions are durable over relatively long
retention intervals once they are established by extensive overtraining.
The first two experiments explored the impact of extensive overtraining
on the acquisition and expression of contextual fear conditioning in rats with BLA lesions. However, the BLA also has been implicated in the acquisition and expression of conditional fear
to discrete cues, such as tone CSs, and the discrete nature of these
cues might alter how extensive overtraining interacts with the effects
of BLA lesions. In fact, it has been reported that deficits in auditory
fear conditioning in rats with BLA lesions can be overcome by extensive
overtraining in a conditional punishment paradigm (Killcross et al.,
1997). Therefore, the third experiment examined whether neurotoxic BLA
lesions mitigate either the acquisition or expression of auditory
fear conditioning after extensive overtraining. Rats were trained
with 75 tone/footshock conditioning trials either 1 week after
(pretraining group) or 1 d before (post-training group) surgery.
Figure 5, A and B,
shows the context and tone extinction tests, respectively, for rats
receiving either sham surgery (SH) or neurotoxic BLA lesions before
(BL-Pre) or after (BL-Post) auditory fear conditioning (the pre- and
post-training sham groups did not differ significantly from each other
and were collapsed for clarity). Consistent with Experiments 1 and 2, neurotoxic BLA lesions eliminated the expression, but not the
acquisition, of freezing to the contextual CS (Fig. 5A).
However, a different pattern of results was obtained in the tone
extinction test. In this case, neurotoxic BLA lesions eliminated
both the acquisition and expression of conditional freezing
to the auditory CS. This pattern of results is illustrated in Figure
5C, which shows the mean of the first 4 min of each
extinction test.
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Figure 5.
Mean ± SEM percentage of freezing during an
8 min context (A) and tone
(B) extinction test in rats receiving sham
surgery (SH) or neurotoxic basolateral amygdala
lesions either 1 week before (BL-Pre) or 1 d after
(BL-Post) training with 75 signaled shocks. The
extinction tests were conducted 1 week after training. The 1 min means
are displayed to illustrate the time course of contextual freezing over
the duration of the extinction test. Tone onset occurred at the start
of the third minute of the tone extinction test. Auditory freezing was
abolished by BLA lesions irrespective of whether the lesions were made
before or after training. In contrast, only post-training BLA lesions
abolished contextual freezing. This interaction is displayed in
C, which shows the mean ± SEM percentage of
freezing during the first 4 min of the context and tone extinction
tests (A, B). Thus, the effect of extensive overtraining
was modality-specific and dependent on the timing of the lesions with
respect to fear conditioning.
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The differential effect of neurotoxic BLA lesions on the acquisition
and expression of conditional freezing to tone and context CSs was
confirmed by a two-way ANOVA with factors of group (sham, BL-Pre, or
BL-Post) and CS (context or tone). This analysis, which was performed
on the 4 min means, revealed a significant main effect of group
[F(2,27) = 19.0; p < 0.0001] and CS [F(1,27) = 20.9;
p < 0.0001] and, importantly, a significant
Group × CS interaction [F(2,27) = 4.0; p < 0.05]. Post hoc
comparisons (p < 0.05) indicated that both pre-
and post-training lesions impaired freezing to the tone CS; however,
only post-training lesions impaired freezing to the context CS. Thus,
extensive overtraining does not mitigate the effects of neurotoxic BLA
lesions on either the acquisition or expression of auditory fear
conditioning, unlike contextual fear conditioning. These results
indicate that the deficits in tone freezing cannot be the result of
freezing performance deficits (Cahill and McGaugh, 1998; Vazdarjanova
and McGaugh, 1998; Cahill et al., 1999) insofar as the same rats that
exhibited impaired tone freezing also exhibited high levels of freezing
to the context CS. These results suggest that the BLA is absolutely
essential for the acquisition and expression of auditory fear
conditioning, and that deficits in auditory fear conditioning are not
attributable to deficits in the performance of freezing behavior.
Interestingly, the differential effects of BLA lesions on auditory and
contextual conditioning also have been reported for measures of lick
suppression (to index tone conditioning) and place preference (to index
context conditioning; Selden et al., 1991).
