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

Abstract

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. In the present study, we introduced a technique to target all diverse cues associated with an aversive event that causes fear. Methods In the human experiments, the 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 the animal experiments, rats underwent contextual fear conditioning under a similar protocol as the used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Results We found that presentation of a lower-intensity US following extinction disrupted the associations between the different CSs and reactivated US in both humans and rats. This disruptive 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 AMPA 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.

Effect of Selective Inhibition of Reactivated Nicotine-Associated Memories With Propranolol on Nicotine Craving

“…14,21,61,62 However, with few exceptions, 45,63 the “translation” of these preclinical studies to people addicted to drugs has not been successful. 25–27 This situation, and the realization that a major limitation of CS-induced retrieval and reconsolidation procedures is their specificity to the reactivated CS, 28,29,33 inspired us to develop an alternative procedure in which the drug-reward memories are reactivated by exposure to the drug itself (the UCS).…”

Selective Inhibition of Amygdala Neuronal Ensembles Encoding Nicotine-Associated Memories Inhibits Nicotine Preference and Relapse

“…However, as mentioned in the introductory paragraphs, with few exceptions (15,16), the translation of these preclinical studies to human addicts has not been successful (19–21). This state of affairs, and the realization that a major limitation of CS-induced retrieval and reconsolidation procedures is that the neuropharmacological manipulations interfere only with reconsolidation of memories selectively associated with the reactivated CS without affecting memories associated with other CSs or the UCS itself (25–27), inspired us to develop alternative memory reconsolidation interference procedures where the drug reward memory is reactivated by exposure to the drug itself (the UCS).…”

“…Based on these considerations and results from threat (fear) conditioning studies showing that interference with memory reconsolidation after memory retrieval by the UCS (aversive shock) prevents subsequent threat conditioning induced by multiple CSs (25–27), we recently developed a UCS-induced memory retrieval–reconsolidation interference procedure and demonstrated its efficacy in decreasing cocaine relapse and craving in rat models (22). However, a limitation of the procedure we introduced in Luo et al .…”

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

“…Crude cytoplasmic and synaptosomal membrane fractions were collected based on our previous studies (Chai et al, 2014;Jian et al, 2014;Liu et al, 2014;Lu et al, 2005). After decapitation, the brains were rapidly extracted and frozen in − 60°C N-hexane.…”