Integration of New Information with Active Memory Accounts for Retrograde Amnesia: A Challenge to the Consolidation/Reconsolidation Hypothesis?

Abstract

Active (new and reactivated) memories are considered to be labile and sensitive to treatments disrupting the time-dependent consolidation/reconsolidation processes required for their stabilization. Active memories also allow the integration of new information for updating memories. Here, we investigate the possibility that, when active, the internal state provided by amnesic treatments is represented and integrated within the initial memory and that amnesia results from the absence of this state at testing. We showed in rats that the amnesia resulting from systemic, intracerebroventricular and intrahippocampal injections of the protein synthesis inhibitor cycloheximide, administered after inhibitory avoidance training or reactivation, can be reversed by a reminder, including re-administration of the same drug. Similar results were obtained with lithium chloride (LiCl), which does not affect protein synthesis, when delivered systemically after training or reactivation. However, LiCl can induce memory given that a conditioned taste aversion was obtained for a novel taste, presented just before conditioning or reactivation. These results indicate that memories can be established and maintained without de novo protein synthesis and that experimental amnesia may not result from a disruption of memory consolidation/reconsolidation. The findings more likely support the integration hypothesis: posttraining/postreactivation treatments induce an internal state, which becomes encoded with the memory, and should be present at the time of testing to ensure a successful retrieval. This integration concept includes most of the previous explanations of memory recovery after retrograde amnesia and critically challenges the traditional memory consolidation/reconsolidation hypothesis, providing a more dynamic and flexible view of memory.

Significance statement: This study provides evidence challenging the traditional consolidation/reconsolidation hypotheses that have dominated the literature over the past 50 years. Based on amnesia studies, that hypothesis states that active (i.e., new and reactivated) memories are similarly labile and (re)established in a time-dependent manner within the brain through processes that require de novo protein synthesis. Our data show that new/reactivated memories can be formed without protein synthesis and that amnesia can be induced by drugs that do not affect protein synthesis. We propose that amnesia results from memory integration of the internal state produced by the drug that is subsequently necessary for retrieval of the memory. This interpretation gives a dynamic view of memory, rapidly stored and easily updated when active.

Keywords: amnesia; consolidation; malleability; memory reactivation; reconsolidation; state dependency.

Figure 1.

Cyclo after conditioning induces amnesia that is reversible with exposure to a reminder or Cyclo. A, Timeline of the experiment. During conditioning, rats were placed in the white compartment of a double box and received two electrical footshocks after entering the black compartment. Pseudoconditioned rats were exposed to the conditioning context but not shocked. All groups of rats (n = 5 to 10; see B, C) were injected twice with intraperitoneal injections with either Cyclo (2.8 mg/kg) or Sal, once just after the end of conditioning and the other 30 min before the retention test, except one group that was exposed to a reminder (45 s exposure to the safe white compartment), 5 min before testing. During testing occurring 48 h after conditioning, rats were placed in the white compartment, and their latency to enter the black compartment was registered (cutoff at 600 s). B, Experiment 1a, Mean ± SEM response latency obtained during the test, 48 h after inhibitory avoidance conditioning with a 0.3 mA electrical footshock, or pseudoconditioning. C, Experiment 1b, Mean ± SEM response latency obtained during the test, 48 h after inhibitory avoidance conditioning with a 0.5 mA electrical footshock. **p < 0.05 versus Sal–Sal; ***p < 0.001 versus Sal–Sal; ⁺p < 0.05 versus Cyclo–Sal; ∧p < 0.05 versus Sal–Sal; ^#p < 0.07 versus Cyclo–Sal. D, Experiment 1b, Mean ± SEM weight obtained during the conditioning day (white bars) and the following day (black bars) in rats receiving a postconditioning injection of Sal or Cyclo. ***p < 0.001 significant groups × treatment interaction.

Figure 2.

