Postretrieval Relearning Strengthens Hippocampal Memories via Destabilization and Reconsolidation

Abstract

Memory reconsolidation is hypothesized to be a mechanism by which memories can be updated with new information. Such updating has previously been shown to weaken memory expression or change the nature of the memory. Here we demonstrate that retrieval-induced memory destabilization also allows that memory to be strengthened by additional learning. We show that for rodent contextual fear memories, this retrieval conditioning effect is observed only when conditioning occurs within a specific temporal window opened by retrieval. Moreover, it necessitates hippocampal protein degradation at the proteasome and engages hippocampal Zif268 protein expression, both of which are established mechanisms of memory destabilization-reconsolidation. We also demonstrate a conceptually analogous pattern of results in human visual paired-associate learning. Retrieval-relearning strengthens memory performance, again only when relearning occurs within the temporal window of memory reconsolidation. These findings link retrieval-mediated learning in humans to the reconsolidation literature, and have potential implications both for the understanding of endogenous memory gains and strategies to boost weakly learned memories.SIGNIFICANCE STATEMENT Memory reconsolidation allows existing memories to be updated with new information. Previous research has demonstrated that reconsolidation can be manipulated pharmacologically and behaviorally to impair problematic memories. In this article, we show that reconsolidation can also be exploited to strengthen memory. This is shown both in rats, in a fear memory setting, and in a human declarative memory setting. For both, the behavioral conditions necessary to observe the memory strengthening match those that are required to trigger memory reconsolidation. There are several behavioral approaches that have previously been shown convincingly to strengthen memory. The present demonstration that reconsolidation can underpin long-lasting memory improvements may both provide an underlying mechanism for such approaches and provide new strategies to boost memories.

Keywords: destabilization; fear conditioning; memory; reconsolidation; retrieval.

Figure 1.

Combination of retrieval and conditioning strengthened contextual fear memory via destabilization and reconsolidation. A, Previously weakly conditioned rats were subjected to retrieval and conditioning on day 2, and were tested again on days 4 and 11. B, With a 15 min interval between retrieval and conditioning on day 2, contextual freezing was increased at the tests compared with when there was no interval. C, There was a similar increase in freezing with a 1 h interval, but not with a 6 h interval. D, Schematic representing the infusion of β-lac into the dorsal hippocampus before retrieval or conditioning within the retrieval-1 h-relearning procedure. E, Infusion of β-lac prevented contextual fear memory strengthening. F, Schematic of the behavioral procedures for the Zif268 expression experiments. G, Retrieval-conditioning, but not retrieval alone, reliably elevated Zif268 levels compared with a nonreactivated control condition, as assessed through Western blots. H, Zif268 expression was also assessed with flow cytometry (image shows representative sample with events plotted according to size [forward scatter (FSC)] and cell granularity [side scatter (SSC)], allowing the isolation of cells from debris and illustrating distinct populations of labeled events [DAPI +ve (blue), NeuN +ve (purple), Zif268 +ve (green), and negative/debris (black)]. I, Flow cytometry also showed an increase in Zif268 expression in retrieval-conditioning. Data are presented as the mean + SEM.

Figure 2.

Retrieval-conditioning strengthens contextual fear memory more reliably than other combinations of experiences. A, With a 15 min interval, both retrieval-conditioning and conditioning-retrieval show greater strengthening than retrieval-retrieval. B, With a 1 h interval, retrieval-conditioning strengthened contextual fear to a greater degree than conditioning-retrieval, and to an equivalent degree as double conditioning. C, D, Conditioning-retrieval with a 1 h interval did not upregulate Zif268 expression as assessed with Western blots (C) and flow cytometry (D). Data are presented as the mean + SEM.

Figure 3.

Retrieval-relearning improves human visual paired-associate memory performance. A, Previously weakly learned paired associates were retrieved and/or relearned after 2 d, and tested again 2 d later. B, Test performance was increased by retrieval-relearning, but also by relearning-retrieval. C, When the same experience was repeated, only relearning-relearning improved memory performance. D, When the interval between retrieval and relearning was increased to 6 h, the memory-strengthening effect of retrieval-relearning was decreased, but that of relearning-retrieval was not. E, When participants were instructed to verbalize the answer at the retrieval session, there was no beneficial effect of the retrieval when conducted before relearning. Data are presented as the mean strengthening score (test performance − learning performance) +/− SEM.