An Unconditioned Stimulus Retrieval Extinction Procedure to Prevent the Return of Fear Memory

Background: Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear. Methods: In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Results: Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. Conclusions: These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear.