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The Journal of Neuroscience, May 19, 2004, 24(20):4787-4795; doi:10.1523/JNEUROSCI.5491-03.2004
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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 andSatoshi 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
Abstract
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Abstract
Introduction
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 show that the temporal dynamics of memory reconsolidation are dependent on the strength and age of the memory, such that younger and weaker 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 et al., 1965
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 in the training context, the animal shows conditioned fear responses such as freezing. Blocking protein synthesis around the time of training blocks long-term consolidation of the contextual fear memory (Abel et al., 1997
Here, we systematically explore both the temporal dynamics of memory processing after retrieval and the biochemical signatures of these processes in mice.
Materials and Methods
Mice. All experiments were conducted according to the Guide for the Care and Use of Laboratory Animals, Japan Neuroscience Society. Male C57BL/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 were at least 8 weeks of age when tested. Testing was performed during the light phase of the cycle. All experiments were conducted blind to the treatment 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-gated calcium channel (LVGCC) antagonist (nimodipine), and an NMDA receptor (NMDAR) antagonist [D(–)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP)]. ANI (150 mg/kg, i.p.; Sigma, St. Louis, MO) was dissolved in PBS (pH adjusted to 7.0–7.4) and administered to mice 30 min before the behavioral manipulation. At this dose, ANI inhibits >90% of protein synthesis in the brain during the first 2 hr (Flood et al., 1973
Contextual fear conditioning. Mice were trained and tested in conditioning chambers (17.5 x 17.5 x 15 cm) that had a stainless steel rod floor through which footshocks could be delivered. Training consisted of placing the mice in the chamber and delivering an unsignaled footshock (2 sec duration; 0.75 mA) 148 sec later. Under more intense training conditions, mice received a series of three footshocks at 30 sec intervals (the first footshock starting 148 sec after placement in the chamber). Mice were returned to the home cage 30 sec after the final footshock.
Twenty-four hours after training, mice were reexposed to the training context (reexposure) for varying lengths of time (0, 1, 3, or 30 min). Memory was assessed 24 hr later (test) as the percentage of time mice spent freezing when replaced in the training context. Freezing behavior (defined as complete lack of movement, except for respiration) was assessed at 5 sec intervals (Blanchard and Blanchard, 1969
For the first experiment (effects of CS reexposure duration on subsequent memory expression), mice were treated with saline or ANI 30 min before training with a single footshock. Memory was assessed 2 or 24 hr later [short-term memory (STM) and LTM, respectively). For experiments involving reexposure, mice were trained drug free with a single footshock and 24 hr later replaced back in the training context for 0, 1, 3, or 30 min, during which freezing behavior was assessed (reexposure). Mice were treated with saline or ANI 30 min before reexposure. Twenty-four hours later, mice were once again placed in the training context (5 min) and freezing behavior was assessed (test). In the case of 0 min reexposure, mice remained in the home cage (not reexposed to training chamber) but were treated with the ANI or saline. For studies examining the time course of reconsolidation, mice were trained with a single footshock and 24 hr later replaced in the training context for 3 min (reexposure). Before reexposure, mice received saline or ANI. Two hours (Fig. 1G) or 1 week (Fig. 1 H) after reexposure, mice were placed back in the training context and memory was assessed for 5 min.
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Figure 1. Effects of CS reexposure duration on stability of reactivated memory and extinction. A–E, G, H, Experimental design used with data presented below. A, Effects of ANI injection on STM and LTM (control group, n = 10; ANI-injected group, n = 10). B, Effects of 0 min reexposure (no reexposure; saline, n=10; ANI, n=10). C, Effects of 1 min reexposure (saline, n=10; ANI, n= 10). D, Effects of 3 min reexposure (saline, n = 10; ANI, n = 10). E, Effects of 30 min reexposure (saline, n = 10; ANI, n = 10). During reexposure, freezing score in 3 min blocks are presented. F, Summary of the relationship between the duration of reexposure at reexposure and freezing scores at test (B–E). G, Disruption of reactivated memory is not observed 2 hr after reexposure (saline, n=10; ANI, n=10). H, Disruption of reactivated memory by anisomycin is observed 1 week after reexposure (saline, n= 10; ANI, n = 10).
