Contextual and Temporal Modulation of Extinction: Behavioral and Biological Mechanisms

Abstract

Extinction depends, at least partly, on new learning that is specific to the context in which it is learned. Several behavioral phenomena (renewal, reinstatement, spontaneous recovery, and rapid reacquisition) suggest the importance of context in extinction. The present article reviews research on the behavioral and neurobiological mechanisms of contextual influences on extinction learning and retrieval. Contexts appear to select or retrieve the current relationship of the conditional stimulus (CS) with the unconditional stimulus (US), and they are provided by physical background cues, interoceptive drug cues, emotions, recent trials, and the passage of time. The current article pays particular attention to the effects of recent trials and trial spacing. Control of fear extinction by physical context involves interactions between the dorsal hippocampus and the lateral nucleus of the amygdala. This interaction may be mediated by gamma-aminobutyric acid (GABA)-ergic and adrenergic mechanisms.

The effects of extinction training in reducing the reinstatement of drug-seeking behavior: Involvement of NMDA receptors

“…Extinction likely involves new learning [4,20,21], and at the molecular level, both NMDAR and nonNMDAR dependent forms of synaptic plasticity are thought to contribute to this type of learning. Although some studies have indicated that extinction learning in conditioned taste aversion [3] or conditioned fear [1] does not require the activation of NMDARs, other reports have indicated a critical role for NMDARs [2,10,22].…”

“…Using other behavioral models, evidence indicates that new learning is occurring during the extinction training experience [4,20,21]. This new learning may be dependent upon the activation of n-methyl-d-aspartate receptors (NMDARs), and either blocking NMDARs with antagonists or enhancing NMDAR activity with coagonists would be expected to affect the ability of an extinction training experience to alter the response to primed reinstatement.…”

Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear

“…This conclusion is based on observations that fear responses can reemerge after unsignaled exposure to the US (reinstatement), following a change in context (renewal), with the passage of time (spontaneous recovery) and that reconditioning occurs faster than initial conditioning (Pavlov, 1927;Rescorla and Heth, 1975;Bouton and Bolles, 1979;Bouton et al, 2006;Robbins, 1990;Westbrook et al, 2002). Further support for this assertion comes from both electrophysiological and psychopharmacological studies of behavioral and synaptic plasticity.…”

On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development

“…The definition of what constitutes an associative context remains broad, but typically includes at least one of the following qualities: (1) unpredictable prediction of the US; (2) longer duration than a common discrete CS; and (3) complex, multimodal features. Contexts have been operationalized in numerous ways in laboratory tasks, including the experimental setting itself, a virtual reality setting, pictures of rooms, and simple cues with an unpredictable US association (e.g., Alvarez et al 2011;Armony and Dolan 2001;Bouton et al 2006;Glenn et al 2014;Grillon 2002;Effting and Kindt 2007;Neumann et al 2007). …”

“…Theoretically, drugs that improve pattern completion and separation could be used prophylactically during or immediately following trauma to improve specificity of learning and prevent overgeneralization of contextual or discrete fear (Glenn et al 2014). Conversely, such drugs may be contraindicated for use in conjunction with exposure therapy for PTSD and other anxiety disorders given concerns that greater contextual specificity of fear extinction learning increases the probability of contextually mediated renewal of fear (Bouton et al 2006;Vervliet et al 2013). …”