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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, Unite´Mixte de Recherche 7624, Universite´ Paris VI, 75005 Paris, France A memory trace in its active state is susceptible to interference when administered immediately after the initial training. These by amnesic agents, such as hypothermia and electroconvulsive results suggest that reactivation of memory triggers a ␤ shock, and by NMDA receptor antagonists, suggesting that a receptor-dependent cascade of intracellular events, recapitu- time-dependent consolidation process occurs each time a lating that which occurs during initial postacquisition consoli- memory is reactivated. The role of ␤ noradrenergic receptors in dation, thus permitting reorganization of the existing memory as reconsolidation in rats was examined in both a positively rein- a function of new information in the retrieval environment. This forced radial maze task and a footshock-reinforced conditioned remarkable lability of an active memory trace provides a new emotional response task. For the former, rats were trained over basis for pharmacotherapeutic intervention in such syndromes several days in a spatial reference memory task and received a as Posttraumatic Stress Disorder. ␤ adrenoreceptor antago- single reactivation trial followed by propranolol. A temporally nists may be promising pharmacological agents for attenuating graded impairment was observed when propranolol treatment debilitating memories at the time of their controlled reactivation.
occurred after the memory reactivation trial. In the emotionaltask, memory impairing effects of propranolol were greater Key words: ␤ receptors; memory reactivation; propranolol; when the drug was administered after a reactivation trial than CREB; post-traumatic stress disorder; amnesia Memories are reactivated by cues associated with the initial 1997). This suggests that the cascade of intracellular events in- acquisition of information. Repeated reactivation of a memory volved in plasticity and memory formation and dependent on may serve to reinforce it and promote its long-term consolidation NMDA receptor action is recapitulated each time the memory (Squire and Alvarez, 1995). A more dynamic view holds that memory is a reconstruction and reorganization of past experi- The question arises as to whether other intracellular pathways ences within the current cognitive context (Bartlett, 1932; Lewis thought to be involved in long-term memory (LTM) formation et al., 1972; Lewis and Bregman, 1973; Spear and Mueller, 1984; are also involved in a reconsolidation process after memory Sara, 1985). According to this view, each time a memory is reactivation. The cAMP response element-binding protein retrieved, it is integrated into ongoing perceptual and emotional (CREB) pathway is one system receiving recent attention con- experiences and becomes part of a new memory.
cerning its possible role in LTM (for review, see Mayford et al., A memory trace in its active state is vulnerable to interference 1995; Yin and Tully, 1996). Mice lacking CREB genes show by amnesic agents, such as electroconvulsive shock (Misanin et deficits in long-term potentiation and LTM (Bourtchuladze et al., al., 1968; Schneider and Sherman, 1968) or hypothermia (Riccio 1994); antisense oligodeoxynucleotides directed against CREB and Stikes, 1969; Richardson et al., 1982). Such experiments mRNA can inhibit LTM (Guzowski and McGaugh, 1997). The ␤ provided experimental evidence that reactivated memories, as noradrenergic receptor is one of a family of receptors positively well as newly acquired information, undergo a time-dependent coupled to adenylcyclase-linked G-protein receptors governing consolidation process, although they did not address the question the cAMP cascade. Indirect evidence for involvement of this of the neurobiological mechanisms involved. We have recently pathway in LTM can be found in studies showing that blockade of provided evidence that NMDA receptors are involved in these the ␤ adrenergic receptor by propranolol immediately after mem- reconsolidation processes, at least in memories for tasks involving ory acquisition can, in some circumstances, produce retrograde spatial information. Blockade of these receptors by the noncom- amnesia in humans (Cahill et al., 1994; Nielsen and Jensen, 1994).
petitive antagonist MK801 as late as 2 hr after reactivating the Furthermore, facilitation of memory retrieval processes by stim- memory produces a memory deficit (Przybyslawski and Sara, ulation of the noradrenergic system is blocked by the ␤ receptor antagonist propranolol (Devauges and Sara, 1991). Finally, there Received April 1, 1999; revised May 11, 1999; accepted May 12, 1999.
is growing evidence that hippocampal synaptic plasticity is de- This research was supported by the European Foundation Programme on the pendent on ␤ receptor-mediated modulation (Harley, 1987; Neural Mechanisms of Learning and Memory and by the Centre National de la Recherche Scientifique, Unite´ Mixte de Recherche 7624. We thank Yves Moricard In the present series of experiments, the role of for help in preparing the figures and this manuscript.
