Retrieval and Reconsolidation Accounts of Fear Extinction

Abstract

Extinction is the primary mode for the treatment of anxiety disorders. However, extinction memories are prone to relapse. For example, fear is likely to return when a prolonged time period intervenes between extinction and a subsequent encounter with the fear-provoking stimulus (spontaneous recovery). Therefore there is considerable interest in the development of procedures that strengthen extinction and to prevent such recovery of fear. We contrasted two procedures in rats that have been reported to cause such deepened extinction. One where extinction begins before the initial consolidation of fear memory begins (immediate extinction) and another where extinction begins after a brief exposure to the consolidated fear stimulus. The latter is thought to open a period of memory vulnerability similar to that which occurs during initial consolidation (reconsolidation update). We also included a standard extinction treatment and a control procedure that reversed the brief exposure and extinction phases. Spontaneous recovery was only found with the standard extinction treatment. In a separate experiment we tested fear shortly after extinction (i.e., within 6 h). All extinction procedures, except reconsolidation update reduced fear at this short-term test. The findings suggest that strengthened extinction can result from alteration in both retrieval and consolidation processes.

Keywords: anxiety disorders; consolidation; extinction; fear; memory; reconsolidation.

Figure 1

Schema of Experiment 1. Tone; 77dB; 30 s each, Shock = 0.8 mA; 2 s each, Inter trial interval (ITI) = 2 min during fear conditioning in context A. Fear conditioning was done on Day-1 and extinction, test 1 and test 2 were done on Day-4, 5 and 25 respectively. On extinction day in context B, Ret-Ext and Ext-Ret groups received a retrieval session consisting of three massed tones, 5 s ITI and extinction session consisted of 50 massed tones, 5 s ITI. Retrieval and extinction sessions were 10 min apart.

Figure 2

Attenuation of fear memory after various extinction procedures. Graphs show fear and extinction learning curves (A,B) and extinction memory during a memory test carried out 1 and 21 day(s) after the end of each extinction procedure in context B (C,D). Mean ± SEM freezing during Baseline (BL) and tone for all rats were measured. (A) Fear acquisition. Rats were fear conditioned with 4 tone-shock pairings on Day-1 in context A. All animals acquired cue fear. (B) Fear retrieval and extinction. Rats received retrieval and extinction procedures in context B on Day-4. Immediate extinction group was fear conditioned in Context A with four tone-shock pairings and 10 min later they received normal fear extinction session in context B. Each data point for extinction trials represent the average of 3 CSs except the 17th data point that represents average of 2 CSs totaling 53 CSs. Data point after the line break represent the average of 3 retrieval CSs for Ret-Ext and Ext-Ret groups. All rats showed significant within session extinction learning on Day-4. (C) Fear extinction memory test. As a measure of extinction memory, rats received 4 tone presentations in context B on Day-5. (D) Spontaneous recovery test. Rats received four tone presentations in context B on Day-26. Normal Ext group showed freezing similar to No Ext group suggesting significant spontaneous recovery of fear. Ret-Ext, Ext-Ret and Immediate Ext groups showed no spontaneous recovery of fear. One-Way ANOVA with Tukey’s multiple comparison test was used for Days-5 and 26. (ns, not significant; **P < 0.01; ***P < 0.001 vs. No Extinction (C,D). ⁺P < 0.05 vs. Normal Extinction (D). Groups: No Ext, no extinction; Normal Ext, normal extinction; Ret Ext, retrieval first + extinction; Ext—Ret, extinction + retrieval later; Immediate Ext, Fear conditioning first + immediate extinction. Rats were tested repeatedly on Day-5 and Day-26.

Figure 3

Schema of Experiment 2. Tone; 77dB; 30 s each, Shock = 0.8 mA; 2 s each, Inter trial interval (ITI) = 2 min during fear conditioning in context A. Fear conditioning was done one Day-1 and extinction was done on Day-4. Short-term test was done 3.25 h after extinction procedures on Day-4. Long-term test was done 24 h after extinction procedures on Day-5. On extinction day in context B, Ret—Ext and Ext—Ret groups received a retrieval session consisted of 3 massed tones, 5 s ITI and extinction session consisted of 50 massed tones, 5 s ITI. Retrieval and extinction sessions were 10 min apart.

Figure 4

Rats failed to show extinction memory 3.25 h after successful retrieval—extinction session. (A) Fear acquisition. Rats were fear conditioned with four tone-shock pairings on Day-1 in context A. All animals acquired cue fear. (B) Fear retrieval and extinction. Rats received retrieval and extinction procedures in context B on Day-4. Immediate extinction group was fear conditioned in Context A with four tone-shock pairing and 10 min later they received normal fear extinction session in context B. All groups showed significant within session extinction learning on Day-4. Each data point for extinction trials represent average of 3 CSs except the 17th data point that represents average of 2 CSs totaling 53 CSs. Data point after the line break represent the average of 3 retrieval CSs for Ret-Ext and Ext-Ret groups. (C) Short-term fear extinction memory test. Rats received four tone only presentations in context B 3.25 h after the extinction procedures. Normal Ext, Ext-Ret, Immediate Ext groups showed significant low fear memory where as Ret-Ext group showed no traces of extinction memory in this test. Extinction during reconsolidation did not cause immediate memory erasure. One-Way ANOVA with Tukey’s multiple comparison test was used for Day-4. (ns, not significant; **P < 0.01; ***P < 0.001 vs. No Extinction (C). ⁺P < 0.05; ⁺⁺P < 0.01 vs. Ret-Ext. Groups: No Ext, no extinction; Normal Ext, normal extinction; Ret-Ext, retrieval first + extinction; Ext-Ret, extinction + retrieval later; Immediate Ext, Fear conditioning first + immediate extinction. To avoid any potential confounding effect of the test by itself, rats tested in short-term memory after extinction were not used on 24 h memory test.

Figure 5

Good extinction memory 24 h after successful retrieval—extinction session. (A) Fear acquisition. Rats were fear conditioned with four tone-shock pairings on Day-1 in context A. All animals acquired cue fear. (B) Fear retrieval and extinction. Rats received retrieval and extinction procedures in context B on Day-4. Immediate extinction group was fear conditioned in Context A with four tone-shock pairings and 10 min later they received normal fear extinction session in context B. All groups showed significant within session extinction learning on Day-4. Each data point for extinction trials represent average of 3 CSs except the 17th data point that represents average of 2 CSs totaling 53 CSs. Data point after the line break represent the average of 3 retrieval CSs for Ret-Ext and Ext-Ret groups. (C) Long-term fear extinction memory test. Rats received four tone only presentations in context B 24 h after the extinction procedures. Normal Ext, Ret-Ext, Ext-Ret, Immediate Ext groups showed significant low fear memory. One-Way ANOVA with Tukey’s multiple comparison test was used for Day-4.) (**P < 0.01, ***P < 0.001 vs. No Ext). Groups: No Ext, no extinction; Normal Ext, normal extinction; Ret-Ext, retrieval first + extinction; Ext-Ret, extinction + retrieval later; Immediate Ext, Fear conditioning first + immediate extinction. To avoid any potential confounding effect of the test by itself, different groups of rats were tested in the short-term memory and 24 h memory tests.