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The Journal of Neuroscience, August 1, 1999, 19(15):6623-6628
Attenuation of Emotional and Nonemotional Memories after their
Reactivation: Role of  Adrenergic Receptors
Jean
Przybyslawski,
Pascal
Roullet, and
Susan J.
Sara
Neuromodulation et Processus Cognitifs, Institut des Neurosciences,
Centre National de la Recherche Scientifique, Unité Mixte de
Recherche 7624, Université Paris VI, 75005 Paris, France
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ABSTRACT |
A memory trace in its active state is susceptible to interference
by amnesic agents, such as hypothermia and electroconvulsive shock, and
by NMDA receptor antagonists, suggesting that a time-dependent consolidation process occurs each time a memory is reactivated. The
role of  noradrenergic receptors in reconsolidation in rats was
examined in both a positively reinforced radial maze task and a
footshock-reinforced conditioned emotional response task. For the
former, rats were trained over several days in a spatial reference
memory task and received a single reactivation trial followed by
propranolol. A temporally graded impairment was observed when
propranolol treatment occurred after the memory reactivation trial. In
the emotional task, memory impairing effects of propranolol were
greater when the drug was administered after a reactivation trial than
when administered immediately after the initial training. These results
suggest that reactivation of memory triggers a receptor-dependent
cascade of intracellular events, recapitulating that which occurs
during initial postacquisition consolidation, thus permitting
reorganization of the existing memory as a function of new information
in the retrieval environment. This remarkable lability of an active
memory trace provides a new basis for pharmacotherapeutic intervention
in such syndromes as Posttraumatic Stress Disorder. adrenoreceptor
antagonists may be promising pharmacological agents for attenuating
debilitating memories at the time of their controlled reactivation.
Key words:
receptors; memory reactivation; propranolol; CREB; post-traumatic stress disorder; amnesia
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INTRODUCTION |
Memories are reactivated by cues
associated with the initial acquisition of information. Repeated
reactivation of a memory may serve to reinforce it and promote its
long-term consolidation (Squire and Alvarez, 1995 ). A more dynamic view
holds that memory is a reconstruction and reorganization of past
experiences within the current cognitive context (Bartlett, 1932; Lewis
et al., 1972; Lewis and Bregman, 1973; Spear and Mueller, 1984; Sara,
1985). According to this view, each time a memory is retrieved, it is integrated into ongoing perceptual and emotional experiences and becomes part of a new memory.
A memory trace in its active state is vulnerable to interference by
amnesic agents, such as electroconvulsive shock (Misanin et al., 1968;
Schneider and Sherman, 1968) or hypothermia (Riccio and Stikes,
1969; Richardson et al., 1982). Such experiments provided experimental
evidence that reactivated memories, as well as newly acquired
information, undergo a time-dependent consolidation process, although
they did not address the question of the neurobiological mechanisms
involved. We have recently provided evidence that NMDA receptors are
involved in these reconsolidation processes, at least in memories for
tasks involving spatial information. Blockade of these receptors by the
noncompetitive antagonist MK801 as late as 2 hr after reactivating the
memory produces a memory deficit (Przybyslawski and Sara, 1997). This
suggests that the cascade of intracellular events involved in
plasticity and memory formation and dependent on NMDA receptor action
is recapitulated each time the memory trace is reactivated.
The question arises as to whether other intracellular pathways thought
to be involved in long-term memory (LTM) formation are also involved in
a reconsolidation process after memory reactivation. The cAMP response
element-binding protein (CREB) pathway is one system receiving recent
attention concerning its possible role in LTM (for review, see Mayford
et al., 1995; Yin and Tully, 1996). Mice lacking CREB genes show
deficits in long-term potentiation and LTM (Bourtchuladze et
al., 1994); antisense oligodeoxynucleotides directed against CREB mRNA
can inhibit LTM (Guzowski and McGaugh, 1997). The noradrenergic
receptor is one of a family of receptors positively coupled to
adenylcyclase-linked G-protein receptors governing the cAMP cascade.
