Learned together, extinguished apart: reducing fear to complex stimuli

Jones, Carolyn E.; Ringuet, Stephanie; Monfils, Marie‐H.

doi:10.1101/lm.031740.113

Cited by 31 publications

(24 citation statements)

References 51 publications

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“…Although others have demonstrated that postretrieval extinction can prevent fear relapse in animals (Auchter et al, 2017; Baker et al, 2013; Clem & Huganir, 2010; Flavell et al, 2011; Jones et al, 2013; Jones & Monfils, 2016; Monfils et al, 2009; Olshavsky et al, 2013; Rao-Ruiz et al, 2011; Shumake & Monfils, 2015) and in humans (Agren et al, 2012a, 2012b, 2017; Björkstrand et al, 2015; Golkar et al, 2017; Liu et al, 2014; Meir Drexler et al, 2014; Meir Drexler & Wolf, 2016a; Oyarzún et al, 2012; Schiller et al, 2010, 2013; Thompson & Lipp, 2017), it is important to consider that prevention of relapse may not equate to erasure of the fear memory. For example, a well-trained extinction memory may be able to outcompete a fear memory for expression, without the fear memory necessarily being eliminated (Lattal & Wood, 2013).…”

Section: Discussionmentioning

confidence: 99%

Extinction after fear memory reactivation fails to eliminate renewal in rats

Goode

Holloway-Erickson

2017

Neurobiology of Learning and Memory

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Retrieving fear memories just prior to extinction has been reported to effectively erase fear memories and prevent fear relapse. The current study examined whether the type of retrieval procedure influences the ability of extinction to impair fear renewal, a form of relapse in which responding to a conditional stimulus (CS) returns outside of the extinction context. Rats first underwent Pavlovian fear conditioning with an auditory CS and footshock unconditional stimulus (US); freezing behavior served as the index of conditioned fear. Twenty-four hours later, the rats underwent a retrieval-extinction procedure. Specifically, 1 h prior to extinction (45 CS-alone trials; 44 for rats receiving a CS reminder), fear memory was retrieved by either a single exposure to the CS alone, the US alone, a CS paired with the US, or exposure to the conditioning context itself. Over the next few days, conditional freezing to the extinguished CS was tested in the extinction and conditioning context in that order (i.e., an ABBA design). In the extinction context, rats that received a CS+US trial before extinction exhibited higher levels of conditional freezing than animals in all other groups, which did not differ from one another. In the renewal context, all groups showed renewal, and none of the reactivation procedures reduced renewal relative to a control group that did not receive a reactivation procedure prior to extinction. These data suggest retrieval-extinction procedures may have limited efficacy in preventing fear renewal.

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Section: Discussionmentioning

confidence: 99%

Extinction after fear memory reactivation fails to eliminate renewal in rats

Goode

Holloway-Erickson

2017

Neurobiology of Learning and Memory

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“…This paradigm was found to result in a persistent reduction in fear expression, possibly suggesting that the original fear memory had been updated. This paradigm has been replicated several times in both non-human animals39404142434445464748 and humans49505152535455. However, there is a large degree of individual variability in extinction alone, and equally as much (if not more) variation in the retrieval + extinction paradigm.…”

Section: Fear Extinctionmentioning

confidence: 99%

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

Auchter

Shumake

González-Lima

et al. 2017

Sci Rep

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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.

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“…One of the most studied forms of reconsolidation-dependent memory updating is the reconsolidation-update procedure in which an isolated retrieval event is followed by a massed extinction session (Monfils et al, 2009). This precise spacing of reconsolidation and extinction procedures results in a persistent attenuation of fear responses to specific cues in both rodents (Baker, McNally, and Richardson, 2013; Jones, Ringuet, and Monfils, 2013; Pineyro, Ferrer Monti, Alfei, Bueno, and Urcelay, 2013) and humans (Oyarzun et al, 2012; Schiller, Kanen, Ledoux, Monfils, and Phelps, 2013; Schiller et al, 2010; Warren et al, 2013) and is regulated by dynamic changes in AMPA receptor expression (Clem and Huganir, 2010; Rao-Ruiz et al, 2011). However, while this reconsolidation-update procedure is effective at attenuating fear responses to newer memories, the paradigm is much less effective with older memories (Clem and Huganir, 2010).…”

Section: Epigenetic Regulation Of Memory Reconsolidationmentioning

confidence: 99%

Epigenetic mechanisms of memory formation and reconsolidation

Jarome

Lubin

2014

Neurobiology of Learning and Memory

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Memory consolidation involves transcriptional control of genes in neurons to stabilize a newly formed memory. Following retrieval, a once consolidated memory destabilizes and again requires gene transcription changes in order to restabilize, a process referred to as reconsolidation. Understanding the molecular mechanisms of gene transcription during the consolidation and reconsolidation processes could provide crucial insights into normal memory formation and memory dysfunction associated with psychiatric disorders. In the past decade, modifications of epigenetic markers such as DNA methylation and posttranslational modifications of histone proteins have emerged as critical transcriptional regulators of gene expression during initial memory formation and after retrieval. In light of the rapidly growing literature in this exciting area of research, we here examine the most recent and latest evidence demonstrating how memory acquisition and retrieval trigger epigenetic changes during the consolidation and reconsolidation phases to impact behavior. In particular we focus on the reconsolidation process, where we discuss the already identified epigenetic regulators of gene transcription during memory reconsolidation, while exploring other potential epigenetic modifications that may also be involved, and expand on how these epigenetic modifications may be precisely and temporally controlled by important signaling cascades critical to the reconsolidation process. Finally, we explore the possibility that epigenetic mechanisms may serve to regulate a system or circuit level reconsolidation process and may be involved in retrieval-dependent memory updating. Hence, we propose that epigenetic mechanisms coordinate changes in neuronal gene transcription, not only during the initial memory consolidation phase, but are triggered by retrieval to regulate molecular and cellular processes during memory reconsolidation.

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Learned together, extinguished apart: reducing fear to complex stimuli

Cited by 31 publications

References 51 publications

Extinction after fear memory reactivation fails to eliminate renewal in rats

Extinction after fear memory reactivation fails to eliminate renewal in rats

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

Epigenetic mechanisms of memory formation and reconsolidation

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