For the second experiment (effect of strength of the memory on memory reconsolidation), mice were trained using a stronger training protocol. Mice were trained with three footshocks and 24 hr later replaced in the training context for 3, 5, or 10 min (reexposure). 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 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 of these 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 have been 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 in each 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 in contextual 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 of freezing 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 of mice either 2 or 24 hr later. In agreement with other studies (Kida et al., 2002Previous 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 of memory.
In the first experiment, we examined the effects of CS duration on reconsolidation. Mice were trained with a single footshock and 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 drug-free 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. 1B,C), suggesting that reconsolidation is not affected under these conditions. In contrast, as shown previously (Kida et al., 2002
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. 1D); 1 week: F(1,18) = 18.06, p < 0.05 (Fig. 1H)]. 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 time-dependent phases of memory processing after memory retrieval: in the first phase, the memory trace is immune to the effects of protein 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 an interaction 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. Twenty-four 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. 1D), after training with three footshocks, ANI did not block reconsolidation (F(1,19) = 0.14; p > 0.05) (Fig. 2A), 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. 2B) 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.
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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
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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 week retention 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) and test (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).
Molecular differences between reconsolidation and 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
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Figure 4. Effects of CB1, LVGCC, and NMDAR antagonists on reconsolidation and extinction. A–C, Experimental design used 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, SR141716A, nimodipine, and CPP on memory extinction. Freezing responses during reexposure are shown only for the highest dose of nimodipine (32 mg/kg), SR141716A (10 mg/kg), and CPP (20 mg/kg). Subsequent test data are shown in the right panel (n = 12 for all groups). C, Control; A, anisomycin; Nimo, nimodipine; SR, SR141716A.
In the second experiment, we examined the effects of these drugs 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. 4B). 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 freezing over the 30 min reexposure. This within-session reduction in freezing (or short-term extinction) was blocked by nimodipine (0 vs 32 mg/kg; drug x 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). The post hoc Newman–Keuls test showed that all drug groups froze significantly more than control groups [control vs ANI, CB1 blocker (3 or 10 mg/kg), nimodipine (16 or 32 mg/kg), or CPP (10 or 20 mg/kg): p < 0.001; control vs CB1 blocker (1 mg/kg): p < 0.05; control vs nimodipine (8 mg/kg): p < 0.01]. Together, these results indicate that extinction depends on protein synthesis and intact function of NMDAR, CB1, and LVGCCs. Therefore, although LVGCCs and CB1 receptor function are not required for consolidation and reconsolidation, they are necessary for extinction. The molecular underpinnings of consolidation and reconsolidation, consequently, differ from that of extinction.
Relationship between reconsolidation and extinction in the Morris water maze
Recent studies of reconsolidation and extinction have focused on contextual fear conditioning. To test whether our results generalize to another hippocampal-dependent task with different sensory, motivational, and performance demands, we trained mice in the Morris water maze. Training took place over 2 d, during which mice were given six trials to find a hidden platform (Fig. 5B). In our contextual fear conditioning experiments, memory was reactivated by reexposure to the training context. Similarly, 24 hr after training in the water maze, mice were given a probe trial in which the platform was removed from the pool (reexposure). Thirty minutes before this probe trial, mice were treated with ANI or saline. As before, memory was subsequently assessed 24 hr later in a probe trial (test). As expected, pretreatment with ANI did not affect recall of the spatial memory; both saline- and ANI-treated mice searched selectively in the quadrant of the pool where the platform was previously located (the TQ) (saline: F(3,32) = 11.27, p < 0.05; ANI: F(3,32) = 6.80, p < 0.05; comparable searching scores 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 ANI-treated, 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 and that this process is protein synthesis dependent.
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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 the hidden 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.
