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. 2011 Feb 2;31(5):1635-43.
doi: 10.1523/JNEUROSCI.4736-10.2011.

Memory Retrieval and the Passage of Time: From Reconsolidation and Strengthening to Extinction

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Free PMC article

Memory Retrieval and the Passage of Time: From Reconsolidation and Strengthening to Extinction

Maria Carmen Inda et al. J Neurosci. .
Free PMC article

Abstract

An established memory can be made transiently labile if retrieved or reactivated. Over time, it becomes again resistant to disruption and this process that renders the memory stable is termed reconsolidation. The reasons why a memory becomes labile after retrieval and reconsolidates still remains debated. Here, using inhibitory avoidance learning in rats, we provide evidence that retrievals of a young memory, which are accompanied by its reconsolidation, result in memory strengthening and contribute to its overall consolidation. This function associated to reconsolidation is temporally limited. With the passage of time, the stored memory undergoes important changes, as revealed by the behavioral outcomes of its retrieval. Over time, without explicit retrievals, memory first strengthens and becomes refractory to both retrieval-dependent interference and strengthening. At later times, the same retrievals that lead to reconsolidation of a young memory extinguish an older memory. We conclude that the storage of information is very dynamic and that its temporal evolution regulates behavioral outcomes. These results are important for potential clinical applications.

Figures

Figure 1.
Figure 1.
Multiple reactivations result in memory strengthening. A, B, Experimental timelines for each panel are shown. Memory acquisition (Tr) and retention are expressed as mean latency ± SEM (in seconds, s). Rats were trained (Tr) and either reactivated (1R) by testing (T1, A) or 10 s context exposure (B) 2 d after training, or remained in the home cage (NR). All rats were tested 4 d after training. At testing, no significant differences in latencies were found between each 1R and NR groups. C, Rats were trained and underwent reactivation by testing 3 times with an interreactivation interval of 2 d (3R). A control group was trained and remained in the home cage (NR). All animals were tested 8 d after training (final test, FT). One day later, they received a reminder footshock (S) and, were re tested 24 h later (RT). FT of rats that underwent reactivations showed a significant latency decrease compared with T1 or NR (**p < 0.01) that was reinstated by S (*p < 0.05). D, Rats were trained and, 2 d later, reactivated by three 10 s context exposures with 2 d interreactivation interval (3 × 10 s); a control group was trained and received three 10 s exposures to a different context (Context B, Cnt), another control group remained in the home cage (NR). At testing (T), the 3 × 10 s group showed a significant increase in latency compared with the NR group (**p < 0.01). E, Rats were trained and reactivated, by either testing (3 × T), or 3 × 10 s, with an interreactivation interval of 1week, or remained in the home cage (NR). Both groups that underwent either type of reactivations showed a significant increase in latency compared with NR (*p < 0.05, **p < 0.01).
Figure 2.
Figure 2.
Recent but not remote memories are strengthen by reconsolidation and are susceptible to be disrupted by protein synthesis inhibitors (PSI). A, Experimental timelines are shown above each experiment. Memory acquisition (Tr) and retention are expressed as mean latency ± SEM (in seconds, s). Rats were trained and underwent either 3 × 10 s reactivations starting 2 d after training or remained in the home cage (NR). Both groups were injected immediately after each reactivation, or at paired time points, with either cycloheximide (Cyc) or vehicle (Veh) and tested 8 d after training (T). At T, 3 × 10 s reactivations significantly increased latency (**p < 0.01). Cycloheximide significantly disrupted this latency (***p < 0.001), which was decreased below that of cycloheximide-NR (**p < 0.01). B, Rats were trained and, 8 d after training, underwent one single 10 s reactivation and two injections (one 15 min before and one immediately after reactivation) of either cycloheximide or vehicle. At testing (T1), 2 d later, cycloheximide significantly disrupted latency compared with vehicle (**p < 0.01). Retention did not reinstated after a shock reminder (S, T2, ***p < 0.001). C, Rats followed the same protocol as in (b), but received 3 × 10 s reactivations starting 2 d after training. Cycloheximide failed to affect latency at testing (T). D, Compared with vehicle, cycloheximide, injected at matched time points as in B and C, had no effect. E, Rats that underwent either 3 × 10 s reactivations 2weeks after training with an interreactivation interval of 2 d or NR had similar, strong latencies at testing, 20 d after training. F, Rats underwent the same reactivation protocol as in E and were injected with either cycloheximide or vehicle after each reactivation. At testing (T), no difference was found between groups.
Figure 3.
Figure 3.
Multiple reactivations make the memory resistant to forgetting. Experimental timelines are shown above the experiment. Animals were trained and divided in 4 groups: one group was tested 2 d after training (NR T2d), the second was tested 20 d after training (NR T20d); the third was tested 55 d after training (NR T55d). The last group underwent 3 × 10 s reactivations starting 2 d after training and with an interreactivation interval of 2 d, and was tested 55 d after training (3R T55d). NR T20d had a significantly stronger latency compared with NR T2d (*p < 0.05). The latency of NR T55d was significantly decreased compare with that of NR T20d (**p < 0.01). This decay of latency was completely rescued in 3R T55d (**p < 0.01).
Figure 4.
Figure 4.
Retrievals of a 4-week-old memory lead to a facilitation of extinction. Experimental timelines are shown on top. The animals were trained and divided into two groups. The first group (1) was tested 34 d after training. The second group (2) underwent 3 × 10 s reactivations starting 28 d after training with an interreactivation interval of 2 d. Both groups were tested 34 d after training (T1). At T1, group 2 had a significantly lower latency than group 1 (*p < 0.05). group 2 underwent a footshock reminder (S) 1 d after T1 and was tested again 1 d later (T2). At T2, latency was significantly higher compared with T1 (*p < 0.05). The group 1, after T1, underwent the same reactivation protocol as group 2 and was tested 2 d later (T2). This T2 latency was significantly lower than that of T1 (*p < 0.05). A reminder footshock (S), given 1 d later, resulted in a significant recovery of the latency at Test 3 the following day (**p < 0.01).

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