The Journal of Neuroscience, May 19, 2004 • 24(20):4787– 4795 • 4787

Behavioral/Systems/Cognitive

Memory Reconsolidation and Extinction Have Distinct
Temporal and Biochemical Signatures
Akinobu Suzuki,1 Sheena A. Josselyn,3,4 Paul W. Frankland,3,4 Shoichi Masushige,1,2 Alcino J. Silva,4 and Satoshi Kida1,2
Departments of 1Agricultural Chemistry and 2Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan,
3Department of Integrative Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada M5G 1X8, and 4Departments of Neurobiology,
Psychology, and Psychiatry and Brain Research Institute, University of California at Los Angeles, Los Angeles, California 90095-1761

Memory retrieval is not a passive phenomenon. Instead, it triggers a number of processes that either reinforce or alter stored information.
Retrieval is thought to activate a second memory consolidation cascade (reconsolidation) that requires protein synthesis. Here, we showthat the temporal dynamics of memory reconsolidation are dependent on the strength and age of the memory, such that younger andweaker memories are more easily reconsolidated than older and stronger memories. We also report that reconsolidation and extinction,
two opposing processes triggered by memory retrieval, have distinct biochemical signatures: pharmacological antagonism of either
cannabinoid receptor 1 or L-type voltage-gated calcium channels blocks extinction but not reconsolidation. These studies demonstrate
the dynamic nature of memory processing after retrieval and represent a first step toward a molecular dissection of underlying
mechanisms.
Key words: consolidation; reconsolidation; extinction; fear conditioning; spatial memory; protein synthesis

Introduction
Memory consolidation is often thought of as a process of fixation(i.e., memories become increasingly immune to disruption as
they mature) (McGaugh, 1966). This process of consolidation
requires gene expression and de novo protein synthesis (Flexner etal., 1965; Davis and Squire, 1984; Abel et al., 1997; McGaugh,
2000). Although it was previously thought that this consolidation
occurs just once, there is growing evidence that memory retrieval
is a dynamic process that either reinforces or alters memory(Misanin et al., 1968; Schneider and Sherman, 1968; Lewis, 1979;
Mactutus et al., 1979; Judge and Quartermain, 1982; Przybyslawski and Sara, 1997; Przybyslawski et al., 1999; Nader et al., 2000a;
Sara, 2000; Anokhin et al., 2002; Pedreira et al., 2002). For example, inhibition of protein synthesis before or immediately after
retrieval of a fear memory disrupts the subsequent expression ofthat memory, suggesting that retrieval triggers a wave of protein
synthesis required for the reconsolidation of memory (Nader etal., 2000a; Taubenfeld et al., 2001; Debiec et al., 2002; Kida et al.,2002). Memory reconsolidation after retrieval may be used to
update or integrate new information into long-term memories(LTMs) (Nader et al., 2000b; Sara, 2000; Dudai, 2002). The finding that LTM may be more dynamic and plastic than previously

Received Dec. 16, 2003; revised April 12, 2004; accepted April 12, 2004.
This work was supported by Grants-in Aid for Scientific Research and High Technology Research from the Ministryof Education, Science and Culture, Japan. We thank R. Costa for helpful discussions, invaluable comments, andcritical reading of this manuscript.
Correspondence should be addressed to Dr. Satoshi Kida, Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan. E-mail:kida@nodai.ac.jp.
DOI:10.1523/JNEUROSCI.5491-03.2004
Copyright © 2004 Society for Neuroscience 0270-6474/04/244787-09$15.00/0

thought may have important clinical implications for the treatment of emotional disorders.
Cued recall of the original memory is the key event that initiates reconsolidation. In pavlovian fear conditioning, a conditioned stimulus (CS; such as a context) is paired with an unconditioned stimulus (US; such as footshock). When placed back inthe training context, the animal shows conditioned fear responses such as freezing. Blocking protein synthesis around thetime of training blocks long-term consolidation of the contextual
fear memory (Abel et al., 1997; Schafe et al., 1999; Kida et al.,2002). Experimentally, cued recall typically involves reexposing
subjects to the CS without the US. This reminder is akin to an
extinction trial in which the CS comes to predict no US and loses
its ability to evoke a conditioned response (Pavlov, 1927; Baum,
1988; Bouton, 1993; Myers and Davis, 2002). Experimental extinction does not reflect forgetting of the original memory trace
but rather reflects new learning. That is, in addition to the previously acquired CS–US association, a new CS–no US association isformed that is thought to inhibit the conditioned response(Konorksi, 1967; Rescorla and Heth, 1975; Robbins, 1990; Rescorla,
2001). Therefore, memory retrieval may initiate two potentially dissociable but opposite processes: reconsolidation and extinction. Reconsolidation acts to stabilize, whereas extinction tends to weaken,
the expression of the original memory. Recent studies using crab andmedaka fish have shown that the duration of a reminder event may
be an important determinant of subsequent memory processing:brief reminders lead to reconsolidation, whereas longer reminders
result in memory extinction (Debiec et al., 2002; Eisenberg et al.,
2003; Pedreira and Maldonado, 2003).
Here, we systematically explore both the temporal dynamics
of memory processing after retrieval and the biochemical signatures of these processes in mice.