Indirect evidence for involvement of this pathway in LTM can be found
in studies showing that blockade of the adrenergic receptor by
propranolol immediately after memory acquisition can, in some
circumstances, produce retrograde amnesia in humans (Cahill et al.,
1994; Nielsen and Jensen, 1994). Furthermore, facilitation of memory
retrieval processes by stimulation of the noradrenergic system is
blocked by the receptor antagonist propranolol (Devauges and Sara,
1991). Finally, there is growing evidence that hippocampal synaptic
plasticity is dependent on receptor-mediated modulation (Harley,
1987; Sarvey, 1988; Huang and Kandel, 1996)
In the present series of experiments, the role of receptors is
evaluated in postreactivation reconsolidation in two distinct behavioral situations: one a nonstressful appetitive task and the other
a conditioned emotional avoidance response. A spatial reference memory
task that draws minimally on working memory was used as the appetitive
task. As a control for the specificity of the amnesic effect on active
memory, two replication experiments included control groups trained,
but not receiving the reactivation trial before the drug treatment. A
final study controlled for possible taste aversion induced by propranolol.
A single trial inhibitory avoidance task was used as the aversive
training. The advantage of this behavioral procedure is that the time
of learning can be fixed with precision. The first phase of this
experiment evaluated the effects of propranolol injected after
acquisition. In the second phase of the experiment, control rats
showing a robust memory (100% avoidance) after the memory had been
reactivated were injected with saline or propranolol and retested 48 hr later.
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MATERIALS AND METHODS |
Animals. One hundred ten naive male Sprague Dawley
rats, weighing between 250 and 300 gm, obtained from IFFA Credo
(Arbresle, France), were used in the three radial maze
experiments, and fifty-eight were used in the avoidance experiments.
They were housed in pairs in wire mesh cages (35 × 20 × 18 cm) and maintained on a 12 hr light/dark cycle with water and food
available ad libitum. They were weighed and
handled daily for 1 week before the beginning of the experiment. Rats
used in the maze experiments were mildly food deprived to ~90% of
freely feeding weight. Chocolate flavored crisp rice cereal (Chocopops;
Kellogg's) was used as reinforcement in the maze, and the rats were
habituated to this food before training. All procedures were performed
according to the policy on the use of animals in neuroscience research
as established by the Society for Neuroscience.
Maze training apparatus and procedure. The training
procedure and apparatus were the same as that used in previous
experiments (Przybyslawski and Sara, 1997). An eight-arm radial maze
was elevated 0.6 m from the floor. Three of the eight arms were
baited, the same three for every trial for an individual rat. The maze
was surrounded by a black curtain, and salient items were hung on the
curtains to serve as distal cues to aid in mapping of the environment.
A radio, always situated in the same position in the room, provided a
distal auditory cue. To ensure that the rats were really basing their
performance on the integration of spatial information provided by the
distal extra maze cues, the maze was rotated between successive trials
during both training and the test sessions. This procedure precluded
any possibility for the individual rat to use intramaze information to
find the baited arms, because the location of the reinforced alleys was
always determined by their relation to the distal cues in the extra
maze environment. The experiment began with 2 d of pretraining in
which the reinforcement was available throughout the maze. After that, the animals were submitted to three daily trials (with a intertrial interval of 5 min), which consisted of placing the rat on the central
platform of the maze and allowing free choice of visits to the alleys,
only three of which were baited. A ceiling time of 5 min was imposed.
The exact sequence of alleys visited was noted, as well as reference
errors (visits to the nonbaited arms) and working errors (repeated
visits). Acquisition criterion was three consecutive trials with a
maximum of one error per trial.
The day after reaching criterion, the rat received a reactivation
trial, which consisted of a single run in the maze, after which it was
returned to its home cage until the scheduled injection time. All rats
performed well on this trial.
Experimental design and data analyses. Rats were divided
into six treatment groups to be injected with propranolol or saline 5 min, 2 hr, or 5 hr after the reactivation trial to determine a temporal
gradient or window of efficacy of drug treatment. A retention session
occurred 24 hr after the reactivation trial. Data were analyzed using a
two-way ANOVA, with one factor being drug treatment and
the other time of injection. Planned comparisons were performed using
the Fischer least significant difference test (Winer, 1962).