Correspondence should be addressed to Susan J. Sara, Neuromodulation et evaluated in postreactivation reconsolidation in two distinct be- Processus Cognitifs, Institut des Neurosciences, Centre National de la Recherche havioral situations: one a nonstressful appetitive task and the Scientifique, Unite´ Mixte de Recherche 7624, Universite´ Paris VI, 9 quai St.
other a conditioned emotional avoidance response. A spatial Copyright 1999 Society for Neuroscience 0270-6474/99/196623-06$05.00/0 reference memory task that draws minimally on working memory 6624 J. Neurosci., August 1, 1999, 19(15):6623–6628
Przybyslawski et al. • ␤ Noradrenergic Blockade Attenuates Reactivated Memory was used as the appetitive task. As a control for the specificity of the rats were tested under the same conditions as the reactivated group the amnesic effect on active memory, two replication experiments included control groups trained, but not receiving the reactiva- To control for possible effects of propranolol on motivation to con- sume Chocopops, a control experiment was performed using eight rats tion trial before the drug treatment. A final study controlled for from the nonreactivated group having served in the final reactivation possible taste aversion induced by propranolol.
replication experiment. The rat was placed in the box in which it had the A single trial inhibitory avoidance task was used as the aversive initial exposure to reinforcement during the pretraining period, and the training. The advantage of this behavioral procedure is that the latency and time taken to consume five Chocopops were recorded. The time of learning can be fixed with precision. The first phase of this rat was then injected with propranolol 5 min later. Twenty-four hours later, the latency and consumption time was again recorded under the experiment evaluated the effects of propranolol injected after same conditions. Data were analyzed by a paired t test comparing latency acquisition. In the second phase of the experiment, control rats to eat and total time to consume the ration, before and after drug showing a robust memory (100% avoidance) after the memory had been reactivated were injected with saline or propranolol and 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 MATERIALS AND METHODS
sec) could be delivered. Rats were placed individually in the white box of Animals. One hundred ten naive male Sprague Dawley rats, weighing the training apparatus facing the closed door. After 15 sec, the door was between 250 and 300 gm, obtained from IFFA Credo (Arbresle, France), raised, and the time to enter the black box was recorded. When the rat were used in the three radial maze experiments, and fifty-eight were used was completely inside the black box, the door was lowered, and the in the avoidance experiments. They were housed in pairs in wire mesh animal received a 2 sec shock. Vocalization and jumping were noted. The cages (35 ϫ 20 ϫ 18 cm) and maintained on a 12 hr light/dark cycle with rat was removed and placed in the home cage. Five minutes after the water and food available ad libitum. They were weighed and handled shock, rats were injected with propranolol (10 mg/kg, i.p) or an equal daily for 1 week before the beginning of the experiment. Rats used in the volume of saline. Rats were assigned to the control (n ϭ 38) or experi- maze experiments were mildly food deprived to ϳ90% of freely feeding mental (n ϭ 20) groups based on their initial latency to enter the dark weight. Chocolate flavored crisp rice cereal (Chocopops; Kellogg’s) was box, so as to have no group differences. For the testing phase 48 hr later, used as reinforcement in the maze, and the rats were habituated to this the rat was placed in the white box as done previously. After 15 sec, the food before training. All procedures were performed according to the door was raised and stayed open for 5 min. No shock was delivered.
policy on the use of animals in neuroscience research as established by 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 Maze training apparatus and procedure. The training procedure and a Student’s t test. Because most control rats avoided placing all four paws apparatus were the same as that used in previous experiments (Przybys- into the dark compartment, yielding a large number of ceiling values of lawski and Sara, 1997). An eight-arm radial maze was elevated 0.6 m 300 sec, the data were transformed into class frequencies of rats avoiding from the floor. Three of the eight arms were baited, the same three for or not avoiding for the 300 sec test period, and a ␹2 test was applied.
