Stability of recent and remote contextual fear memory

Abstract

Following initial encoding, memories undergo a prolonged period of reorganization. While such reorganization may occur in many different memory systems, its purpose is not clear. Previously, we have shown that recall of recent contextual fear memories engages the dorsal hippocampus (dHPC). In contrast, recall of remote contextual fear memories engages a number of different cortical regions, including the anterior cingulate cortex (ACC). To examine whether this reorganization leads to greater memory stability, we examined reconsolidation of 1 d-old (recent) and 36 d-old (remote) contextual fear memory in mice. We infused the protein synthesis inhibitor, anisomycin (ANI), into either the dHPC or ACC immediately following retrieval of either a recent or remote contextual fear memory. In the dHPC, ANI infusions disrupted subsequent expression of recent, but not remote, contextual fear memory. Similar infusions into the ACC had no effect on either recent or remote contextual fear memories, whereas systemically applied ANI blocked subsequent remote memory expression when long re-exposure durations were used. Together, these data suggest that as memories mature they become increasingly stable. Furthermore, the dissociation between the effects of systemically and centrally administered ANI on remote memory suggests that stability is due, in part, to the distributed nature of remote contextual fear memories.

Figure 1.

ANI infusions into the ACC attenuate Fos expression induced by systemic injections of PTZ. (A) Representative photomicrographs of ACC in mice receiving either PBS or ANI infusions into the ACC. PTZ induction of Fos is reduced by pretreatment with ANI. (B) Quantification of Fos expression in mice pretreated with PBS and ANI (*P < 0.05; see text for details). Number of Fos-positive nuclei per 100 × 100-μm field are shown.

Figure 2.

Systemic ANI injections attenuate cortex-wide Fos expression induced by systemic injections of PTZ. Representative photomicrographs of ACC (top), retrosplenial cortex (middle), and perirhinal cortex (bottom) in mice pretreated with either PBS or ANI. In each of these cortical regions, Fos expression is reduced in mice pretreated with ANI.

Figure 3.

Post-reactivation blockade of protein synthesis in dHPC. Intra-dHPC infusions of ANI following context re-exposure disrupted subsequent expression of recent (A), but not remote (B), contextual fear memory. The percent time spent freezing is shown during the training (TR), re-exposure (RE), and test phases (TE) of the experiment. A summary of the test freezing scores for these mice is shown in C. The destabilizing effects of intra-dHPC ANI on recent contextual fear memory are contingent on memory reactivation. When context re-exposure was omitted, ANI infusions into the dHPC had no effect on subsequent memory expression (D). Intra-dHPC infusions of ANI also block reconsolidation of a weaker contextual fear memory. In this experiment, mice were trained with one, rather than three shocks (E). Significant differences are marked by an asterisk (*P < 0.05, see text for details).

Figure 4.

Post-reactivation blockade of protein synthesis in the ACC. Intra-ACC infusions of ANI following context re-exposure did not disrupt subsequent expression of recent (A), or remote (B), contextual fear memory. The percent time spent freezing is shown during the training (TR), re-exposure (RE), and test phases (TE) of the experiment. A summary of the test freezing scores for these mice is shown in C.

Figure 5.

Effects of context re-exposure duration on reconsolidation of remote contextual fear memory. For each experiment, the percent time spent freezing is shown during the training (TR), re-exposure (RE), and test phases (TE) of the experiment. (A) Intra-ACC infusions of ANI had no effect on subsequent expression of remote contextual fear memory using either 10- or 15-min context re-exposures. These test data are summarized in the graph on the far right. (B) Systemic injections of ANI blocked reconsolidation of remote contextual fear memory only when the longer (15-min) context re-exposure was used. These test data are summarized in the graph on the far right. (C) Systemic injection of ANI immediately following (rather than preceding) a 15-min re-exposure also blocks reconsolidation (left). The destabilizing effects of ANI on remote contextual fear memory are contingent on memory reactivation. When context re-exposure was omitted, systemic ANI injections had no effect on subsequent memory expression (right). Significant differences are marked by an asterisk (*P < 0.05, see text for details).