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DISCUSSION |
The present results shed light on the nature and causes of
impairments in Pavlovian fear conditioning in rats with neurotoxic BLA
lesions. Experiments 1 and 2 demonstrate that rats with BLA lesions
show marked deficits in both the acquisition and expression of
contextual fear conditioning. Freezing deficits in rats with pretraining BLA lesions were overcome by extensive overtraining, although extensive overtraining in intact rats did not mitigate the
deleterious effects of post-training BLA lesions. The ability of
extensive overtraining to mitigate freezing deficits in rats with BLA
lesions was modality-specific, insofar as rats with BLA lesions were
unable to acquire or express auditory fear conditioning even after
extensive overtraining. Collectively, these results define a narrow set
of conditions under which intact performance of conditional freezing is
obtained in rats with BLA damage. These findings have important
implications for understanding the role of the BLA in learning versus
performing conditional fear responses. Moreover, they reveal that
neural systems outside of the amygdala can mediate some forms of fear
conditioning, at least after extensive overtraining, in rats with BLA lesions.
Nearly unanimous consensus has emerged regarding the important role for
the BLA in aversively motivated learning (Fanselow, 1994; Maren, 1996;
McGaugh et al., 1996; Davis, 1997; LeDoux, 1998; Fanselow and LeDoux,
1999), although there has been recent debate concerning its precise
role in the learning versus performance of conditional fear responses
in Pavlovian paradigms (Cahill and McGaugh, 1998; Maren, 1998;
Vazdarjanova and McGaugh, 1998; Cahill et al., 1999; Fanselow and
LeDoux, 1999). The pattern of results obtained in the present
experiments indicates that BLA lesions impair mnemonic aspects of
Pavlovian fear conditioning, rather than affecting the performance of
the freezing response per se. This claim is supported by the following
lines of evidence: (1) the acquisition rate of conditional freezing in
rats with BLA lesions was severely impaired (they required at least 10 times more conditioning trials to achieve the levels of performance exhibited by controls), (2) the level of asymptotic performance of rats
with BLA lesions was normal (once they achieved asymptote), (3)
deficits in freezing to contextual CSs (for example, in rats with
post-training BLA lesions) could not be explained by performance deficits insofar as the same rats that exhibited freezing deficits exhibited normal freezing when given extensive reacquisition training (Experiment 2), (4) deficits in freezing to tone CSs (for example, in
rats with pretraining BLA lesions) could not be explained by performance deficits insofar as the same rats that exhibited tone freezing deficits exhibited normal context freezing, and (5) the deleterious effect of neurotoxic BLA lesions on conditional freezing was generally pervasivethere was only one set of conditions
(pretraining lesions, extensive overtraining, contextual CS) that
produced conditional freezing in rats with BLA lesions.
In addition to the data from these lesion experiments, several other
lines of evidence are consistent with a role for the BLA in associative
processes during fear conditioning (for review, see Maren, 1999). For
example, intra-BLA infusions of NMDA receptor antagonists impair
the acquisition of conditional fear (Miserendino et al., 1990; Campeau
et al., 1992; Fanselow and Kim, 1994; Maren et al., 1996b; Gewirtz and
Davis, 1997; Lee and Kim, 1998). Furthermore, reversible inactivation
of the BLA during training prevents the acquisition of conditional fear
(Helmstetter and Bellgowan, 1994; Muller et al., 1997), and associative
neuronal firing develops in the BLA during fear conditioning (Maren et
al., 1991; Quirk et al., 1995). Increases in the amplitude of BLA field
potentials have been observed after fear conditioning (McKernan and
Shinnick-Gallagher, 1997; Rogan et al., 1997), and these changes mirror
those associated with the induction of long-term potentiation (LTP)
in vivo (Clugnet and LeDoux, 1990; Maren and Fanselow, 1995;
Rogan and LeDoux, 1995). Consistent with a role for amygdaloid LTP in
fear conditioning, a recent study reports that genetic manipulations
that eliminate amygdaloid LTP also impair fear conditioning (Brambilla
et al., 1997).
