Preventing the return of fear using reconsolidation updating and methylene blue is differentially dependent on extinction learning

Abstract

Many factors account for how well individuals extinguish conditioned fears, such as genetic variability, learning capacity and conditions under which extinction training is administered. We predicted that memory-based interventions would be more effective to reduce the reinstatement of fear in subjects genetically predisposed to display more extinction learning. We tested this hypothesis in rats genetically selected for differences in fear extinction using two strategies: (1) attenuation of fear memory using post-retrieval extinction training, and (2) pharmacological enhancement of the extinction memory after extinction training by low-dose USP methylene blue (MB). Subjects selectively bred for divergent extinction phenotypes were fear conditioned to a tone stimulus and administered either standard extinction training or retrieval + extinction. Following extinction, subjects received injections of saline or MB. Both reconsolidation updating and MB administration showed beneficial effects in preventing fear reinstatement, but differed in the groups they targeted. Reconsolidation updating showed an overall effect in reducing fear reinstatement, whereas pharmacological memory enhancement using MB was an effective strategy, but only for individuals who were responsive to extinction.

Data-driven criteria to assess fear remission and phenotypic variability of extinction in rats

“…Study 2 used data from 215 subjects from two published studies [10,11]. Auchter et al [10] included 124 male Sprague-Dawley rats, acquired from Harlan (now Envigo) (250-300 g).…”

“…Subjects underwent fear conditioning, extinction and reinstatement as described in two published studies [10,11]. Briefly, rats were habituated to the context for 10 min [10] or 15 min [11] the day prior to fear conditioning. Fear conditioning consisted of three 20 s presentations of a tone CS co-terminating with a 0.7 mA footshock.…”

“…a different ITI between each CS), and the average ITI was either 1 min or 2 min. In Auchter et al [11], all subjects received variable extinction ITIs, and the average ITI was 2 min in all groups. However, following extinction, half of the subjects were given an injection of mitochondrial enhancer USP methylene blue, while the other half received saline.…”

Neurochemical and molecular mechanisms underlying the retrieval-extinction effect

“…animals that are poor at extinction learning do not appear to benefit from DCS administration. However, despite the common reduction in fear reinstatement, there appear to be differences in the mechanisms underlying the attenuation of fear produced by DCS and retrieval-extinction; specifically, unlike DCS administration, the efficacy of the retrieval-extinction procedure does not depend on the variability in extinction learning (Auchter et al 2017). Further work in selectively bred animals may identify predictors of extinction performance, but as of yet, no differences in any preceding exploratory behaviours could foretell how animals perform in extinction training or during retrieval-extinction (Shumake et al 2014).…”

Embarking on discovering the mechanisms of resilience: combining language use analysis with neuroscience.

“…The relationship between NE and fear extinction appears to be complex and depend on NE levels, timing, brain region, etc 91,113,[117][118][119][120][121][122][123] . NE was shown to facilitate and possibly be critical for contextual fear extinction.…”