Relapse of extinguished fear after exposure to a dangerous context is mitigated by testing in a safe context

Goode, Travis D.; Kim, Janice J.

doi:10.1101/lm.037028.114

Cited by 6 publications

(6 citation statements)

References 89 publications

(94 reference statements)

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“…1 B ). Although pre-tone freezing levels for the immediate extinction groups were high, we found this behavior to be common in the literature when extinction training sessions were given shortly after fear conditioning (Maren and Chang, 2006; Chang and Maren, 2009; Chan et al, 2010; Goode et al, 2015). A three-way repeated-measures general linear model (extinction × interval × trial) for the percentage of time spent freezing during exposure to either the extinction training (EXT) or context B (No-Ext) groups found significant, but equivalent changes in freezing behavior, as indicated by a significant main effect of trial ( F (2,36) = 47.8; p < 0.0001 b ) and extinction × trial interaction ( F (2,36) = 8.47; p = 0.001 c ), but no significant interval × trial ( F (4,74) = 1.53; p = 0.21 d ) or extinction × interval × trial ( F (4,74) = 0.322; p = 0.86 e ; Fig.…”

Section: Resultsmentioning

confidence: 64%

Involvement of CRFR₁in the Basolateral Amygdala in the Immediate Fear Extinction Deficit

Hollis¹,

Sevelinges²,

Grosse³

et al. 2016

eNeuro

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Several animal and clinical studies have highlighted the ineffectiveness of fear extinction sessions delivered shortly after trauma exposure. This phenomenon, termed the immediate extinction deficit, refers to situations in which extinction programs applied shortly after fear conditioning may result in the reduction of fear behaviors (in rodents, frequently measured as freezing responses to the conditioned cue) during extinction training, but failure to consolidate this reduction in the long term. The molecular mechanisms driving this immediate extinction resistance remain unclear. Here we present evidence for the involvement of the corticotropin releasing factor (CRF) system in the basolateral amygdala (BLA) in male Wistar rats. Intra-BLA microinfusion of the CRFR1 antagonist NBI30775 enhances extinction recall, whereas administration of the CRF agonist CRF6–33 before delayed extinction disrupts recall of extinction. We link the immediate fear extinction deficit with dephosphorylation of GluA1 glutamate receptors at Ser845 and enhanced activity of the protein phosphatase calcineurin in the BLA. Their reversal after treatment with the CRFR1 antagonist indicates their dependence on CRFR1 actions. These findings can have important implications for the improvement of therapeutic approaches to trauma, as well as furthering our understanding of the neurobiological mechanisms underlying fear-related disorders.

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Section: Resultsmentioning

confidence: 64%

Involvement of CRFR₁in the Basolateral Amygdala in the Immediate Fear Extinction Deficit

Hollis¹,

Sevelinges²,

Grosse³

et al. 2016

eNeuro

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“…Renewal is not the only way in which fear can relapse: fear reinstates after reexposure to the US (Rescorla and Heth 1975;Bouton and Bolles 1979b;Bouton and King 1983;Westbrook et al 2002;Morris et al 2005;Goode et al 2015a) and fear can spontaneously recover after a passage of time in the absence of the CS (Pavlov 1927;Rescorla 2004). Distinct mechanisms are thought to underlie these and other various forms of relapse (and are examined elsewhere in detail: Bouton 2002Bouton , 2004Vervliet et al 2013;Goode and Maren 2014;Haaker et al 2014;McConnell and Miller 2014;Maren and Holmes 2016), but it should be noted that contextual information is thought to be critical for many of these phenomena (Bouton et al 2006).…”

Section: Learning To Fearmentioning

confidence: 99%

Role of the bed nucleus of the stria terminalis in aversive learning and memory

Goode

2017

Learn. Mem.