every trial for an individual rat. The maze was surrounded by a black Twenty-one control rats avoided the dark box for the entire 5 min curtain, and salient items were hung on the curtains to serve as distal cues testing period. Five minutes after the test, these rats were injected with to aid in mapping of the environment. A radio, always situated in the propranolol (n ϭ 11) or with NaCl (n ϭ 10). A second test was conducted same position in the room, provided a distal auditory cue. To ensure that 48 hr later in the same conditions with the same behavioral measures.
the rats were really basing their performance on the integration of spatial Drug treatment. DL-Propranolol obtained from Sigma (St. Louis, MO) information provided by the distal extra maze cues, the maze was rotated was prepared in saline at a concentration of 10 mg/ml and was injected between successive trials during both training and the test sessions. This intraperitoneally in a volume of 1 ml/kg. This single dose was used procedure precluded any possibility for the individual rat to use in- because previous experiments in our laboratory indicated the 10 mg/kg tramaze information to find the baited arms, because the location of the intraperitoneally in the rat has no effect on spontaneous locomotor reinforced alleys was always determined by their relation to the distal activity or exploratory behavior (Sara et al., 1995) and is effective in cues in the extra maze environment. The experiment began with 2 d of blocking noradrenergically induced increases in excitability of hippocam- pretraining in which the reinforcement was available throughout the pal neurons (Harley and Sara, 1992).
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 Temporal gradient of efficacy of propranolol after
reference errors (visits to the nonbaited arms) and working errors reactivation of a nonemotional spatial memory
(repeated visits). Acquisition criterion was three consecutive trials with a Twenty-four hours after the reactivation session, control rats The day after reaching criterion, the rat received a reactivation trial, showed very good retention performance. On the other hand, rats which consisted of a single run in the maze, after which it was returned injected with propranolol for up to 2 hr after reactivation made to its home cage until the scheduled injection time. All rats performed more errors than at the reactivation trial, as shown in Figure 1.
Data for the test session concerning the difference in total number Experimental design and data analyses. Rats were divided into six of errors from reactivation to test trial were submitted to a 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 two-way ANOVA. There was a significant overall drug effect window of efficacy of drug treatment. A retention session occurred 24 hr (F(1,52) ϭ 5.37; p ϭ 0.024); the interaction approached signifi- after the reactivation trial. Data were analyzed using a two-way ANOVA, with one factor being drug treatment and the other time of (2,52) ϭ 2.77; p ϭ 0.07]. Planned comparisons using the Fischer least significant difference test (Winer, 1962) indicated a injection. Planned comparisons were performed using the Fischer least significant difference test (Winer, 1962).
significant difference between propranolol-treated and saline Two complementary experiments replicated the effect of propranolol groups at the 5 min delay ( p Ͻ 0.01) and a significant difference on a reactivated memory and controlled for the specificity of the effect by between the propranolol group treated at 5 min and 5 hr after adding a group that was not subjected to a reactivation trial. The rats reactivation ( p Ͻ 0.05). The group treated with propranolol at 2 were trained as in the preceding experiment, and one group was sub- jected to a reactivation trial followed by an injection of propranolol 2 hr hr after training had an intermediary performance, which was not later in one replication and 5 min later in the second replication. The significantly different from either the 5 min group or the 5 hr control groups received an injection of propranolol in the vivarium, and Przybyslawski et al. • ␤ Noradrenergic Blockade Attenuates Reactivated Memory J. Neurosci., August 1, 1999, 19(15):6623–6628 6625
vation in the passive avoidance task caused a marked perfor- mance decrement when the animals were retested, as shown in Figure 5. There was a decrease in the latency to place two paws (t(19) ϭ 2.68; p Ͻ 0.05) and in the frequency distribution of number of rats to enter the dark box with all four paws (␹2 ϭ 3.231; 0.01 Ͻ p Ͻ 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.