Thus, a wealth of data bolsters the view that the BLA is essential for
the learning and memory of Pavlovian fear conditioning in rats. This
conclusion departs from that of McGaugh and colleagues (Cahill and
McGaugh, 1998; Vazdarjanova and McGaugh, 1998; Cahill et al., 1999),
who have suggested that the BLA is not necessary for Pavlovian fear
conditioning but is essential only for generating conditional fear
responses. Several points argue against this view. First, we have
demonstrated clearly that rats with BLA lesions are capable of high
levels of freezing under some conditions. In fact, we have demonstrated
that individual rats are capable of exhibiting both normal
freezing (to an overtrained context CS, for example) and severely
impaired freezing (to a tone CS, for example). Second, manipulations
that reversibly disrupt the BLA during conditioning yield deficits in
conditional fear when the rats are tested later with an intact and
functional BLA (Miserendino et al., 1990; Campeau et al., 1992;
Fanselow and Kim, 1994; Helmstetter and Bellgowan, 1994; Maren et al.,
1996b; Muller et al., 1997). Third, the fact that excitotoxic BLA
lesions do not abolish all aversively motivated memories does not imply
that the BLA is not involved in the acquisition and expression of
Pavlovian fear conditioning (Vazdarjanova and McGaugh, 1998). For
example, humans with amygdala damage (e.g., patient S.M.) do not
acquire classically conditioned galvanic skin responses (GSRs), despite
exhibiting intact declarative memory for the conditioning experience
(Bechara et al., 1995). Likewise, McGaugh and colleagues have shown
that rats with BLA lesions exhibit conditional freezing deficits but
retain their ability to avoid a compartment in which footshock was
delivered (Vazdarjanova and McGaugh, 1998). A similar pattern of
results has been reported by Selden and colleagues (1991). This sort of evidence does not diminish the role of the BLA in the acquisition and
expression of Pavlovian fear responses, such as freezing or GSRs. It
merely indicates that other neural systems engaged during Pavlovian
fear conditioning acquire information that can yield explicit recall,
in the case of patient S.M., or passive avoidance, in the case of a rat.
The fact that rats with pretraining BLA lesions can acquire contextual
freezing after extensive overtraining suggests that another neural
system is capable of mediating at least some forms of conditional fear
in the absence of the BLA. Importantly, however, this neural system
does not appear to be engaged in intact rats undergoing extensive
overtraining insofar as savings is not evident in rats with
post-training BLA lesions. The locus of this other neural system is
unknown, but considerable evidence indicates that the midbrain
periaqueductal gray (Bandler and Shipley, 1994; De Oca et al., 1998),
superior colliculus (Dean et al., 1988), and cerebellar vermis (Supple
et al., 1987) are involved in generating defensive responses, including
freezing. In the absence of the BLA these midbrain defense systems may
be able to mediate some forms of fear conditioning (e.g., contextual
fear conditioning) during extensive overtraining. Further work is
required to examine this hypothesis.
In sum, the present results indicate that the BLA has an essential role
in the associative processes underlying Pavlovian fear conditioning.
The severely retarded acquisition yet normal asymptotic performance of
contextual freezing in rats with pretraining BLA lesions and the global
deficits in the expression of conditional freezing in rats with
post-training BLA lesions indicate that performance interpretations
cannot account for the range of deficits exhibited by rats with BLA
lesions. Indeed, the robust and nearly global fear conditioning
deficits in rats with excitotoxic BLA lesions in the face of
extensive overtraining attests to the crucial role for this brain
structure in both the formation and storage of fear memories. On the
basis of these results, we conclude that performance hypotheses cannot
account for the effects of BLA lesions on conditional freezing and,
therefore, that the BLA is essential for learning as opposed to
performing fear responses.
| |
FOOTNOTES |
Received June 7, 1999; revised July 10, 1999; accepted July 21, 1999.
This work was supported by grants from the National Institute of Mental
Health (R29MH57865) and the University of Michigan. I thank Bill Holt
and Ki Goosens for technical assistance.
Correspondence should be addressed to Dr. Stephen Maren, Department of
Psychology, University of Michigan, 525 East University Avenue, Ann
Arbor, MI 48109-1109.
| |
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TOP
ABSTRACT
INTRODUCTION
