Post-retrieval oxytocin facilitates next day extinction of threat memory in humans

Abstract

Rationale: Memories can return to a labile state and become amenable to modification by pharmacological and behavioral manipulations after retrieval. This process may reduce the impact of aversive memories and provide a promising therapeutic technique for the treatment of anxiety disorders. A growing body of evidence suggests that the mammalian neuropeptide oxytocin (OT) plays a role in the regulation of emotional memories in animals. However, the effects of OT on threat memory in humans remain largely unknown.

Objectives: This study aimed to investigate the effects of OT administration following threat memory retrieval on subsequent memory expression in human participants.

Methods: In a double-blind, randomized, placebo-controlled, between-subject design, 61 healthy human individuals completed a 3-day experiment. All the participants underwent threat conditioning on day 1. On day 2, the participants were randomized to receive an intranasal dose of OT (40 IU) or placebo after memory retrieval, or an intranasal dose of OT (40 IU) without retrieval. On day 3, the participants were tested for extinction and reinstatement.

Results: On day 3, all groups showed equivalent stimulus discrimination during the early phase of extinction. However, the group that received OT following a memory reminder showed a greater decline in stimulus discrimination by the late phase of extinction relative to the two other groups.

Conclusions: The results indicate that OT did not block reconsolidation to prevent the return of threat memory but rather interacted with post-retrieval processes to facilitate next day extinction. The study provides novel preliminary evidence for the role of OT in human threat memory.

Keywords: Extinction; Fear conditioning; Oxytocin; Reactivation; Reconsolidation.

Figure. 1. Schematic depiction of the experimental design.

Figure 2.. Stimulus discrimination during threat acquisition.

Means with 95% confidence intervals in each group during four blocks of acquisition. Confidence intervals that do not cross the vertical dashed line at zero indicate that the corresponding contrast is different from zero and thus statistically significant. The results show successful and similar acquisition in all groups.

Figure 3.. Stimulus discrimination during threat extinction.

Means with 95% confidence intervals in each group during four blocks of extinction. Confidence intervals that do not cross the vertical dashed line at zero indicate that the corresponding contrast is different from zero and thus statistically significant. A significant 3-way interaction of group x block x stimulus and follow-up t-tests confirmed memory recovery in all groups at the beginning of day 3 extinction (24 hours after drug administration), but only the group that had post-retrieval administration of OT showed successful and adequate extinction by the end of extinction session.

Figure. 4. The reduction of stimulus discrimination from block 1 to block 4 during extinction.

Paired sample t-tests confirmed significant and gradual reduction of stimulus discrimination (CS+ minus CS-) in the reminder+OT group (R+OT), but not in the reminder+placebo group (R+PLC) or the no reminder+OT group (NR+OT). *P < 0.05, ** P < 0.01. Error bars represent standard errors.

Figure 5.. Threat extinction index by treatment group.

Independent sample t-tests confirmed significantly higher extinction index (stimulus discrimination in first minus last block of extinction) in reminder+OT group (R+OT) compared to the no reminder+OT group (NR+OT). *P < 0.05, Error bars represent standard errors.

Figure 6.. Stimulus discrimination in reinstatement.

Means with 95% confidence intervals in each group of four blocks of reinstatement. Confidence intervals that do not cross the vertical dashed line at zero indicate that the corresponding contrast is different from zero and thus statistically significant. One-way ANOVA and paired sample t-tests confirmed that both reminder+placebo group (R+PLC) and no reminder+OT group (NR+OT) showed significant stimulus discrimination in the second block of reinstatement, and they are both significantly higher than reminder+OT group (R+OT).