Self Cite

115

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Surviving threats in the environment requires brain circuits for detecting (or anticipating) danger and for coordinating appropriate defensive responses (e.g., increased cardiac output, stress hormone release, and freezing behavior). The bed nucleus of the stria terminalis (BNST) is a critical interface between the "affective forebrain"-including the amygdala, ventral hippocampus, and medial prefrontal cortex-and the hypothalamic and brainstem areas that have been implicated in neuroendocrine, autonomic, and behavioral responses to actual or anticipated threats. However, the precise contribution of the BNST to defensive behavior is unclear, both in terms of the antecedent stimuli that mobilize BNST activity and the consequent defensive reactions. For example, it is well known that the BNST is essential for contextual fear conditioning, but dispensable for fear conditioning to discrete conditioned stimuli (CSs), at least as indexed by freezing behavior. However, recent evidence suggests that there are circumstances in which contextual freezing may persist independent of the BNST. Furthermore, the BNST is involved in the reinstatement (or relapse) of conditioned freezing to extinguished discrete CSs. As such, there are critical gaps in understanding how the BNST contributes to fundamental processes involved in Pavlovian fear conditioning. Here, we attempt to provide an integrative account of BNST function in fear conditioning. We discuss distinctions between unconditioned stress and conditioned fear and the role of BNST circuits in organizing behaviors associated with these states. We propose that the BNST mediates conditioned defensive responses-not based on the modality or duration of the antecedent threat or the duration of the behavioral response to the threat-but rather as consequence the ability of an antecedent stimulus to predict when an aversive outcome will occur (i.e., its temporal predictability). We argue that the BNST is not uniquely mobilized by sustained threats or uniquely involved in organizing sustained fear responses. In contrast, we argue that the BNST is involved in organizing fear responses to stimuli that poorly predict danger will occur, no matter the duration, modality, or complexity of those stimuli. The concepts discussed in this review are critical to understanding the contribution of the human BNST to fear and anxiety disorders.

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“…Two forms of fear relapse have received considerable attention over the years: “reinstatement” and “renewal.” Reinstatement of fear occurs when an aversive, unsignaled US is experienced prior to presentation of the extinguished CS ( Rescorla and Heth, 1975 ; Bouton and Bolles, 1979 ). Reinstatement is most robust in contexts in which reinstating shocks are delivered, although it can also occur in contexts never paired with shock ( Westbrook et al, 2002 ; see also Morris et al, 2005a ; Halladay et al, 2012 ; Goode et al, 2015 ). This suggests that reinstatement can be mediated by either direct context–US associations ( Bouton and King, 1983 ; Bouton et al, 2006 ) or though stress states that generalize across contexts ( Haroutunian and Riccio, 1977 ; Morris et al, 2005b ; Deschaux et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Reversible Inactivation of the Bed Nucleus of the Stria Terminalis Prevents Reinstatement But Not Renewal of Extinguished Fear

Goode

Kim

Maren

2015

eneuro

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The extinction of conditioned fear is labile. For example, fear to an extinguished conditioned stimulus (CS) returns after presentation of an aversive stimulus (“reinstatement”) or a change in context (“renewal”). Substantial research implicates the bed nucleus of the stria terminalis (BNST) in the stress-induced relapse of extinguished behaviors, such as in instrumental drug seeking, but its role in the relapse of extinguished fear responses is not clear. Here, we explored the role of the BNST in both the reinstatement and renewal of fear, two forms of relapse that are differentially triggered by stress. In Experiment 1, rats received pairings of an auditory CS and footshock unconditioned stimulus (US) followed by an extinction procedure. After extinction, rats received an unsignaled US to reinstate fear to the extinguished CS. Twenty-four hours later, they were infused with either muscimol or vehicle into the BNST immediately prior to a CS retrieval test. In Experiment 2, rats were conditioned and extinguished in two distinct contexts. Twenty-four hours after extinction, the rats were infused with muscimol, NBQX, or vehicle immediately prior to a CS retrieval test in either the extinction context or a different (but familiar) context. In both experiments, freezing behavior served as the index of conditioned fear. The results revealed that BNST inactivation prevented reinstatement (Experiment 1), but not renewal (Experiment 2), of conditioned freezing to the extinguished CS. Hence, the BNST is critical for the reinstatement of extinguished fear in an aversive context, but not for the contextual retrieval processes that mediate fear renewal.

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Relapse of extinguished fear after exposure to a dangerous context is mitigated by testing in a safe context

Cited by 6 publications

References 89 publications

Involvement of CRFR₁in the Basolateral Amygdala in the Immediate Fear Extinction Deficit

Involvement of CRFR₁in the Basolateral Amygdala in the Immediate Fear Extinction Deficit

Role of the bed nucleus of the stria terminalis in aversive learning and memory

Reversible Inactivation of the Bed Nucleus of the Stria Terminalis Prevents Reinstatement But Not Renewal of Extinguished Fear

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Relapse of extinguished fear after exposure to a dangerous context is mitigated by testing in a safe context

Cited by 6 publications

References 89 publications

Involvement of CRFR1in the Basolateral Amygdala in the Immediate Fear Extinction Deficit

Involvement of CRFR1in the Basolateral Amygdala in the Immediate Fear Extinction Deficit

Role of the bed nucleus of the stria terminalis in aversive learning and memory

Reversible Inactivation of the Bed Nucleus of the Stria Terminalis Prevents Reinstatement But Not Renewal of Extinguished Fear

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Product

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Involvement of CRFR₁in the Basolateral Amygdala in the Immediate Fear Extinction Deficit

Involvement of CRFR₁in the Basolateral Amygdala in the Immediate Fear Extinction Deficit