4788 • J. Neurosci., May 19, 2004 • 24(20):4787– 4795

Suzuki et al. • Memory Reconsolidation and Extinction

Materials and Methods
Mice. All experiments were conducted according to the Guide for the Care and Use of Laboratory Animals, Japan Neuroscience Society. MaleC57BL/6 mice (Charles River, Yokohama, Japan) were housed in cages of five or six, maintained on a 12 hr light/dark cycle, and allowed
ad libitum access to food and water. Mice wereat least 8 weeks of age when tested. Testing was
performed during the light phase of the cycle.
All experiments were conducted blind to thetreatment condition of the mouse.
Drugs. Because the neural sites critically responsible for acquisition, extinction, and reconsolidation of fear memories may be different, we used systemic rather than intracranial
injections of a protein synthesis inhibitor [anisomysin (ANI)], a cannabinoid receptor 1 (CB1)antagonist (SR141716A), an L-type voltage-gatedcalcium channel (LVGCC) antagonist (nimodipine), and an NMDA receptor (NMDAR) antagonist [D(⫺)-3-(2-carboxypiperazine-4-yl)-propyl1-phosphonic acid (CPP)]. ANI (150 mg/kg, i.p.;
Sigma, St. Louis, MO) was dissolved in PBS (pHadjusted to 7.0–7.4) and administered to mice 30
min before the behavioral manipulation. At thisdose, ANI inhibits ⬎90% of protein synthesis in
the brain during the first 2 hr (Flood et al.,1973). SR141716A was synthesized (RinaldiCarmona et al., 1994). SR141716A (1, 3, or 10
mg/kg, i.p.) was dissolved in solution (1 drop of
Tween 80 in 3 ml of 2.5% dimethylsulphoxideand 10% Cremophor in saline) and administered to mice 20 min before the behavioral manipulation. Nimodipine (8, 16, or 32 mg/kg,
i.p.; Sigma) was sonicated into 100% Cremophor EL (Sigma) and then diluted to make thefinal vehicle 10% Cremophor in solution (1drop of Tween 80 in 3 ml of 2.5% dimethylsulFigure 1. Effects of CS reexposure duration on stability of reactivated memory and extinction. A–E, G, H, Experimental designphoxide). Nimodipine was administered toused with data presented below. A, Effects of ANI injection on STM and LTM (control group, n ⫽ 10; ANI-injected group, n ⫽ 10).
mice 20 min before the behavioral manipulaB, Effects of 0 min reexposure (no reexposure; saline, n ⫽ 10; ANI, n ⫽ 10). C, Effects of 1 min reexposure (saline, n ⫽ 10; ANI, n ⫽tion. CPP (10 or 20 mg/kg, i.p.; Sigma) was dis10). D, Effects of 3 min reexposure (saline, n ⫽ 10; ANI, n ⫽ 10). E, Effects of 30 min reexposure (saline, n ⫽ 10; ANI, n ⫽ 10).
solved in saline solution (1 drop of Tween 80 in
During reexposure, freezing score in 3 min blocks are presented. F, Summary of the relationship between the duration of reexpo3 ml of 2.5% dimethylsulphoxide and 10% Cresure at reexposure and freezing scores at test ( B–E). G, Disruption of reactivated memory is not observed 2 hr after reexposure
mophor in saline) and administered to mice 60(saline, n ⫽ 10; ANI, n ⫽ 10). H, Disruption of reactivated memory by anisomycin is observed 1 week after reexposure (saline, n ⫽min before the behavioral manipulation. Drug
10; ANI, n ⫽ 10).
doses were determined according to previous
reports showing effective doses for the blockadeof long-term extinction (Santini et al., 2001; Cain et al., 2002; Marsicano
ments involving reexposure, mice were trained drug free with a single
et al., 2002).
footshock and 24 hr later replaced back in the training context for 0, 1, 3,
Contextual fear conditioning. Mice were trained and tested in condior 30 min, during which freezing behavior was assessed (reexposure).
tioning chambers (17.5 ⫻ 17.5 ⫻ 15 cm) that had a stainless steel rod
Mice were treated with saline or ANI 30 min before reexposure. Twentyfloor through which footshocks could be delivered. Training consisted offour hours later, mice were once again placed in the training context (5placing the mice in the chamber and delivering an unsignaled footshockmin) and freezing behavior was assessed (test). In the case of 0 min(2 sec duration; 0.75 mA) 148 sec later. Under more intense training
reexposure, mice remained in the home cage (not reexposed to training
conditions, mice received a series of three footshocks at 30 sec intervals
chamber) but were treated with the ANI or saline. For studies examining(the first footshock starting 148 sec after placement in the chamber).
the time course of reconsolidation, mice were trained with a single footMice were returned to the home cage 30 sec after the final footshock.
shock and 24 hr later replaced in the training context for 3 min (reexpoTwenty-four hours after training, mice were reexposed to the trainingsure). Before reexposure, mice received saline or ANI. Two hours (Fig.
context (reexposure) for varying lengths of time (0, 1, 3, or 30 min).
1G) or 1 week (Fig. 1 H) after reexposure, mice were placed back in the
Memory was assessed 24 hr later (test) as the percentage of time mice spent
training context and memory was assessed for 5 min.
freezing when replaced in the training context. Freezing behavior (defined as
For the second experiment (effect of strength of the memory on memcomplete lack of movement, except for respiration) was assessed at 5 sec
ory reconsolidation), mice were trained using a stronger training protointervals (Blanchard and Blanchard, 1969; Fanselow, 1980).
col. Mice were trained with three footshocks and 24 hr later replaced in
For the first experiment (effects of CS reexposure duration on subsethe training context for 3, 5, or 10 min (reexposure). Mice received
quent memory expression), mice were treated with saline or ANI 30 min
saline or ANI 30 min before reexposure. Twenty-four hours after this,before training with a single footshock. Memory was assessed 2 or 24 hr
mice were replaced in the training context and memory was assessedfor 5 min (test).
later [short-term memory (STM) and LTM, respectively). For experi-