Two complementary experiments replicated the effect of propranolol on a
reactivated memory and controlled for the specificity of the effect by
adding a group that was not subjected to a reactivation trial. The rats
were trained as in the preceding experiment, and one group was
subjected to a reactivation trial followed by an injection of
propranolol 2 hr later in one replication and 5 min later in the second
replication. The control groups received an injection of propranolol in
the vivarium, and the rats were tested under the same conditions as the
reactivated group 24 hr later.
To control for possible effects of propranolol on motivation to consume
Chocopops, a control experiment was performed using eight rats from the
nonreactivated group having served in the final reactivation
replication experiment. The rat was placed in the box in which it had
the initial exposure to reinforcement during the pretraining period,
and the latency and time taken to consume five Chocopops were recorded.
The rat was then injected with propranolol 5 min later. Twenty-four
hours later, the latency and consumption time was again recorded under
the same conditions. Data were analyzed by a paired t test
comparing latency to eat and total time to consume the ration, before
and after drug treatment.
Inhibitory avoidance training apparatus and procedure. The
apparatus consisted of two 18 cm cubic boxes constructed from Perspex, one white and one black, each with a transparent cover. The white box
had a Perspex floor and was separated by a sliding door from the black
box, which had a grid floor through which a scrambled shock (0.25 mA
for 2 sec) could be delivered. Rats were placed individually in the
white box of the training apparatus facing the closed door. After 15 sec, the door was raised, and the time to enter the black box was
recorded. When the rat was completely inside the black box, the door
was lowered, and the animal received a 2 sec shock. Vocalization and
jumping were noted. The rat was removed and placed in the home cage.
Five minutes after the shock, rats were injected with propranolol (10 mg/kg, i.p) or an equal volume of saline. Rats were assigned to the
control (n = 38) or experimental (n = 20) groups based on their initial latency to enter the dark box, so as
to have no group differences. For the testing phase 48 hr later, the
rat was placed in the white box as done previously. After 15 sec, the
door was raised and stayed open for 5 min. No shock was delivered.
Latency to place two paws in the black box and latency to enter with
all four paws were recorded. The latency to place two paws was
subjected to a Student's t test. Because most control rats
avoided placing all four paws into the dark compartment, yielding a
large number of ceiling values of 300 sec, the data were transformed
into class frequencies of rats avoiding or not avoiding for the 300 sec
test period, and a  2 test was applied.
Twenty-one control rats avoided the dark box for the entire 5 min
testing period. Five minutes after the test, these rats were injected
with propranolol (n = 11) or with NaCl
(n = 10). A second test was conducted 48 hr later in
the same conditions with the same behavioral measures.
Drug treatment. DL-Propranolol obtained from
Sigma (St. Louis, MO) was prepared in saline at a concentration of 10 mg/ml and was injected intraperitoneally in a volume of 1 ml/kg. This
single dose was used because previous experiments in our laboratory
indicated the 10 mg/kg intraperitoneally in the rat has no effect on
spontaneous locomotor activity or exploratory behavior (Sara et al.,
1995) and is effective in blocking noradrenergically induced increases in excitability of hippocampal neurons (Harley and Sara, 1992).
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RESULTS |
Temporal gradient of efficacy of propranolol after reactivation of
a nonemotional spatial memory
Twenty-four hours after the reactivation session, control rats
showed very good retention performance. On the other hand, rats
injected with propranolol for up to 2 hr after reactivation made more
errors than at the reactivation trial, as shown in Figure 1. Data for the test session concerning
the difference in total number of errors from reactivation to test
trial were submitted to a two-way ANOVA. There was a significant
overall drug effect (F(1,52) = 5.37;
p = 0.024); the interaction approached significance (F(2,52) = 2.77; p = 0.07].
Planned comparisons using the Fischer least significant difference test
(Winer, 1962) indicated a significant difference between
propranolol-treated and saline groups at the 5 min delay
(p < 0.01) and a significant difference between
the propranolol group treated at 5 min and 5 hr after reactivation (p < 0.05). The group treated with propranolol
at 2 hr after training had an intermediary performance, which was not
significantly different from either the 5 min group or the 5 hr
group.