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 treated with ANI or saline in the home cage 24 hr later (but not reexposed to the pool) and then given a probe test 24 hr later. ANI failed to disrupt subsequent expression of the spatial memory (saline: F(3,36) = 12.76, p < 0.05; ANI: F(3,36) = 16.66, p < 0.05; comparable searching scores in the TQ between saline and ANI: t(18) = –1.94, p > 0.05) (Fig. 6B), suggesting that the amnestic effects of ANI are contingent on reexposure to the training environment in spatial memory as well as fear conditioning.
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Figure 6. Memory reactivation during a probe trial is necessary for the disruption of the reactivated memory by anisomycin. A, Experimental design. B, Probe trial 48 hr after the last training (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.
In our fear conditioning experiments, prolonged reexposure initiated extinction; consolidation of this extinction memory was blocked by ANI treatment. To test whether this holds true for spatial memory, mice were trained as described above, but reexposure was extended (a greater number of probe trials). Thirty minutes after pretreatment with ANI or saline, mice were given a series of 10 probe trials (spaced 3 min apart). Both ANI- and saline-treated mice searched selectively in the TQ in the first probe 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 of this selectivity over successive probe trials (saline: F(1,8) = 12.74, p < 0.05; ANI: F(1,9) = 26.60, p < 0.05) (Fig. 7C). In the final probe trial, neither the ANI- nor saline-treated mice showed a preference for the TQ, indicating extinction of the spatial memory (saline: F(3,32) = 1.70, p > 0.05; ANI: F(3,36) = 0.59, p > 0.05) (Fig. 7D). Therefore, ANI did not disrupt short-term extinction of spatial memories (for drug: F(1,17) = 2.07, p > 0.05; for time: F(9,153) = 35.24, p < 0.05; for drug x time: F(9,153) = 1.20, p > 0.05) (Fig. 7C). However, when these mice were tested 24 hr later, the ANI-treated, but not the saline-treated, mice searched selectively in the quadrant in which the platform was previously located (saline: F(3,32) = 1.32, p > 0.05; ANI: F(3,36) = 17.22, p < 0.05) (Fig. 7E). These results show that long-term extinction of a spatial memory is blocked by protein synthesis inhibition.
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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 spent swimming 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.
Discussion
There has been renewed interest in memory processing after retrieval: brief exposure to the CS seems to trigger a second wave of memory consolidation (reconsolidation), whereas prolonged exposure to the CS leads to the formation of a new memory that competes with the original memory (extinction). However, many of the findings supporting current views on reconsolidation, and extinctions 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., 2000aIn 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
The results presented here reveal three distinct time-dependent phases of memory processing after memory retrieval. During the first phase, the retrieved memory is in a state that precedes both the reconsolidation and extinction processes. Further extending reexposure, however, initiates the protein synthesis-dependent reconsolidation processes 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 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 to note that our results also indicate that there is an interaction between the extinction and reconsolidation processes: although blocking 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 at the time of CS reexposure in contextual fear conditioning and the 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 the reactivated memory or block long-term extinction (data not shown) 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 is determined in part by the duration of the reexposure. Whereas reconsolidation acts on the original memory (Nader et al., 2000a
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 not initial learning (Cain et al., 2002
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 easier to activate the reconsolidation of younger than older memories. Whereas initial encoding and storage of fear memories depend on the hippocampus, permanent storage is proposed to depend on the neocortex (Kim and Fanselow, 1992
Surprisingly, we also found that memory strength affected the ease of reconsolidation. Increasing the strength of memory (by increasing the number of shocks during training), increased the resistance of these fear memories to disruption by ANI. Similar to the 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
The studies presented here demonstrate the dynamic nature of memory processing after retrieval. They also identify three fundamental 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.
Footnotes
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 Ministry of Education, Science and Culture, Japan. We thank R. Costa for helpful discussions, invaluable comments, and critical 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{at}nodai.ac.jp.
DOI:10.1523/JNEUROSCI.5491-03.2004
Copyright © 2004 Society for Neuroscience 0270-6474/04/244787-09$15.00/0
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