Peripheral and central administration of Cyclo after reactivation of memory induces amnesia that is reversible with exposure to Cyclo. A, Timeline of the experiment. Reactivation (15 s exposure to the safe white compartment) or no reactivation took placed 48 h after conditioning. All groups of rats (n = 6–10; see B–E) received two injections: one given after reactivation (immediately or 6 h later) and one given 30 min before testing. Rats were injected with Cyclo (2.8 mg/kg) or Sal. The retention test occurred 48 h after the reactivation. B, Experiment 2a, Mean ± SEM response latency obtained during the test, 48 h after inhibitory avoidance conditioning, for rats given intraperitoneal injections. **p < 0.01 versus RSal–Sal; ⁺⁺p < 0.01 versus RCyclo–Cyclo. C, Experiment 2b, Preexposure to Cyclo 1 week before conditioning did not affect the memory deficits produced by Cyclo treatment after a reactivation. *p < 0.05 versus RSal–Sal; ⁺p < 0.05 versus RCyclo–Cyclo. D, Experiment 3, Mean ± SEM response latency obtained for rats given intraventricular infusion. **p < 0.01 versus RSal–Sal; ⁺p < 0.05 versus RCyclo–Cyclo. E, Experiment 4, Mean ± SEM response latency obtained for rats given intrahippocampal infusion. ***p < 0.001 versus RVeh–Veh; ⁺⁺⁺p < 0.001 versus RCyclo–Cyclo.

Figure 3.

LiCl after conditioning induces CTA and inhibitory avoidance amnesia that is reversible with exposure to a reminder or LiCl. A, Timeline of experiment. After sucrose (S) exposure, groups of rats (n = 9–11; see B) received one injection of LiCl (0.25 m; 300 mg/kg) or Sal just after conditioning and another injection of Sal or LiCl (0.15 m; 127 mg/kg) 30 min before the retention test. Another group that received an LiCl injection after conditioning and was exposed to the reminder, 5 min before testing. B, Experiment 5, Mean ± SEM response latency obtained during the test, 48 h after inhibitory avoidance conditioning or pseudoconditioning. ***p < 0.001 versus Sal; ⁺⁺p < 0.01 versus LiCl. C, Experiment 5, Values displayed as mean ± SEM amount of sucrose intake obtained during the CTA occurring 48 h after exposure to the sucrose solution and the inhibitory avoidance conditioning test or pseudoconditioning. ***p < 0.001 versus Sal; ⁺⁺p < 0.05 versus LiCl; ^#p < 0.05 versus LiCl60. D, Experiment 5, Mean ± SEM weight obtained in nondeprived rats receiving an injection of Sal or Cyclo, 1 week after testing (white bars) and the following day (black bars). **p < 0.01 versus Sal.

Figure 4.

LiCl after reactivation of memory induces CTA and inhibitory avoidance amnesia that is reversible with exposure to LiCl. A, Timeline of experiment. Reactivation or no reactivation took placed just after sucrose exposure, 48 h after conditioning or pseudoconditioning. All groups of rats (n = 7–9; B, C) received a Sal or LiCl (0.25 m; 300 mg/kg) injection delivered either just after the end of reactivation or 120 min later. The CTA occurred 48 h after memory reactivation. B, Experiment 6a, Values displayed as mean ± SEM response latency obtained during the test, 48 h after reactivation of inhibitory avoidance conditioning. C, Experiment 6a, Values displayed as mean ± SEM amount of sucrose intake obtained during the test for CTA. **p < 0.01 versus RSal; ***p < 0.001 versus RSal. D, Experiment 6b, In this experiment, rats received an additional injection of Sal or LiCl (0.15 m; 127 mg/kg), 30 min before the retention test. Values displayed mean ± SEM response latency obtained during the test, 48 h after reactivation of inhibitory avoidance conditioning. ***p < 0.001 versus RSal versus rSal–Sal. E, Experiment 6b, Values displayed as mean ± SEM amount of sucrose intake obtained during the CTA test. **p < 0.01 versus RSal–Sal; ***p < 0.001 versus RSal–Sal.