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Figure 1.
Effect of propranolol at different time intervals
after a reactivation trial in the radial maze task. Twenty-four hours
after the reactivation session, control rats had good retention
performance, whereas propranolol-injected rats (10 mg/kg, i.p.) showed
amnesia when the injections were made up to 2 hr after the reactivation
trial. **p < 0.01, significantly greater than
saline group;  p < 0.05, significantly
less than 5 min injection delay group.
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Effect of propranolol with or without reactivation
Injection 5 min after a reactivation trial produced a significant
performance decrement 24 hr later compared with the rats receiving a
propranolol injection in the animal vivarium, as shown in Figure
2. (t(14) = 4.015; p = 0.001). Propranolol injections 2 hr after
reactivation also induced some amnesia, because these animals made more
errors at the retention test than the control group injected without a
reactivation trial. A t test revealed a significant effect
of treatment on the difference between number of errors on the last
training trial and the mean of three test trials
(t(26) = 2.30; p < 0.05).
Note that the last training trial was used as a baseline performance in
these experiments, because one group did not receive a reactivation
trial.
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Figure 2.
Effect of propranolol on memory with or without
reactivation trial. A, Rats received a propranolol
injection (10 mg/kg, i.p.) in the animal vivarium 2 hr after a
reactivation trial or after no reactivation trial
(n = 14 in each group). There was a significant
performance deficit in the group that had the reactivation trial before
the drug treatment compared with the group that received drug alone.
*p < 0.05. B, Procedure the same as
in A, except that injections were made 5 min after a
reactivation trial or in the vivarium (n = 8 in
each group). There was a significant performance deficit in rats
receiving the injection after a reactivation trial compared with those
rats receiving drug treatment without reactivation. Note the nearly
errorless performance of this group on the test trial.
**p < 0.001.
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In these two experiments, only rats that had the behavioral trial
before the propranolol treatment showed amnesia, although they had been
subjected to one more trial than the nonreactivated rats. Thus, the
effect of a propranolol injection was limited to a period of up to 2 hr
after memory comes to an active state.
Effect of propranolol on reward incentive
There were no differences in the latencies or total time to
consume the Chocopops before or after propranolol treatment, as indicated in Figure 3. (paired
t tests; latency, t(7) = 1.3;
total time, t(7) = 1.36; p > 0.05).
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Figure 3.
Effect of propranolol on reward incentive. Latency
(left) and total time (right) to consume
five Chocopops before (white bars) and 24 hr after
(black bars) injection of propranolol. There is no
significant change in either measure (paired t test),
indicating that the drug did not induce an aversion to the
reinforcement.
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Propranolol injection after inhibitory avoidance training
Propranolol-treated rats had a shorter latency to place two paws
into the dark box (t(56) = 2.19;
p < 0.05), as shown in Figure 4. There was no effect of treatment on
percentage of rats completely entering the dark box
(2 = 0.82, NS), as illustrated in Figure 4. Thus,
propranolol has only a small effect on memory, as measured by the
immediate step into response. The two other behavioral measures most
often used to evaluate memory in the passive avoidance task,
step-through latency and total time spent in the shock compartment,
were not modified by post-training propranolol injection.
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Figure 4.
Effect of propranolol injection 5 min after
passive avoidance training. Left, Latency to place two
paws into the dark box in the test session 48 hr after training.
Propranolol (10 mg/kg, i.p.) significantly decreased this measure of
retention. Right, Percentage of rats completely entering
the dark box; there was no difference between control
(n = 38) and propranolol-injected
(n = 20) rats on this measure of retention.
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Propranolol after reactivation of avoidance training
Saline-treated animals continued to show good avoidance behavior
at the second test. Propranolol injected 5 min after a reactivation in
the passive avoidance task caused a marked performance decrement when
the animals were retested, as shown in Figure
5. There was a decrease in the latency to
place two paws (t(19) = 2.68;
p < 0.05) and in the frequency distribution of number of rats to enter the dark box with all four paws (2 = 3.231; 0.01 < p < 0.05). Note that the mean
performance of the saline control group in this phase of the experiment
was better than at the test (reactivation) trial (Fig. 4) because only
those animals treated with saline and having an optimal avoidance
performance at reactivation were used for the postreactivation study,
half being treated again with saline and half being treated with
propranolol after reactivation.
