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The Journal of Neuroscience, August 1, 1999, 19(15):6615-6622
Basolateral Amygdala Is Involved in Modulating Consolidation of
Memory for Classical Fear Conditioning
Almira
Vazdarjanova and
James L.
McGaugh
Center for the Neurobiology of Learning and Memory and Department
of Neurobiology and Behavior, University of California, Irvine,
California 92697-3800
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ABSTRACT |
Previous findings indicate that the basolateral amygdala complex of
nuclei (BLC) is involved in modulating (i.e., enhancing or impairing)
memory consolidation for aversive training such as inhibitory
avoidance. The present study examined whether the BLC also modulates
the consolidation of memory for classical fear conditioning in which a
specific context is paired with footshock. Adult male rats with
bilateral cannulae targeting the BLC were allowed, first, to
habituate in a Y maze that had differently shaped and textured arms. On
the next day the rats were placed in one maze arm (shock arm), and they
received four unsignaled footshocks. In Experiment 1, immediately after
the training some rats received BLC inactivation with lidocaine (10 µg/0.2 µl per side), and control rats received buffered saline. In
Experiment 2, rats received immediate post-training intra-BLC infusions
of the muscarinic receptor agonist oxotremorine (10 ng/0.2 µl per side) or saline. On a 24 hr retention test each rat was placed in a
"safe" arm of the maze and allowed to access all maze arms. Lidocaine-treated rats had impaired memory for the classical fear conditioning when they were compared with the saline-treated controls: they spent less time freezing, entered the shock arm more readily and
more often, and spent more time in it. In contrast,
oxotremorine-treated rats had a stronger memory for the
context-footshock association as assessed by all measures of memory.
Thus, post-training treatments affecting BLC function modulate memory
for Pavlovian contextual fear conditioning in a manner similar to that
found with other types of training.
Key words:
basolateral; amygdala; contextual; fear; conditioning; inhibitory; memory; consolidation; freezing; avoidance; post-training; temporary lesion; lidocaine; oxotremorine; modulation; enhancing
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INTRODUCTION |
There is extensive evidence that the
amygdaloid complex modulates memory consolidation by mediating the
effects of adrenal stress hormones as well as drugs affecting
opioid-peptidergic, GABAergic, and cholinergic systems (Liang et al.,
1986 ; Brioni and McGaugh, 1988; McGaugh et al., 1988; Quirarte et al.,
1997; Roozendaal and McGaugh, 1997a,b; Salinas et al., 1997; Cahill and
McGaugh, 1998). Enhancement of memory for aversive experiences appears
to involve muscarinic cholinergic receptor activation in the amygdala.
Post-training intra-amygdala injections of muscarinic cholinergic
agonists produce dose-dependent enhancement of memory for inhibitory
avoidance (IA) and changes in reward magnitude (Introini-Collison et
al., 1996; Salinas et al., 1997). Additionally, the blockade of
amygdala muscarinic receptors prevents memory enhancement induced by
systemic administration of muscarinic receptor agonists (Dalmaz et al.,
1993; Introini-Collison et al., 1996).
Other recent evidence suggests that the modulation of memory
consolidation by post-training treatments selectively involves the
basolateral amygdala complex (BLC; defined as the lateral, basolateral/basal, and basomedial/accessory basal nuclei). Selective inactivation of the BLC with lidocaine
(2-diethylamino-N-[2,6-dimethiphenyl]-acetamide) as well
as blockade of the NMDA or glucocorticoid receptors in the BLC
shortly after inhibitory avoidance training produces retrograde amnesia
(Liang et al., 1994; Parent and McGaugh, 1994; Roozendaal and McGaugh,
1997b). Additionally, post-training blockade of the muscarinic
cholinergic receptors in the BLC blocks the memory enhancement induced
by systemically administered glucocorticoids (Power et al., 1998).
Although much research investigating the role of the BLC in memory
consolidation has used IA tasks, recent evidence indicates that the BLC
also modulates the consolidation of memory for aversive, as well as
appetitive, spatial/hippocampal-dependent training (Schroeder and
Packard, 1998; Hatfield and McGaugh, 1999).
The BLC is also involved in the learning and retention of Pavlovian
contextual fear conditioning (CFC), although the precise nature of the
involvement remains controversial (Helmstetter and Bellgowan, 1994;
Maren et al., 1996a,b; Muller et al., 1997; Maren, 1998; Vazdarjanova
and McGaugh, 1998). Because the procedures used during CFC are similar
to those in IA training (in both tasks the animals receive a footshock
in a particular context), it may be expected that the BLC also
modulates memory storage for CFC training. Maren et al. (1996b),
however, report that post-training inactivation of the NMDA receptors
in the BLC did not affect CFC memory as measured by freezing behavior.
It has been suggested that the BLC differentially influences memory
storage for CFC and IA training because these learning tasks differ in
response contingency (Maren et al., 1996a; Maren, 1998). Indeed, in IA the footshock is contingent on the animals' response of entering the
region of the apparatus where footshock is administered, whereas in CFC
training there is no such contingency rats are placed in a context in
which they receive inescapable footshocks regardless of their behavior.
If the response contingency in IA is the critical element that
determines the involvement of the BLC in modulating memory storage,
then post-training treatments would not be expected to influence memory
for CFC as they do for IA. The present experiments examined this issue
further by investigating whether a general post-training BLC
inactivation with lidocaine will impair, and stimulation of the
cholinergic system of the BLC will enhance, memory for CFC as assessed
by freezing as well as avoidance of the footshock-paired context.
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EXPERIMENT 1 |
Effects of post-training lidocaine infusions in the basolateral
complex of the amygdala on memory for contextual fear conditioning
In Experiment 1, rats were trained on a CFC task as described in
Materials and Methods. Immediately after the training session, temporary bilateral inactivation of the BLC was induced by intra-BLC infusions of a reversible sodium channel blocker, lidocaine. Because lidocaine has a well documented short-lived action on neuronal activity
(Albert and Madryga, 1980; Martin, 1991; Welsh and Harvey, 1991;
Boeijinga et al., 1993), any impairment in retention test performance
1 d later could be attributed to memory impairment resulting from
the disruption of consolidation processes. The purpose of this
experiment was to determine whether post-training inactivation of the
BLC with lidocaine impairs memory for CFC.
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Materials and Methods |
Subjects. The subjects were 25 male Sprague Dawley
rats (275-325 gm at the time of surgery) obtained from Charles River
Breeding Laboratories (Boston, MA). They were housed individually in a light- and temperature-controlled vivarium (22°C, 12 hr light/dark cycle; lights on at 7:00 A.M.). Food and water were available ad
libitum.
Surgery. One week after their arrival, the rats were
anesthetized with sodium pentobarbital (55 mg/kg, i.p.; Abbott Labs, Irving, TX) and injected with 0.2 ml of atropine sulfate
intraperitoneally (Phoenix Pharmaceuticals, St. Joseph, MO) to ensure
unobstructed respiration. The head of each rat was affixed to a
stereotaxic apparatus (Kopf Instruments, Tujunga, CA). After the skull
was exposed, burr holes were drilled for the placement of bilateral cannulae (15 mm long, 23-gauge). The cannulae were lowered at coordinates 3.0 mm posterior to bregma and 5.0 mm lateral to the midline (nose bar at  3.3 mm) just dorsal to the BLC (6.0 mm from
the skull) and fixed in place with dental cement and two jewel screws
attached to the skull. The scalp incision was closed with wound clips,
and 15-mm-long stylets were inserted in the cannulae to prevent
clogging. The animals received 3 ml of saline (subcutaneously) to
prevent dehydration during recovery. The rats were placed in a
temperature-controlled incubator, and their recovery was monitored.
After recovery from anesthesia, they were returned to the home cages.
All rats were handled every other day after the surgery. During the
handling the stylets were removed, and 15-mm-long sham needles were
inserted into the cannulae to habituate the rats to the injection
procedures (see below).
Behavioral apparatus. The CFC training and testing were
performed in a Y maze. The three differently shaped and textured arms of the maze were 50 cm long and 18 cm deep, separated by 120° and
covered with transparent lids. The shock arm was constructed of
stainless steel plates that were electrified by a shock generator (Lafayette Instruments, Lafayette, IN) controlled by a timer. The
rats' behavior in the maze was observed in a mirror suspended 1.2 m above the maze on a side wall of the room.
Training procedure. All training and testing were performed
between 12:00 and 5:00 P.M. The arms of the apparatus were cleaned thoroughly with 10% ethanol between subjects. On the habituation day
(day 1) each rat was placed into one of the three arms and allowed to
explore the entire maze for 8 min. The time spent freezing (lack of any
movement except for respiration) and the latency to each arm entry were
recorded. On the training day (day 2) the shock arm was blocked off
from the rest of the maze by an opaque door. Each rat was placed in the
shock arm and 60 sec later received a series of 4 footshocks (1 sec, 1 mA, spaced 60 sec apart). The time spent freezing after each footshock
was recorded. Then 1 min after the last footshock the rat was taken out
of the maze, given a drug or control microinfusion in the BLC, and then
returned to its cage. On the test day (day 3) each rat was placed into a maze arm in which shock was not delivered during the training. The
latencies to each arm entry and the total time spent freezing during
the 8 min retention test were recorded. All behavior was scored
continuously by a trained experimenter "blind" to the treatment conditions.
Drugs and infusion procedures. Lidocaine (Sigma, St. Louis,
MO) was dissolved in buffered saline, pH 7.4, to a concentration of 50 µg/µl. A fresh drug solution was prepared before each experiment and was kept in a light-proof vial to prevent inactivation. Bilateral post-training infusions of saline or lidocaine were made through 30-gauge injection needles connected to a 10 µl Hamilton syringe by
polyethylene tubing. The needles protruded 2 mm beyond the tip of the
cannulae to reach the BLC. A total of 10 µg in volume of 0.2 µl per
side was infused by an automated syringe pump (Sage Instruments,
Boston, MA) over a period of 23 sec. The needles were retained in place
for an additional 60 sec to allow for diffusion within the BLC. The
injection volume was chosen on the basis of previous findings reporting
functional spread within the BLC, but not to the adjacent central
nucleus (Parent and McGaugh, 1994; Roozendaal and McGaugh, 1997b;
DaCunha et al., 1999), and that lesions of the BLC induced with 0.2 or
0.3 µl of NMDA do not affect neurons in the central nucleus (Hatfield
et al., 1996; Roozendaal and McGaugh, 1996; Roozendaal et al., 1996;
Vazdarjanova and McGaugh, 1998).
Histology. At the completion of all behavioral testing, the
rats were anesthetized deeply with an overdose of sodium pentobarbital (200 mg/kg, i.p.) and perfused intracardially with 0.9% saline, followed by 10% formaldehyde. The brains were removed and stored in
10% formaldehyde overnight and then transferred to 30% sucrose in
10% formaldehyde solution for at least 3 d. The brains were sliced on a sliding microtome at 60 µm sections. Every other section was mounted on a gelatin-coated slide and stained with cresyl violet.
Two independent observers examined the slides under a light microscope
to determine the placement of the injector tips.
Statistics. Only rats with injection needle tip placements
within the BLC were included in the statistical analyses. The avoidance measures (initial latency to enter the shock arm, total time per arm,
and total number of entries) were calculated from the latency to each
arm entry measure. A repeated measure ANOVA with freezing after
each footshock as a repeated measure and drug treatment as an
independent variable assessed the freezing behavior during training.
The effects of the drug treatments on memory during the test were
analyzed with a one-way ANOVA, with drug treatment as an independent
variable and freezing as a dependent variable, and a MANOVA,
with treatment as an independent variable and all three avoidance
measures as dependent variables. When the main effect of MANOVA was
significant, the effect of a drug treatment on each individual
avoidance measure was evaluated with a one-way ANOVA. Analysis with a
paired Student's t test examined the differences between
pre- and post-training levels of the dependent variables (freezing and
avoidance measures) for each drug treatment condition. A probability of
<0.05 was considered significant.
Results
Figure 1A
illustrates the injection needle tip placements of rats in the saline
(n = 11) and lidocaine groups (n = 9).
A photomicrograph of a representative placement in the BLC is shown on
Figure 1B. There were no differences on any
behavioral measure between the rats assigned to the saline or lidocaine
groups before the post-training injections. During the habituation
period the rats did not show any freezing, nor did they avoid the arm
in which they were to receive footshocks in (shock arm) (see Fig.
4B,C, dashed lines). Figure
2 shows that during training the rats
displayed increasingly more freezing after each subsequent unsignaled
footshock, F(1,4) = 289.32;
p < 0.0001. There was no difference in the level of freezing of the rats to be injected with lidocaine and those to be
injected with saline after the training, as revealed by the lack of a
main effect of treatment, F(1,18) = 0.65, not significant (NS).
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Figure 1.
A, A schematic drawing illustrating
the injector tip placements of saline-injected rats
(circles) and lidocaine-injected rats
(crosses). Numbers indicate relative
position of the coronal sections in millimeters posterior to bregma
(Paxinos and Watson, 1997). B, A microphotograph of a
representative injector tip location. L, Lateral
nucleus; CE, central nucleus; BL,
basolateral/basal nucleus; Pir. Cx,
piriform cortex. Scale bar, 0.5 mm.
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Figure 2.
Mean percentage of time spent freezing (±SEM) on
day 2 before (PreShock) and during (1st-4th
PostShock periods) training in rats that received infusions of
saline (open circles) or lidocaine (filled
squares) into the BLC after the training.
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On the 24 hr retention test rats that had received post-training
infusions of lidocaine in the BLC were impaired on all memory measures
when compared with the saline-injected controls. Figure 3 shows that the lidocaine-treated rats
spent significantly less time freezing
[F(1,18) = 29.03; p < 0.0001]. As shown in Figure 4 and
confirmed by a significant main effect of MANOVA [Wilks' lambda = 0.37; F(3,16) = 9.10; p < 0.001], the rats in the lidocaine group avoided the shock arm less
than did the saline controls. Subsequent ANOVAs showed that rats in the
lidocaine group entered the shock arm more quickly (Fig.
4A) [F(1,18) = 27.65;
p < 0.0001], more often (Fig. 4B)
[F(1,18) = 16.40; p < 0.001], and spent more time (Fig. 4C)
[F(1,18) = 13.96; p < 0.005] in the shock arm than did the rats in the saline group.
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Figure 3.
Impaired freezing of rats that had received
post-training BLC inactivation. Shown is the mean time spent freezing
(±SEM) during the retention test on day 3 in saline-treated rats
(open bar) and lidocaine-treated rats (shaded
bar). *p < 0.0001 compared with the saline
group.
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Figure 4.
Impaired avoidance of rats that had
received post-training BLC inactivation. A, Mean
latencies, in seconds, to the first entry into the shock arm (±SEM)
during the retention test on day 3 for the saline group (open
bar) and the lidocaine group (shaded bar).
B, Mean number of entries in the shock arm (±SEM)
during the habituation period (dashed lines) and the
retention test (bars). C, Mean percentage
of time spent per arm during the habituation period on day 1 (dashed line) and the retention test on day 3 (bars; ±SEM). *p < 0.005 compared
with the saline group; **p < 0.05 compared with
the respective group's percentage of time in either of the "safe"
arms; +, p < 0.005 compared with the habituation
period.
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The findings of Experiment 1 indicate that memory for Pavlovian
contextual fear conditioning, like that for IA, is impaired if the BLC
is inactivated shortly after the training. These findings suggest that
the involvement of the BLC in memory consolidation for fear-based
learning does not depend on whether the fear-eliciting stimulus is
contingent on an animal's response during the training.
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EXPERIMENT 2 |
Effects of post-training oxotremorine infusions in the basolateral
complex of the amygdala on memory for contextual fear conditioning
The finding of Experiment 1 indicating that post-training
inactivation of the BLC impairs memory for CFC suggests that the BLC
modulates memory strength for classical fear conditioning. A direct
implication of this hypothesis is that post-training activation of the
BLC should enhance CFC memory as it does IA memory. In Experiment 2 we
examined whether post-training activation of the cholinergic muscarinic
receptors in the BLC with oxotremorine enhances memory for CFC.
Anatomical evidence indicates that one of the distinguishing
characteristics of the basal nucleus of the amygdala is a high level of
cholinergic activity evidenced by a dense acetylcholineesterase and
choline acetyltransferase staining (de Olmos et al., 1985; Amaral et
al., 1992). Furthermore, the excitability of BLC neurons is increased
after muscarinic receptor activation (Washburn and Moises, 1992; Womble
and Moises, 1992, 1993). Post-training intra-amygdala infusions of
oxotremorine enhance memory for both IA and changes in reward magnitude
(Introini-Collison et al., 1996; Salinas et al., 1997).