Suzuki et al. • Memory Reconsolidation and Extinction

For the third experiment (effect of age of memory on subsequent
memory expression), mice were trained with a single footshock and replaced in the training context (for 3 min; reexposure) either 1, 3, or 8
weeks later. Mice received saline or ANI 30 min before reexposure.
Twenty-four hours after this, mice were replaced in the training context
and memory was assessed for 5 min (test).
For the fourth experiment (molecular differences between reconsolidation and extinction), the effects of the CB1 antagonist SR141716A(1-10 mg/kg), nimodipine (8-32 mg/kg), CPP (10 or 20 mg/kg), and ANI(150 mg/kg) on LTM were assessed (as above). To assess the effects ofthese drugs on reconsolidation, mice were trained as in the reconsolidation experiments above and treated with these drugs before a 3 min
reexposure.
Morris water maze. The water maze apparatus and procedures havebeen described (Bourtchaleze et al., 1994). Spatial learning and memory
were assessed in probe trials with the platform removed from the pool. In
probe trials, mice were allowed to swim for 60 sec and the time spent ineach quadrant of the pool was scored. Mice were trained with 6 trials per
day for 2 d (at 1 min intervals). Twenty-four hours later, mice were given
either a single probe trial or a series of 10 probe trials (at 3 min intervals;
reexposure). Mice were treated with saline or ANI 30 min before reexposure. A final probe trial was given 24 hr later (test).
Data analysis. Data were analyzed with ANOVA. A single-factor
ANOVA and post hoc comparisons were used to analyze the difference
between probe trials in the Morris water maze and the effects of drugs incontextual fear conditioning. Planned comparisons, using a nonpaired t
test, were used to analyze differences of the time spent in the target
quadrant (TQ) in the Morris water maze between two groups. Planned
comparisons using a paired t test were used to analyze differences offreezing scores from the contextual conditioning of each group between
the first 3 min reexposure during 30 min reexposure and test. All values
in the text and figure legends are means ⫾ SEM.

Results

Effects of CS reexposure duration on subsequent
memory expression
To test whether under our conditions protein synthesis is critical
for the stabilization of LTM but not STM, we first administered
the protein synthesis inhibitor ANI or saline 30 min before contextual fear training and assessed memory in separate groups ofmice either 2 or 24 hr later. In agreement with other studies (Kidaet al., 2002), we found that ANI blocked memory assessed 24 hr(F(1,18) ⫽ 33.89; p ⬍ 0.05), but not 2 hr (F(1,18) ⫽ 0.42; p ⬎ 0.05),
after contextual conditioning (Fig. 1 A).
Previous studies suggest that protein synthesis may also be
required for restabilizing memories after retrieval, a process referred to as reconsolidation. We examined the importance of
three variables on reconsolidation: (1) duration of memory reactivation (CS reexposure); (2) strength of memory; and (3) age ofmemory.
In the first experiment, we examined the effects of CS duration
on reconsolidation. Mice were trained with a single footshockand 24 hr later reexposed to the training context (30 min after
ANI or saline treatment) for different amounts of time (0, 1, 3, or
30 min; reexposure). Memory was assessed 24 hr later as drugfree mice were once again placed in the training context (test).
We found that memory (freezing) tested 24 hr after reexposure
was not affected by ANI treatment after very short (0 or 1 min)reexposures (0 min: F(1,18) ⫽ 0.72, p ⬎ 0.05; 1 min: F(1,18) ⫽ 0.73,
p ⬎ 0.05) (Fig. 1 B, C), suggesting that reconsolidation is notaffected under these conditions. In contrast, as shown previously(Kida et al., 2002), reconsolidation after a longer reexposure (3min) was disrupted by ANI (F(1,18) ⫽ 27.83; p ⬍ 0.05) (Fig. 1 D).
When longer reexposures were used (30 min), conditioned freezing levels decreased over time within the session in both thesaline- and ANI-treated groups (saline: F(1,9) ⫽ 24.04, p ⬍ 0.05;