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Figure 5.
Effect of propranolol 5 min after a reactivation
in passive avoidance task. Left, Latency to place two
paws in the shock compartment in the test session 48 hr after
reactivation session. Propranolol-injected rats (10 mg/kg, i.p.) show a
significant decrease in latency. Right, Percentage of
rats completely entering the dark box. There was a significant increase
in the propranolol-treated group on this measure of retention (control,
n = 10; propranolol, n = 11;
*p < 0.05). Note that only those rats treated with
saline and showing perfect retention at the reactivation phase were
used in this phase of the experiment, which accounts for the
improvement in performance in saline-treated group shown here compared
with Figure 4. Half were treated again with saline and half received
propranolol after the reactivation trial.
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DISCUSSION |
These experiments provide clear evidence that pharmacological
blockade of receptors by systemic injections of propranolol up to 2 hr after reactivation of a memory trace induces amnesia when rats are
tested 1 or 2 d later. The amnesia is transient or partial in that
the rats are capable of relearning the task with considerable savings.
Thus far, studies of the role of noradrenergic receptors in rats
have suggested that these receptors play a role in memory consolidation
mainly by interaction with other neurotransmitter systems, particularly
GABAergic (Introini-Collison et al., 1994), cholinergic
(Introini-Collison et al., 1996), and opioid (Introini-Collison et al.,
1989), the site of action being the amygdala (for review, see McGaugh
and Cahill, 1997). An early study in adult rats did, however, show an
amnesic effect of propranolol alone when injected 5 min after passive
avoidance training. Interestingly, the animals were able to express
memory for up to 6 hr after treatment, the amnesia appearing only in
those tested 1 d after training (Cohen and Hamburg, 1975),
corroborating later views that receptors govern the
adenylcyclase-linked cAMP cascade leading to protein synthesis-dependent LTM.
A recent study in humans suggests that propranolol selectively
attenuates memories for emotionally charged events (Cahill et al.,
1994). Another study in elderly humans reports that blockers, at
clinically antihypertensive doses, can block the beneficial effects of
arousal on memory performance (Nielsen and Jensen, 1994). It should be
noted that, aside from these two studies, there are few reports of
memory impairment associated with clinical doses of blockers,
despite their widespread use as antihypertensives. This is probably
because of the use of hydrophilic forms, which do not readily
cross the blood-brain barrier.
Systemic injections, such as those used in the present experiments, are
useful if the drug treatment might have a clinical application, as
discussed below. However, this leaves open the question of site of drug
action. There are compelling arguments for the effect being mediated by
blockade of receptors in the CNS. Systemically administered
propranolol has little or no effect on cerebral blood flow to account
for its memory impairing effects (Olesen, 1986). Peripherally
administered propranolol, a lipophilic molecule, readily crosses the
blood-brain barrier; after chronic treatment in humans, the ratio of
brain/plasma concentrations of the drug is ~20:1 (Cruickshank et al.,
1980; Neil-Dwyer et al., 1981). An important recent study has provided
strong evidence that the central effects of propranolol are responsible
for the amnesia for emotional events in man by comparing the effects of propranolol with a hydrophilic antagonist, which does not cross the
blood-brain barrier. The latter had no memory-impairing effects. Finally, in a recent study from our laboratory,
intracerebroventricular injection of the antagonist timolol
impaired a reactivated memory in a paradigm similar to the one used in
the present experiments. Intracerebroventricular injections allowed a
temporal resolution of drug action and a window of efficacy was found
at 1 hr after the reactivation trial; intracerebroventricular
injections earlier or later did not impair memory.
The present results reinforce previous studies showing that reactivated
memories are susceptible to interference by a variety of amnesic agents
(Misanin et al., 1968; Schneider and Sherman, 1968; Riccio and Stikes,
1969; Lewis et al., 1972; Lewis and Bregman, 1973). The results of
those early experiments, although they did not extend our knowledge of
the neurobiological processes underlying these reconsolidation
processes, did reinforce the notion that memory is dynamic and that new
memories are formed on the foundation of reactivated old memories. That
postreactivation amnesia can be induced by both NMDA receptor
(Przybyslawski and Sara, 1997) and receptor blockade (Roullet and
Sara, 1998) suggests intracellular mechanisms involving the same second
messenger pathways as involved in synaptic plasticity and initial
memory formation.