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Materials and Methods |
The methods and procedures were identical to those described in
Experiment 1 except that the footshock intensity was 0.3 mA and the
drug administered after the training was oxotremorine (as
sesquifumarate salt; Sigma). A lower level of footshock (compared with
1.0 mA in Experiment 1) was used to avoid maximum levels of freezing
and avoidance behavior in the control group, thus enabling the
detection of any memory-enhancing effects of oxotremorine. The drug
dose (10 ng/0.2 µl per side) was determined on the basis of pilot
experiments and published data (Salinas et al., 1997).
Results
Figure 5 shows the injection needle
tip placements of rats in the saline (n = 12) and the
oxotremorine groups (n = 13). On the habituation
session the rats that were going to receive post-training injections of
oxotremorine or control solutions did not differ on any behavioral
measure. The rats did not display any freezing, nor did they avoid the
shock arm during the habituation session (see Fig. 8C).
During the footshock training session the rats displayed increasingly
more freezing after each subsequent unsignaled footshock presentation
as confirmed by a significant effect of footshock,
F(1,4) = 204.94; p < 0.0001. There was no difference between the groups to be injected with
saline or oxotremorine as revealed by the lack of a main effect of
treatment, F(1,23) = 0.05, NS (Fig.
6). With the lower intensity footshock
used in this experiment (0.3 mA), the rats displayed less freezing than did the rats in Experiment 1 (which used 1.0 mA footshock).
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Figure 5.
Injector tip placements for the subjects in the
saline group (circles) and the subjects in the
oxotremorine group (crosses). Numbers
indicate relative position of the coronal sections in millimeters
posterior to bregma (Paxinos and Watson, 1997).
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Figure 6.
Mean percentage of time spent freezing (±SEM) on
day 2 before (PreShock) and during (1st-4th
PostShock periods) training in rats that received infusions of
saline (open circles) or oxotremorine
(filled squares) into the BLC after
the training.
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Rats given post-training intra-BLC infusions of oxotremorine displayed
enhanced memory on the 24 hr retention test as assessed by all
behavioral measures. Figure 7 shows that,
in comparison with the saline-injected controls, the
oxotremorine-treated rats spent significantly more time freezing
[F(1,23) = 12.46; p < 0.005]. Additionally, as shown in Figure
8 and confirmed by a significant main
effect of MANOVA [Wilks' lambda = 0.43;
F(3,21) = 9.36; p < 0.0005], the rats in the oxotremorine group avoided the shock arm more
than did the rats in the saline group. Subsequent one-way ANOVAs showed
that the oxotremorine-treated rats entered the shock arm less readily
(Fig. 8A) [F(1,23) = 20.73; p < 0.0001], less often (Fig.
8B) [F(1,23) = 19.55;
p < 0.0005], and spent less time (Fig. 8C)
[F(1,23) = 30.38; p < 0.0001] in that arm than did the rats in the saline group. These
findings support the hypothesis suggested by the results of Experiment
1 that the BLC modulates memory consolidation for CFC training. They
further suggest that this memory modulation involves muscarinic
cholinergic receptor activation in the BLC.
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Figure 7.
Enhanced freezing of rats that had received
muscarinic cholinergic receptor activation of the BLC after the
training. Shown is the mean time spent freezing (±SEM) during the
retention test on day 3 in rats that received post-training intra-BLC
infusions of saline (open bar) or oxotremorine
(shaded bar). *p < 0.005 compared
with the saline group.
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Figure 8.
Enhanced avoidance of rats that had
received muscarinic cholinergic receptor activation of the BLC after
the training. A, Mean latencies, in seconds, to the
first entry into the shock arm (±SEM) during the retention test on day
3 for rats in the saline group (open bar) and the
oxotremorine group (shaded bar). B, Mean
number of entries in the shock arm (±SEM) during the habituation
period (dashed line) and the retention test
(bars). C, Mean percentage of the time
spent per arm during the habituation period on day 1 (dashed
line) and the retention test on day 3 (bars;
±SEM). *p < 0.005 compared with the saline group;
**p < 0.01 compared with the respective group's
percentage of time in either of the "safe" arms; +,
p < 0.0001 compared with the habituation
period.