J. Neurosci., May 19, 2004 • 24(20):4787– 4795 • 4789

ANI: F(1,9) ⫽ 13.05, p ⬍ 0.05). Measurements 24 hr after this 30
min reexposure confirmed that the extinction of conditioned
freezing was persistent in saline-treated mice (first block in reexposure session versus test; t(9) ⫽ 7.325; p ⬍ 0.05) (Fig. 1 E). However, extinction tested 24 hr after the 30 min reexposure wasblocked by ANI (F(1,18) ⫽ 19.37; p ⬍ 0.05), indicating that thelong-term stability of extinction requires protein synthesis. Because freezing levels during the reexposure were not affected by
ANI treatment, our results also show that protein synthesis is not
required for recall of a conditioned fear memory. The effects ofreexposure duration on protein synthesis-dependent reconsolidation of contextual fear memory are summarized in Figure 1 F.
Together, these results indicate that under certain circumstances, ANI produces amnesia for previously consolidated conditioned fear memories. To further investigate the temporal dynamics of this impairment, we varied the length of time between
reexposure and test (2 hr, 24 hr, or 1 week). ANI did not impair
memory tested 2 hr after reexposure (F(1,18) ⫽ 1.03; p ⬎ 0.05)(Fig. 1G) but did block memory tested 24 hr or 1 week after
reexposure [24 hr (Fig. 1 D); 1 week: F(1,18) ⫽ 18.06, p ⬍ 0.05 (Fig.
1 H)]. Therefore, the amnestic effects of ANI on reconsolidation
are observed 24 hr after training and are stable for at least 1 week.
These results revealed the presence of three distinct timedependent phases of memory processing after memory retrieval:in the first phase, the memory trace is immune to the effects ofprotein synthesis inhibition. With our experimental conditions,this phase lasts approximately 1 min. Further extending reexposure triggers a second wave of memory consolidation processes(reconsolidation) required for the stability of the memory trace.
Hence, blocking protein synthesis during this second phase compromises the long-term stability of the trace. Finally, prolonged
reexposures to the CS in the absence of the US trigger the formation of a new “extinction” trace (CS–no US). Inhibition of protein synthesis at this stage blocks the formation of the new extinction memory, leaving expression of the old memory unchanged.
It is important to note that our results indicate that there is aninteraction between the extinction and reconsolidation phases,
because blocking both reconsolidation and extinction with protein synthesis inhibitors appears to leave the original memory
unaffected, whereas blocking protein synthesis during the reconsolidation phase alone disrupts the original memory.
Effects of strength of the memory on memory reconsolidation
It is possible that stronger memories are more resistant to reconsolidation than weaker memories. To test this possibility, we
trained mice with three, rather than one, footshocks. Twentyfour hours after training, mice were reexposed to the training
context for 3 min (30 min after ANI or saline treatment; reexposure). Memory was assessed 24 hr after reexposure (test). In contrast to the results of our previous experiments with one footshock (Fig. 1 D), after training with three footshocks, ANI did not
block reconsolidation (F(1,19) ⫽ 0.14; p ⬎ 0.05) (Fig. 2 A), suggesting that stronger memories are more resistant to disruption,
perhaps because they are more widely represented in neural networks. However, it is possible that longer reexposures can trigger
the reconsolidation of stronger memories. To test this, we trained
mice as described above but increased the duration of reexposure
to the training context from 3 min to either 5 or 10 min. ANI did
not block reconsolidation after a 5 min reexposure (F(1,18) ⫽ 0.01;
p ⬎ 0.05) (Fig. 2 B) but blocked it after a 10 min reexposure(F(1,18) ⫽ 16.63; p ⬍ 0.05) (Fig. 2C), indicating that longer reexposures are required to reconsolidate stronger memories.

4790 • J. Neurosci., May 19, 2004 • 24(20):4787– 4795

Figure 2. Effects of memory strength on the stability of reactivated memories. A–C, Experimental design used with data presented below. Mice were trained with three footshocks. A,
Effects of 3 min reexposure on freezing during test (saline, n ⫽ 10; ANI, n ⫽ 11). B, Effects of 5
min reexposure on freezing during test (saline, n ⫽ 10; ANI, n ⫽ 10). C, Effects of 10 min
reexposure on freezing during test (saline, n ⫽ 10; ANI, n ⫽ 11).

Effects of age of the memory on subsequent
memory expression
Another important variable that may determine the stability of a
retrieved memory is its age (Milekic and Alberini, 2002). To test
whether older memories are less likely to undergo reconsolidation, we trained separate groups of mice with a single footshockand reexposed them to the training context (for 3 min) 1, 3, or 8
weeks later. As in previous experiments, memory was assessed 24
hr after reexposure (test). Young (1 or 3 weeks) but not old (8weeks) memories were disrupted by ANI treatment given before
reexposure (1 week: F(1,18) ⫽ 20.31, p ⬍ 0.05; 3 weeks: F(1,18) ⫽153.45, p ⬍ 0.05; 8 weeks: F(1,18) ⫽ 0.72, p ⬎ 0.05) (Fig. 3A–C).
Consistent with previous findings (Milekic and Alberini, 2002),
these results indicate that older memories are immune to thedisruptive effects of protein synthesis inhibition during retrieval.
However, it is possible that, like stronger memories, older memories undergo reconsolidation with longer reexposure. To test
this, we trained another group of mice and reexposed them to thetraining context 8 weeks after training, but this time we used a 10
min, rather than 3 min, reexposure. ANI disrupted reconsolidation after this longer duration reexposure (F(1,18) ⫽ 13.95, p ⬍0.05) (Fig. 3D). Whereas previous studies suggested that older
memories do not undergo protein synthesis-dependent reconsolidation (Milekic and Alberini, 2002), our results show thatolder memories do require protein synthesis for re-storage after
longer duration reexposure.
Molecular differences between reconsolidationand extinction
Recent studies using pharmacology or mouse genetics identified
two genes (CB1 and LVGCCs) that may be required for extinction but not initial memory consolidation (Cain et al., 2002; Mar-

