Memory reconsolidation and extinction have distinct temporal and biochemical signatures

Abstract

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.

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).

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).

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).

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.

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.

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.

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.