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DISCUSSION |
The findings of the present experiments are the first to show that
the BLC is involved in modulating the consolidation of memory for
Pavlovian CFC. Post-training inactivation of the BLC resulted in
impaired memory for CFC (Experiment 1), and post-training muscarinic
cholinergic receptor activation of the BLC enhanced CFC memory
(Experiment 2). It should be noted that both somatic and cognitive
indices of fear memory were affected. In Experiment 1 BLC inactivation
with lidocaine after the training resulted in a decreased level of both
freezing and avoidance behaviors assessed at the retention test. The
memory impairment most likely was attributable to inactivation of the
cells in the BLC and not the fibers passing through this area, because
post-training activation of the BLC muscarinic receptors with
oxotremorine (Experiment 2) resulted in increased levels of both
freezing and avoidance at the test. Although freezing may be viewed as
causal to avoidance (if rats freeze, they also avoid the shock arm),
the two behaviors are readily dissociable. In a recent study we showed
that 24 hr after CFC training (very similar to that used in the present
experiments) BLC lesioned rats did not freeze, yet they avoided the
shock arm (Vazdarjanova and McGaugh, 1998). As noted above, the lower
retention scores of the control rats in Experiment 2 as compared with
the control rats of Experiment 1 were attributable to the lower
intensity of footshock that they received during the training.
Because the drug treatments were administered after the training, the
results do not reflect drug influences on acquisition (McGaugh, 1989).
Additionally, the results were not likely attributable to the
nonspecific drug effects on retention performance because both drugs
have been reported previously to have no effect on performance 24 hr
after intra-amygdala injections (Parent and McGaugh, 1994; Salinas et
al., 1997). Thus the present findings are consistent with a large
number of studies examining the role of the BLC in memory consolidation
in both rats and humans (Cahill and McGaugh, 1998; McGaugh et al.,
1999). Excitotoxic BLC lesions either do not affect memory for IA
(Tomaz et al., 1992; Roozendaal and McGaugh, 1996, 1997a) or, at most,
attenuate such memory (Parent et al., 1995) or memory for CFC (Maren,
1998; Vazdarjanova and McGaugh, 1998). However, BLC lesions block
glucocorticoid-induced modulation of memory for both IA and the spatial
version of the Morris water maze task (Roozendaal and McGaugh, 1996;
Roozendaal et al., 1996). Furthermore, post-training intra-BLC
infusions of hormones and drugs are effective in either impairing or
enhancing memory for training in these tasks. Post-training blockade of the sodium channels in the BLC (but not the adjacent central nucleus, CEA) attenuates memory for IA in a time-dependent manner (Lorenzini et
al., 1994; Parent and McGaugh, 1994). Similarly, blockade of the
high-affinity glucocorticoid receptors (GRs) in the BLC, but not the
CEA, impairs memory for training in the spatial version of the Morris
water maze task (Roozendaal and McGaugh, 1997b). Additionally,
retention of IA is enhanced by post-training intra-BLC, but not
intra-CEA, infusions of a GR agonist (Roozendaal and McGaugh, 1997b) or
a benzodiazepine receptor antagonist (DaCunha et al., 1999). Last,
post-training intra-amygdala NMDA receptor blockade (with the majority
of the injection sites located within the BLC) impaired memory for IA,
and post-training activation of the NMDA or noradrenergic receptors
reversed the memory impairment produced from pre-training NMDA receptor
blockade (Liang et al., 1993, 1994).
Maren et al., 1996b reported that immediate post-training blockade of
the NMDA receptors in the BLC was ineffective in disrupting memory
consolidation of CFC as measured by freezing. The discrepancy between
these findings and the present results might be attributed to the fact
that the subjects used in that experiment previously had undergone the
same fear-conditioning procedure. Although the first training took
place in a different context, it is possible that the initial highly
aversive training masked the effect of a post-training memory
impairment affecting the second training. It is also possible that the
single dose used in that study was not optimal for influencing memory
consolidation processes (although the same dose influenced
acquisition). Thus, the present data and the majority of the cited
studies support the view that the BLC has a role in modulating memory
consolidation that is not task-specific.