In the present series of experiments, the effect of propranolol is not
limited to conditioned emotional responses but can be obtained in
appetitive situations in which the animals are only mildly
food-deprived and are well trained in the task. Two control procedures
ensured that the behavioral deficit was not caused by a proactive
effect of propranolol on performance at the time of test. Those animals
injected 5 hr after reactivation and tested 24 hr later showed no such
performance decrement nor did those that were not subjected to a
reactivation trial before drug treatment. Memory must be in an active
state for propranolol to be effective, and the temporal limit for
treatment efficacy under these experimental conditions is between 2 and
5 hr.
It is surprising that the effect of propranolol appeared to be more
robust after reactivation of inhibitory avoidance training than after
the original learning. Such increased vulnerability to amnesic agents
after reactivation is not, however, unprecedented. Mactutus et al.
(1979) reported that memory reactivated by exposure to the place where
a footshock had been administered was more susceptible to
hypothermia-induced amnesia than immediately after the initial
acquisition. Further investigation is required to determine whether
reactivated memories, in general, are more labile and vulnerable to
amnesic agents or whether it is particular to the conditioned emotional
response elicited by the passive avoidance test. It is possible that
the increased vulnerability to the amnesic agent after the
retention-reactivation test is because the rat receives no footshock
during the exposure. Some extinction could be occurring, although this
is not seen in the subsequent behavior of the saline-injected control
group, who maintain maximal avoidance behavior at the second retention
test. We are currently developing rapidly learned appetitive tasks in
our laboratory to perform comparative studies between emotional and
nonemotional memories and effects of reactivation procedures (Sara et
al., 1999).
This demonstration of lability of reactivated memories suggests a
possible clinical application in the pharmacotherapeutic treatment of
Posttraumatic Stress Disorder (PTSD). This psychiatric syndrome
is characterized by vivid recall of the traumatic events with the
accompanying severe emotional responses. Individuals report that
terrifying experiences are often recalled with intensity, the traumatic
events being reexperienced unchanged over years (van der Kolk and
Fisler, 1995). There is rather extensive evidence that points to
dysregulation of the noradrenergic system in PTSD, and there has been
some suggestion of how this might be related to the hypermnesia.
Over-responsiveness of the noradrenergic system during stress could
recreate the internal state induced by the original trauma and thereby
"reinstate" the memory (Grillon et al., 1996). The potential
usefulness of noradrenergic receptor-blocking agents in PTSD has
already been pointed out by Cahill (1997), who suggests that treatment
with blockers as soon as possible after the traumatic event might
prevent the development of PTSD. The lability of memory in its active
state, demonstrated in the present experiments, adds a new dimension to
this potential use. Effective treatment might lie in reactivation of
the traumatic memory under psychotherapeutic conditions combined with
pharmacological treatment with a receptor antagonist to reduce the
strength of the memory. The results of the present experiments suggest that treatment with propranolol, especially at the time of spontaneous or clinically elicited reinstatement of the traumatic memory, should
serve to attenuate the active memory by blocking reconsolidation processes.
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FOOTNOTES |
Received April 1, 1999; revised May 11, 1999; accepted May 12, 1999.
This research was supported by the European Foundation Programme on the
Neural Mechanisms of Learning and Memory and by the Centre National de
la Recherche Scientifique, Unité Mixte de Recherche 7624. We
thank Yves Moricard for help in preparing the figures and this manuscript.
Correspondence should be addressed to Susan J. Sara, Neuromodulation et
Processus Cognitifs, Institut des Neurosciences, Centre National de la
Recherche Scientifique, Unité Mixte de Recherche 7624, Université Paris VI, 9 quai St. Bernard, 75005 Paris, France.
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TOP
ABSTRACT
INTRODUCTION
Compound via MeSH