DISCUSSION
These experiments provide clear evidence that pharmacological
blockade of ␤ receptors by systemic injections of propranolol up Figure 1. Effect of propranolol at different time intervals after a reacti- to 2 hr after reactivation of a memory trace induces amnesia vation trial in the radial maze task. Twenty-four hours after the reacti- when rats are tested 1 or 2 d later. The amnesia is transient or vation session, control rats had good retention performance, whereas propranolol-injected rats (10 mg/kg, i.p.) showed amnesia when the partial in that the rats are capable of relearning the task with injections were made up to 2 hr after the reactivation trial. **p Ͻ 0.01, considerable savings. Thus far, studies of the role of ␤ noradren- significantly greater than saline group; ‡p Ͻ 0.05, significantly less than 5 ergic receptors in rats have suggested that these receptors play a role in memory consolidation mainly by interaction with other neurotransmitter systems, particularly GABAergic (Introini- Effect of propranolol with or without reactivation
Collison et al., 1994), cholinergic (Introini-Collison et al., 1996), Injection 5 min after a reactivation trial produced a significant and opioid (Introini-Collison et al., 1989), the site of action being performance decrement 24 hr later compared with the rats re- the amygdala (for review, see McGaugh and Cahill, 1997). An ceiving a propranolol injection in the animal vivarium, as shown early study in adult rats did, however, show an amnesic effect of propranolol alone when injected 5 min after passive avoidance (14) ϭ 4.015; p ϭ 0.001). Propranolol injections 2 hr after reactivation also induced some amnesia, because these an- training. Interestingly, the animals were able to express memory imals made more errors at the retention test than the control for up to 6 hr after treatment, the amnesia appearing only in those group injected without a reactivation trial. A t test revealed a tested 1 d after training (Cohen and Hamburg, 1975), corrobo- significant effect of treatment on the difference between number rating later views that ␤ receptors govern the adenylcyclase- of errors on the last training trial and the mean of three test trials linked cAMP cascade leading to protein synthesis-dependent (26) ϭ 2.30; p Ͻ 0.05). Note that the last training trial was used as a baseline performance in these experiments, because one A recent study in humans suggests that propranolol selectively group did not receive a reactivation trial.
attenuates memories for emotionally charged events (Cahill et al., In these two experiments, only rats that had the behavioral trial 1994). Another study in elderly humans reports that ␤ blockers, at before the propranolol treatment showed amnesia, although they clinically antihypertensive doses, can block the beneficial effects had been subjected to one more trial than the nonreactivated rats.
of arousal on memory performance (Nielsen and Jensen, 1994). It Thus, the effect of a propranolol injection was limited to a period should be noted that, aside from these two studies, there are few of up to 2 hr after memory comes to an active state.
reports of memory impairment associated with clinical doses of ␤ blockers, despite their widespread use as antihypertensives. This Effect of propranolol on reward incentive
is probably because of the use of hydrophilic forms, which do not There were no differences in the latencies or total time to con- readily cross the blood–brain barrier.
sume the Chocopops before or after propranolol treatment, as Systemic injections, such as those used in the present experi- indicated in Figure 3. (paired t tests; latency, t(7) ϭ 1.3; total time, ments, are useful if the drug treatment might have a clinical t(7) ϭ 1.36; p Ͼ 0.05).
application, as discussed below. However, this leaves open the Propranolol injection after inhibitory avoidance training
question of site of drug action. There are compelling arguments Propranolol-treated rats had a shorter latency to place two paws for the effect being mediated by blockade of ␤ receptors in the CNS. Systemically administered propranolol has little or no effect (56) ϭ 2.19; p Ͻ 0.05), as shown in Figure 4.
There was no effect of treatment on percentage of rats completely on cerebral blood flow to account for its memory impairing effects entering the dark box (␹2 ϭ 0.82, NS), as illustrated in Figure 4.
(Olesen, 1986). Peripherally administered propranolol, a li- Thus, propranolol has only a small effect on memory, as measured pophilic molecule, readily crosses the blood–brain barrier; after by the immediate step into response. The two other behavioral chronic treatment in humans, the ratio of brain/plasma concen- measures most often used to evaluate memory in the passive trations of the drug is ϳ20:1 (Cruickshank et al., 1980; Neil- avoidance task, step-through latency and total time spent in the Dwyer et al., 1981). An important recent study has provided shock compartment, were not modified by post-training propran- strong evidence that the central effects of propranolol are respon- sible for the amnesia for emotional events in man by comparing the effects of propranolol with a hydrophilic ␤ antagonist, which Propranolol after reactivation of avoidance training
does not cross the blood–brain barrier. The latter had no Saline-treated animals continued to show good avoidance behav- memory-impairing effects. Finally, in a recent study from our ior at the second test. Propranolol injected 5 min after a reacti- laboratory, intracerebroventricular injection of the ␤ antagonist 6626 J. Neurosci., August 1, 1999, 19(15):6623–6628
Przybyslawski et al. • ␤ Noradrenergic Blockade Attenuates Reactivated Memory 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 ϭ 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 Ͻ 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 ϭ 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 Ͻ 0.001.