Suzuki et al. • Memory Reconsolidation and Extinction

Figure 3. Effect of memory age on the stability of reactivated memories. A–D, Experimental
design used with data presented below. A, Effect of 1 week retention on freezing during test
between reexposure (3 min) and test (control, n ⫽ 10; ANI, n ⫽ 10). B, Effect of 3 weekretention on freezing during test between reexposure (3 min) and test (control, n ⫽ 10; ANI,n ⫽ 10). C, Effect of 8 week retention on freezing during test between reexposure (3 min) andtest (control, n ⫽ 10; ANI, n ⫽ 10). D, Effect of 8 week retention on freezing during test
between reexposure (10 min) and test (control, n ⫽ 10; ANI, n ⫽ 10).

sicano et al., 2002; but see Bauer et al., 2002). To compare themolecular mechanisms underlying consolidation, reconsolidation, and extinction, we examined the effects of antagonists for
CB1, LVGCCs, and NMDAR on these three processes. First, we
examined the effects of these drugs on initial memory consolidation (LTM). Mice received the CB1 antagonist SR141716A (1–10
mg/kg), LVGCC inhibitor (nimodipine; 8 –32 mg/kg), NMDAR
antagonist (CPP; 10 –20 mg/kg), or ANI (150 mg/kg; positive
control) before contextual fear training (as described above).
ANI and CPP disrupted initial memory consolidation, whereas
nimodipine (8 –32 mg/kg) or SR141716A (1–10 mg/kg) did not(F(9, 90) ⫽ 22.01, p ⬍ 0.05) (Fig. 4 A). The post hoc Newman–Keuls
test showed that the ANI and CPP groups froze significantly lessthan the other groups 24 hr after training. These results suggestthat both protein synthesis and NMDAR function, but not
LVGCCs or CB1 receptor function, are required for initial memory consolidation.
In the second experiment, we examined the effects of thesedrugs on reconsolidation after a 3 min reexposure. ANI and CPP
disrupted reconsolidation, whereas nimodipine or SR141716A
did not (F(9,90) ⫽ 7.23, p ⬍ 0.05) (Fig. 4 B). The post hoc Newman–Keuls test showed that the ANI and CPP groups froze significantly less than the other groups.
To examine the effects of these drug treatments on extinction,
we reexposed separate groups of mice to the context for 30 min.
As above, saline-treated mice showed decreasing levels of freezingover the 30 min reexposure. This within-session reduction infreezing (or short-term extinction) was blocked by nimodipine (0vs 32 mg/kg; drug ⫻ time: F(9,198) ⫽ 2.85, p ⬍ 0.05; drug: F(1,22) ⫽9.49, p ⬍ 0.05; time: F(9,198) ⫽ 18.68, p ⬍ 0.05) (Fig. 4C). However, all drug treatments impaired the stability of extinction measured 24 hr after reexposure (F(9,110) ⫽ 6.72, p ⬍ 0.05) (Fig. 4C).