Consistent with extensive previous findings, the present results
(Experiment 2) stress the importance of muscarinic cholinergic receptor
activation in the amygdala. Memory enhancement induced by post-training
systemic administration of the muscarinic receptor agonist oxotremorine
is blocked by a concurrent intra-amygdala blockade of the muscarinic
receptors with atropine (Dalmaz et al., 1993; Introini-Collison et al.,
1996). Additionally, post-training blockade of the muscarinic receptors
in the amygdala prevents the memory enhancement by a concurrent
intra-amygdala activation of  -noradrenergic receptors
(Introini-Collison et al., 1996). Furthermore, the results of
Experiment 2 are consistent with recent findings from our laboratory
suggesting that the BLC may be a locus of action of the muscarinic
cholinergic activation in the amygdala (Power et al., 1998). This
suggestion is supported further by evidence that the basal and
accessory basal nuclei (along with the amygdala hippocampal area and
the nucleus of the lateral olfactory tract) have the highest
concentration of cholinergic activity among all amygdala nuclei (de
Olmos et al., 1985; Amaral et al., 1992).
Because it has been suggested previously that the BLC stores memory for
CFC training (Maren et al., 1996b; Maren, 1998), there are at least two
possible explanations for the memory-enhancing effect of muscarinic
receptor activation in the BLC observed in the present study. Such
activation either may facilitate memory storage in the BLC itself or
may contribute to BLC activation that, in turn, facilitates memory
storage in other brain regions. Although the present data do not
discriminate directly between these two possibilities, previous studies
have shown that memory enhancement induced by systemic cholinergic
activation is blocked by lesions of the stria terminalis, a major
amygdala input-output pathway (Introini-Collison et al., 1989).
Because systemic cholinergic activation has a primary locus of action
in the amygdala (Dalmaz et al., 1993) and stria terminalis lesions do
not have an effect on performance by themselves (Introini-Collison et
al., 1989; Flood et al., 1995; Packard et al., 1996), these data
strongly suggest that the amygdala cholinergic activation modulates
memory storage in other brain regions (McGaugh et al., 1996).
Consistent with the latter hypothesis is extensive evidence that the
excitability level of pyramidal neurons in the BLC is increased greatly
after muscarinic cholinergic receptor activation or stimulation of
cholinergic afferents to the BLC (Washburn and Moises, 1992; Womble and
Moises, 1992, 1993). Such heightened excitability is reflected by an
increased rate of neuronal firing and is caused by a reduction of one
component of the afterhyperpolarization, namely reduction of the slow
calcium-activated potassium current (Womble and Moises, 1993). Taken
together with these electrophysiological data, the present results
provide further support for the hypothesis that BLC affects memory
consolidation by enhancing memory storage in other brain regions
(McGaugh et al., 1996).
The second important finding of the present studies is that the BLC is
involved in modulating the storage of memory for aversive tasks
regardless of the response contingency during the training. The present
findings based on Pavlovian CFC are highly comparable to those obtained
previously in studies that used IA (Brioni et al., 1989; Jerusalinsky
et al., 1992; Liang et al., 1993, 1994; Lorenzini et al., 1994; Parent
and McGaugh, 1994; Introini-Collison et al., 1996). As noted above, in
IA the footshock delivery is contingent on a behavioral response
whereas in Pavlovian CFC the shock delivery is not response-contingent.
Because treatments affecting BLC functioning modulate memory for both
tasks, it appears that the differences in response contingency are not
critical in determining whether the BLC is involved in modulating
memory storage. Furthermore, memory storage in both tasks is influenced by muscarinic cholinergic activation of the BLC.
In summary, the results of the present experiments indicate that the
BLC is involved in modulating the storage of memory for Pavlovian
contextual fear conditioning. Thus, these results are consistent with
extensive evidence that the BLC is involved in modulating the storage
of emotionally based memory in a wide variety of learning situations
and that its involvement does not depend on the specific behavioral
contingencies during training.
| |
FOOTNOTES |
Received Feb. 10, 1999; revised April 5, 1999; accepted May 10, 1999.
This research was supported by University of California, Irvine
Regent's Fellowship and Schneiderman Graduate Fellowship (A.V.) and
United States Public Health Service Grant MH12526 from the National
Institute of Mental Health (J.L.M.). We thank Anguel Mantchev and Lila
Avila for histological assistance. We also thank Dr. Benno Roozendaal,
Dr. Georg Striedter, and Thane Plummer for helpful comments on a
draft of this paper.
Correspondence should be addressed to Dr. Almira Vazdarjanova, 218 Bonney Laboratory, Center for the Neurobiology of Learning and Memory,
University of California, Irvine, CA 92697-3800.
| |
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ABSTRACT
INTRODUCTION
Compound via MeSH