of amnesic agents (Misanin et al., 1968; Schneider and Sherman,1968; Riccio and Stikes, 1969; Lewis et al., 1972; Lewis andBregman, 1973). The results of those early experiments, althoughthey did not extend our knowledge of the neurobiological pro-cesses underlying these reconsolidation processes, did reinforcethe notion that memory is dynamic and that new memories areformed on the foundation of reactivated old memories. Thatpostreactivation amnesia can be induced by both NMDA recep-tor (Przybyslawski and Sara, 1997) and ␤ receptor blockade (Roullet and Sara, 1998) suggests intracellular mechanisms in-volving the same second messenger pathways as involved in syn-aptic 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 ob-tained in appetitive situations in which the animals are only mildlyfood-deprived and are well trained in the task. Two controlprocedures ensured that the behavioral deficit was not caused bya proactive effect of propranolol on performance at the time oftest. Those animals injected 5 hr after reactivation and tested 24hr later showed no such performance decrement nor did thosethat were not subjected to a reactivation trial before drug treat-ment. Memory must be in an active state for propranolol to beeffective, and the temporal limit for treatment efficacy under Figure 3. Effect of propranolol on reward incentive. Latency (left) and total time (right) to consume five Chocopops before (white bars) and 24 hr these experimental conditions is between 2 and 5 hr.
after (black bars) injection of propranolol. There is no significant change It is surprising that the effect of propranolol appeared to be in either measure (paired t test), indicating that the drug did not induce more robust after reactivation of inhibitory avoidance training than after the original learning. Such increased vulnerability toamnesic agents after reactivation is not, however, unprecedented.
timolol impaired a reactivated memory in a paradigm similar to Mactutus et al. (1979) reported that memory reactivated by ex- the one used in the present experiments. Intracerebroventricular posure to the place where a footshock had been administered was injections allowed a temporal resolution of drug action and a more susceptible to hypothermia-induced amnesia than immedi- window of efficacy was found at 1 hr after the reactivation trial; ately after the initial acquisition. Further investigation is required intracerebroventricular injections earlier or later did not impair to determine whether reactivated memories, in general, are more labile and vulnerable to amnesic agents or whether it is particular The present results reinforce previous studies showing that to the conditioned emotional response elicited by the passive reactivated memories are susceptible to interference by a variety avoidance test. It is possible that the increased vulnerability to the Przybyslawski et al. • ␤ Noradrenergic Blockade Attenuates Reactivated Memory J. Neurosci., August 1, 1999, 19(15):6623–6628 6627
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 ϭ 38) and propranolol-injected (n ϭ 20) rats on this measure of retention.
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 ϭ 10; propranolol, n ϭ 11; *p Ͻ 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.
amnesic agent after the retention–reactivation test is because the a possible clinical application in the pharmacotherapeutic treat- rat receives no footshock during the exposure. Some extinction ment of Posttraumatic Stress Disorder (PTSD). This psychiatric could be occurring, although this is not seen in the subsequent syndrome is characterized by vivid recall of the traumatic events behavior of the saline-injected control group, who maintain max- with the accompanying severe emotional responses. Individuals imal avoidance behavior at the second retention test. We are report that terrifying experiences are often recalled with inten- currently developing rapidly learned appetitive tasks in our lab- sity, the traumatic events being reexperienced unchanged over oratory to perform comparative studies between emotional and years (van der Kolk and Fisler, 1995). There is rather extensive nonemotional memories and effects of reactivation procedures evidence that points to dysregulation of the noradrenergic system in PTSD, and there has been some suggestion of how this might This demonstration of lability of reactivated memories suggests be related to the hypermnesia. Over-responsiveness of the nor- 6628 J. Neurosci., August 1, 1999, 19(15):6623–6628
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