Suzuki et al. • Memory Reconsolidation and Extinction

J. Neurosci., May 19, 2004 • 24(20):4787– 4795 • 4791

F(3,32) ⫽ 11.27, p ⬍ 0.05; ANI: F(3,32) ⫽6.80, p ⬍ 0.05; comparable searchingscores in the TQ between saline and ANI:t(16) ⫽ 0.34, p ⬎ 0.05) (Fig. 5C). However,when these mice were tested 24 hr later(test), the saline-treated, but not ANItreated, mice searched selectively in the
TQ (saline: F(3,32) ⫽ 5.67, p ⬍ 0.05; ANI:
F(3,32) ⫽ 2.29, p ⬎ 0.05) (Fig. 5D). Therefore, these data suggest that reexposure to
the training environment triggers memory
reconsolidation of spatial memory andthat this process is protein synthesis
dependent.
The amnestic effects of ANI in our fear
conditioning experiments were contingent on reexposure to the training context(see above). To test whether this holds true
for spatial memories, mice were trained in
the water maze as above but were treatedwith ANI or saline in the home cage 24 hrlater (but not reexposed to the pool) andthen given a probe test 24 hr later. ANI
failed to disrupt subsequent expression of
the spatial memory (saline: F(3,36) ⫽ 12.76,
Figure 4. Effects of CB1, LVGCC, and NMDAR antagonists on reconsolidation and extinction. A–C, Experimental design usedp ⬍ 0.05; ANI: F(3,36) ⫽ 16.66, p ⬍ 0.05;
with data presented below. A, Effects of ANI, SR141716A, nimodipine, and CPP on memory consolidation (n ⫽ 10 for all groups).
B, Effects of ANI, SR141716A, nimodipine, and CPP on memory reconsolidation (n ⫽ 10 for all groups). C, Effects of ANI, comparable searching scores in the TQ beSR141716A, nimodipine, and CPP on memory extinction. Freezing responses during reexposure are shown only for the highest tween saline and ANI: t(18) ⫽ ⫺1.94, p ⬎dose of nimodipine (32 mg/kg), SR141716A (10 mg/kg), and CPP (20 mg/kg). Subsequent test data are shown in the right panel 0.05) (Fig. 6 B), suggesting that the amnestic effects of ANI are contingent on reex(n ⫽ 12 for all groups). C, Control; A, anisomycin; Nimo, nimodipine; SR, SR141716A.
posure to the training environment in spatial memory as well as fear conditioning.
The post hoc Newman–Keuls test showed that all drug groups
In our fear conditioning experiments, prolonged reexposure
froze significantly more than control groups [control vs ANI,
initiated extinction; consolidation of this extinction memory was
CB1 blocker (3 or 10 mg/kg), nimodipine (16 or 32 mg/kg), or
blocked by ANI treatment. To test whether this holds true for
CPP (10 or 20 mg/kg): p ⬍ 0.001; control vs CB1 blocker (1spatial memory, mice were trained as described above, but reexmg/kg): p ⬍ 0.05; control vs nimodipine (8 mg/kg): p ⬍ 0.01].
posure was extended (a greater number of probe trials). Thirty
Together, these results indicate that extinction depends on prominutes after pretreatment with ANI or saline, mice were given atein synthesis and intact function of NMDAR, CB1, andseries of 10 probe trials (spaced 3 min apart). Both ANI- and
LVGCCs. Therefore, although LVGCCs and CB1 receptor funcsaline-treated mice searched selectively in the TQ in the firsttion are not required for consolidation and reconsolidation, theyprobe trial (reexposure) (saline: F(3,32) ⫽ 46.15, p ⬍ 0.05; ANI:
F(3,36) ⫽ 68.67, p ⬍ 0.05) (Fig. 7B) but showed a progressive loss
are necessary for extinction. The molecular underpinnings ofof this selectivity over successive probe trials (saline: F(1,8) ⫽consolidation and reconsolidation, consequently, differ from12.74, p ⬍ 0.05; ANI: F(1,9) ⫽ 26.60, p ⬍ 0.05) (Fig. 7C). In thethat of extinction.
final probe trial, neither the ANI- nor saline-treated mice showeda preference for the TQ, indicating extinction of the spatial memRelationship between reconsolidation and extinction in theory (saline: F(3,32) ⫽ 1.70, p ⬎ 0.05; ANI: F(3,36) ⫽ 0.59, p ⬎ 0.05)
Morris water maze
(Fig. 7D). Therefore, ANI did not disrupt short-term extinction
Recent studies of reconsolidation and extinction have focused onof spatial memories (for drug: F(1,17) ⫽ 2.07, p ⬎ 0.05; for time:
contextual fear conditioning. To test whether our results generF(9,153) ⫽ 35.24, p ⬍ 0.05; for drug ⫻ time: F(9,153) ⫽ 1.20, p ⬎alize to another hippocampal-dependent task with different sen0.05) (Fig. 7C). However, when these mice were tested 24 hr later,sory, motivational, and performance demands, we trained mice
the ANI-treated, but not the saline-treated, mice searched selecin the Morris water maze. Training took place over 2 d, during
tively in the quadrant in which the platform was previously lowhich mice were given six trials to find a hidden platform (Fig.
cated (saline: F(3,32) ⫽ 1.32, p ⬎ 0.05; ANI: F(3,36) ⫽ 17.22, p ⬍5B). In our contextual fear conditioning experiments, memory0.05) (Fig. 7E). These results show that long-term extinction of a
was reactivated by reexposure to the training context. Similarly,
spatial memory is blocked by protein synthesis inhibition.
24 hr after training in the water maze, mice were given a probe
trial in which the platform was removed from the pool (reexpoDiscussionsure). Thirty minutes before this probe trial, mice were treated
There has been renewed interest in memory processing after rewith ANI or saline. As before, memory was subsequently assessedtrieval: brief exposure to the CS seems to trigger a second wave of
24 hr later in a probe trial (test). As expected, pretreatment withmemory consolidation (reconsolidation), whereas prolonged exANI did not affect recall of the spatial memory; both saline- andposure to the CS leads to the formation of a new memory that
ANI-treated mice searched selectively in the quadrant of the poolcompetes with the original memory (extinction). However, many
where the platform was previously located (the TQ) (saline:

4792 • J. Neurosci., May 19, 2004 • 24(20):4787– 4795

Suzuki et al. • Memory Reconsolidation and Extinction

Figure 6. Memory reactivation during a probe trial is necessary for the disruption of thereactivated memory by anisomycin. A, Experimental design. B, Probe trial 48 hr after the lasttraining (saline, n ⫽ 10; ANI, n ⫽ 10). Mice were given injections of anisomycin or saline 24.5
hr before the probe trial. Time (seconds) spent in target (T), adjacent left (L), adjacent right (R),and opposite (O) quadrants during the probe trial (60 sec) is shown.
Figure 5. Effects of protein synthesis inhibition during a probe trial on reactivated memory
for platform position in the Morris water maze. A, Experimental design. B, Time to find thehidden platform (saline, n ⫽ 9; ANI, n ⫽ 9). Data are indicated in blocks of two trials. C, Probe
trial after 24 hr last training (reexposure). Mice were given injections of ANI or saline 30 min
before reexposure. D, Probe trial conducted 24 hr after reexposure (test). C, D, Time spent(seconds) in target (T), adjacent left (L), adjacent right (R), and opposite (O) quadrants during
the probe trial (60 sec) is shown.

of the findings supporting current views on reconsolidation, andextinctions remain controversial. For example, although several
investigators found that inhibition of protein synthesis before or
immediately after memory retrieval disrupts the subsequent expression of memory, suggesting that reconsolidation is protein
synthesis dependent (Nader et al., 2000a; Taubenfeld et al., 2001;
Debiec et al., 2002; Kida et al., 2002; Milekic and Alberini, 2002),
others did not (Lattal and Abel, 2001). Similarly, there is disagreement about the role of protein synthesis in memory extinction:some groups found that protein synthesis inhibition at the timeof memory retrieval impairs memory extinction (Berman andDudai, 2001; Vianna et al., 2001; Eisenberg et al., 2003; Pedreiraand Maldonado, 2003), whereas others did not (Lattal and Abel,
2001). These discrepancies suggest that there may be fundamental methodological variables that influence the memory processes
activated during retrieval.
In this series of experiments, we identified three key variables
that control subsequent behavior after memory retrieval. We
provided a systematic demonstration of how reexposure duration, the age of the memory, and the strength of the memory
interact to influence behavior in tasks that model declarative
memory in mice. As proposed previously (Debeic et al., 2002;
Nader, 2003), our results show that the duration of reexposure isa key variable that controls subsequent behavior. Memory re-trieval initiates two competing processes [reconsolidation (CS–US) and extinction (CS–no US)], and the duration of reexposure
helps determine which of these processes is dominant in the control of subsequent behavior. The present results are consistent
with previous results using crab, medaka fish, and snail (Eisenberg et al., 2003; Pedreira and Maldonado, 2003; Sangha et al.,2003a,b). Furthermore, we showed that these competing processes have distinct temporal and biochemical signatures.
The results presented here reveal three distinct timedependent phases of memory processing after memory retrieval.
During the first phase, the retrieved memory is in a state thatprecedes both the reconsolidation and extinction processes. Further extending reexposure, however, initiates the protein
synthesis-dependent reconsolidation processes required for thestability of the memory trace. Hence, blocking protein synthesis
during this second phase compromises the long-term stability ofthe trace. Finally, prolonged reexposures to the CS in the absenceof the US trigger the formation of a new memory trace that encodes the dissociation between the CS and the US (CS–no US;
extinction memory), therefore competing with the original
memory (CS–US). Inhibition of protein synthesis at this stage
blocks the formation of this new extinction memory, leaving expression of the original memory unchanged. It is important tonote that our results also indicate that there is an interaction
between the extinction and reconsolidation processes: althoughblocking protein synthesis during short reexposures (reconsolidation) disrupts the original memory, blocking protein synthesis
during prolonged reexposure, conditions in which both reconsolidation and extinction would be expected to be initiated, leaves
the original memory unaffected.
Lattel and Abel (2001) found that inhibiting protein synthesis

Suzuki et al. • Memory Reconsolidation and Extinction

Figure 7. Effects of protein synthesis inhibition during 10 probe trials on memory extinction
for platform position in the Morris water maze. A, Experimental design. B, First probe trial
during 10 trials after 24 hr last training (reexposure; saline, n ⫽ 9; ANI, n ⫽ 10). Mice were
given injections of ANI or saline 30 min before reexposure. C, Extinction curve of time spentswimming in the TQ during 10 probe trials. D, Last probe trial during 10 trials at reexposure. E,
Probe trial 24 hr after reexposure (test). B, D, E, Time (seconds) spent in target (T), adjacent left(L), adjacent right (R), and opposite (O) quadrants during the probe trial (60 sec) is shown.

at the time of CS reexposure in contextual fear conditioning andthe Morris water maze produced no effect on subsequent memory expression. This lack of effect may be attributed to the duration of reexposure used in those experiments. Accordingly, we
found that ANI treatments (Fig. 1) failed to either disrupt thereactivated memory or block long-term extinction (data notshown) with certain reexposure durations.
Our results indicate that after retrieval behavior is controlled
by ensuing competing processes: reconsolidation and extinction.
The process that prevails and dominates subsequent behavior isdetermined in part by the duration of the reexposure. Whereas
reconsolidation acts on the original memory (Nader et al., 2000a;

J. Neurosci., May 19, 2004 • 24(20):4787– 4795 • 4793

Taubenfeld et al., 2001; Anokhin et al., 2002; Debiec et al., 2002;
Kida et al., 2002; Kraus et al., 2002; Milekic and Alberini, 2002;
Pedreira et al., 2002), extinction involves the formation of distinct alternative (CS–no US) memories (Quirk et al. 2000). Ourdata suggest that these two processes have different temporalprofiles. After retrieval, there is a brief time window for reconsolidation, whereas extinction only occurs after prolonged reexposure. These two processes may be dissociable at the anatomicallevel. In fear conditioning, for example, extinction learning isthought to depend on the medial prefrontal cortex (Teich et al.,
1989; Morgan et al., 1993; Morgan and LeDoux, 1995, 1999; Morrow et al., 1999; Quirk et al., 2000). In contrast, reconsolidation offear memories is thought to be mediated by the amygdala (Naderet al., 2000a) or hippocampus (Debiec et al., 2002).
Recent reports using pharmacology or mouse genetics indicate that the downstream signaling transduction pathways of
LVGCCs and CB1 are essential for long-term extinction but notinitial learning (Cain et al., 2002; Marsicano et al., 2002). Because
reconsolidation and extinction are dissociable both temporally
and anatomically, this raises the possibility that the two processes
are also dissociable biochemically. Consistent with this, we foundthat pharmacological blockade of either CB1 or LVGCCs blocked
extinction but not reconsolidation. In contrast, blocking
NMDARs or protein synthesis disrupts both reconsolidation andextinction, as well as initial consolidation. These findings are thefirst to demonstrate that the competing processes of reconsolidation and extinction require different molecular components.
Furthermore, the observation that the inhibition of LVGCCs impairs both short- and long-term extinction processes indicatesthat LVGCCs function upstream of protein synthesis mechanisms required for the stability of the extinction memory. Additionally, we identified a role for CB1 receptors in long-term extinction of contextual, as well as cued (Marsicano et al., 2002),
fear memory, suggesting a general role of CB1 in extinction offear memories.
We also examined how reexposure duration interacts with
two other characteristics of a memory: its age and strength. Our
results show that memories become increasingly resistant to disruption with age. After contextual fear conditioning, ANI treatment before CS reexposure (3 min) disrupted the subsequent
expression of 1- and 3-week-old memories but not 8-week-old
memories. However, increasing the duration of the reexposure
made even 8-week-old memories susceptible to disruption by
ANI. These results suggest that there is a time-dependent change
in the activation of reconsolidation processes, as if it were easierto activate the reconsolidation of younger than older memories.
Whereas initial encoding and storage of fear memories dependon the hippocampus, permanent storage is proposed to dependon the neocortex (Kim and Fanselow, 1992; Eichenbaum et al.,
1994; McClelland et al., 1995; Squire and Alvarez, 1995; Anagnostaras et al., 1999, 2001; Quevedo et al., 1999; LeDoux, 2000;
McGaugh, 2000; Frankland et al., 2001). Therefore, the reactivation of an old memory should activate a cortical, rather thanhippocampal, trace. This cortical trace is more resistant to disruption by protein synthesis inhibitors, perhaps because it isbroadly distributed across different cortical regions (McClelland
et al., 1995; Bontempi et al., 1999). Of interest are the findings
using inhibitory avoidance that show that an old memory is immune to protein synthesis inhibition after retrieval using shortduration reexposure (Taubenfeld et al., 2001). Our data indicatethat longer duration reexposures are necessary to destabilize
older memories.
Surprisingly, we also found that memory strength affected the4794 • J. Neurosci., May 19, 2004 • 24(20):4787– 4795

ease of reconsolidation. Increasing the strength of memory (byincreasing the number of shocks during training), increased theresistance of these fear memories to disruption by ANI. Similar tothe studies with older memories, longer reexposures were required to induce reconsolidation of stronger memories. Therefore, the activation of reconsolidation processes seems to be dependent both on the age and the strength of the memory.
The majority of previous studies have used conditioned fear to
examine reconsolidation (Nader et al., 2000a; Taubenfeld et al.,
2001; Anokhin et al., 2002; Debiec et al., 2002; Kida et al., 2002;
Kraus et al., 2002; Milekic and Alberini, 2002; Pedreira et al.,2002). To test whether these results generalize to anotherhippocampal-dependent task with different sensory, motivational, and performance demands, we trained mice in the Morris
water maze. Again, we found that memory retrieval initiates twocompeting processes (reconsolidation and extinction) and thatthe length of reexposure (in this case, the number of reinforced
probe trials) determines in part which process is dominant: oneprobe trial (similar to a brief reexposure to the context in fear
conditioning) initiates reconsolidation of a spatial memory thatis blocked by ANI treatment. Ten probe trials (similar to a more
prolonged reexposure to the context in fear conditioning) initiate
extinction. As with fear conditioning, ANI treatment blocks thelong-term consolidation of this extinction memory. These findings indicate contextual fear conditioning and spatial learning
have similar reconsolidation and extinction processes, extending
previous studies using the radial arm maze (Przybyslawski andSara, 1997; Przybyslawski et al., 1999).
The studies presented here demonstrate the dynamic natureof memory processing after retrieval. They also identify threefundamental variables (duration of CS exposure, age of memory,strength of memory) affecting the stability of reactivated memories and show how these variables interact to determine the fate of
the memory trace.

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