Repeated labilization-reconsolidation processes strengthen declarative memory in humans

Abstract

The idea that memories are immutable after consolidation has been challenged. Several reports have shown that after the presentation of a specific reminder, reactivated old memories become labile and again susceptible to amnesic agents. Such vulnerability diminishes with the progress of time and implies a re-stabilization phase, usually referred to as reconsolidation. To date, the main findings describe the mechanisms associated with the labilization-reconsolidation process, but little is known about its functionality from a biological standpoint. Indeed, two functions have been proposed. One suggests that destabilization of the original memory after the reminder allows the integration of new information into the background of the original memory (memory updating), and the other suggests that the labilization-reconsolidation process strengthens the original memory (memory strengthening). We have previously reported the reconsolidation of human declarative memories, demonstrating memory updating in the framework of reconsolidation. Here we deal with the strengthening function attributed to the reconsolidation process. We triggered labilization-reconsolidation processes successively by repeated presentations of the proper reminder. Participants learned an association between five cue-syllables and their respective response-syllables. Twenty-four hours later, the paired-associate verbal memory was labilized by exposing the subjects to one, two or four reminders. The List-memory was evaluated on Day 3 showing that the memory was improved when at least a second reminder was presented in the time window of the first labilization-reconsolidation process prompted by the earlier reminder. However, the improvement effect was revealed on Day 3, only when at least two reminders were presented on Day 2 and not as a consequence of only retrieval. Therefore, we propose central concepts for the reconsolidation process, emphasizing its biological role and the parametrical constrains for this function to be operative.

Figure 1. Memory strengthening by repeated triggering of labilization-reconsolidation.

A) Experiment 1A (n = 13). A.1) Experimental protocol. A three-day experiment. TR, stands for the training session, R_c for the cue reminder, and TS for the testing session. Groups differ in the number of reminders that they received on Day 2. Group R_c received a cue reminder, Group R_cx2 received two cue reminders, and Group R_cx4 received the cue reminder four times. A.2) Testing session. Mean number of total errors +/- SEM on Day 3. *, p<0,05. Black bar stands for Group R_c, white bar for Group R_cx2 and stripe bar for the Group R_cx4. A.3) Error Type. A.3.1) Mean number of Void-type errors +/− SEM on Day 3. A.3.2) Intralist-type errors A.3.3) Confusion-type errors. Symbols as above. B) Experiment 1B (n = 10). B.1) Experimental protocol. A three-day experiment. Symbols as in experiment 1A. Group R_c received a cue reminder on Day 2 and Group received no reminder. B.2) Testing session. Mean number of total errors +/− SEM on Day 3. Black bar stands for Group R_c, grey bar for Group no-R. B.3) Error Type. B.3.1) Mean number of Void-type errors +/− SEM on Day 3. B.3.2) Intralist-type errors B.3.3) Confusion-type errors. Symbols as above.

Figure 2. Experiment 2 (n = 10).

Successive retrievals do not strengthen the declarative memory. A) Experimental protocol. A three-day experiment. Symbols as in experiment 1, R_c-r stands for the cue-response reminder. Group R_c received a cue reminder, Group R_c-rx2 received the cue-response reminder twice. B) Testing session. Mean number of total errors +/− SEM on Day 3. Black bar stands for Group R_c, grey bar for Group R_c-rx2. C) Error Type. C.1) Mean number of Void-type errors +/− SEM on Day 3. C.2) Intralist-type errors C.3) Confusion-type errors. Symbols as above.

Figure 3. Experiment 3 (n = 10).

Memory strengthening by repeated labilization processes is not expressed before reconsolidation takes place. A) Experimental protocol. A two-day experiment. On Day 1 subjects received the training (TR), on Day 2 they received the cue reminder (R_c) before being tested (TS). Group R_c-ST received a cue reminder, Group R_cx2-ST received the cue reminder twice. B) Testing session. Mean number of total errors +/− SEM on Day 2. Black bar stands for Group R_c-ST, grey bar for Group R_cx2-ST C) Error Type. C.1) Mean number of Void-Type errors +/− SEM on Day 2. C.2) Intralist-type errors C.3) Confusion-type errors. Symbols as above.

Figure 4. Experiment 4 (n = 12) and 5 (n = 10).

Strengthening effect of repeated reactivations only appears when the second labilization occurs in the time window during the first. A) Experimental protocols. A.1) A four-day experiment. On Day 1 subjects received the training session (TR), on Day 2 they received the cue reminder (R_c), on Day 3 only one Group received the cue reminder, and subjects were tested on Day 4 (TS). Group R_c received a cue reminder on Day 2, but received no treatment on Day 3. Group R_cx2-24h received the cue reminder on Day 2 and 3. A.2) A three-day experiment. Symbols as in experiment 1, R_ctx stands for the context reminder. Groups differ in the number of reminders that they received on Day 2. Group R_c received a cue reminder, Group R_cx2 received two cue reminders separated by 2 hours, and Group R_cR_ctx-2h received a cue reminder and a context separated by 2 hours. B) Experiment 4, testing session. Mean number of total errors +/− SEM on Day 4. Black bar stands for Group R_c, grey bar for Group R_cx2-24h. C) Experiment 4, error type. C.1) Mean number of Void-Type errors +/− SEM on Day 4. C.2) Intralist-type errors C.3) Confusion-type errors. Symbols as above. D) Experiment 5, testing session. Mean number of total errors +/− SEM on Day 3. *, p<0,05. White bar stands for Group R_cx2, striped bar for Group R_cx2-2h and grey bar for the Group R_cR_ctx-2h. E) Experiment 5, error type. E.1) Mean number of Void-Type errors +/− SEM on Day 3. E.2) Intralist-type errors E.3) Confusion-type errors. Symbols as above. ***, p<0,001.

Figure 5. Experimental Protocol.

A) Actual trial. It was formed by the context period: specific combination of a light (color illumination of the room), image (a picture on the monitor) and sound (music melody from earphones); and by a syllable period: six seconds after the stimuli presentation, five pairs of cue-response syllables were presented successively and in random order. B) Paired-associated memory. The List presented in the training and testing sessions. C) Types of reminders. (Top diagram) The cue reminder (R_c) included the specific context, subjects had to press the expectancy keys (YES-NO), then one cue-syllable was presented after which the trial was abruptly interrupted, thus not allowing the subject to answer with the respective response-syllable. (Middle diagram) The context reminder (R_ctx) consisted of the presentation of specific context, subjects had to press the expectancy keys (YES-NO) and the trial was abruptly interrupted before any syllable presentation. (Bottom diagram) The cue-response reminder (R_c-r) included the specific context, subjects had to press the expectancy keys (YES-NO), then one cue-syllable was presented and subjects were allowed to write down the first response-syllable and after that the trial was interrupted. Scissors stand for the full-stop of each type of reminder.