Reconsolidation and Extinction of Conditioned Fear: Inhibition and Potentiation

Abstract

NMDA receptors are important for the acquisition, reconsolidation, and extinction of memories. NMDA receptor antagonists impair these memory processes, whereas the partial agonist D-cycloserine (DCS) potentiates both learning and extinction. Here, we used DCS and the noncompetitive NMDA receptor antagonist (ϩ)-5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) to investigate the effects of enhancing and blocking NMDA receptor-mediated glutamatergic transmission on the reconsolidation and extinction of a conditioned fear memory. Either long extinction training or short memory reactivation sessions were used to preferentially engage extinction and reconsolidation processes, respectively. MK-801 blocked extinction to maintain high levels of conditioned freezing, and DCS potentiated extinction to reduce freezing, when they were administered before a long extinction training session. However, the opposite behavioral outcome was observed when the brief memory reactivation session was used: MK-801 administration impaired, whereas DCS increased, freezing, likely reflecting impairment and enhancement of reconsolidation, respectively. Finally, by using localized intracerebral infusions, we showed that the basolateral amygdala is a primary locus of action of systemically administered DCS. Thus, intrabasolateral amygdala DCS potentiated both the extinction and the reconsolidation of fear conditioning, depending on the length of the extinction/memory reactivation session. Therefore, memory reconsolidation can be both disrupted and enhanced, and extinction can be both potentiated and impaired, either to reduce or increase conditioned fear. These results have important implications for the use of reconsolidation blockade and potentiation of extinction as treatment strategies for maladaptive memory disorders.

‘It's not over when it's over’: persistent neurobiological abnormalities in recovered depressed patients

“…From this viewpoint it will be important to establish which of the biological abnormalities we have described are present before the onset of illness and which apparently occur after the first few depressive episodes. It may be that, in the future, more therapeutic attention needs to be given to the biological consequences of acute depressive episodes, perhaps through the development of treatments with neuroprotective effects or those that might regulate the formation and recall of emotional memories (Lee et al 2006).…”

Prediction error and trace dominance determine the fate of fear memories after post-training manipulations

“…The results suggest that with enough CS exposure the new (extinction) memory is dominant, and administration of an amnestic will have the effect of disrupting the extinction memory, leading to an increase in responding at test relative to the appropriate control conditions (Eisenberg et al 2003; Lee et al 2006). Intriguingly, recent studies have shown that intermediate amounts of posttraining CS exposure, a point at which presumably neither CS-US nor CS-NoUS trace is dominant, have revealed insensitivity to amnestic (Flavell and Lee 2013;Merlo et al 2014;Sevenster et al 2014).…”

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

“…These mixed results have suggested a number of potential issues that need consideration when designing treatment trials for DCS (and other putative extinction enhancing treatments): (1) are the effects of DCS more on speed of response rather than magnitude of response to exposure, two differing hypotheses that will require different experimental designs/analysis to probe efficacy; (2) what is the correct dosing/timing of treatment; (3) does DCS's cognitive enhancement promote inhibitory learning to the extinction context, which might subsequently contribute to contextual renewal of fear (Vervliet 2008); and (4) does DCS need to be targeted toward only the successful therapy sessions [for a detailed review, see Hofmann et al (2015)]. This latter issue is because DCS is a broad cognitive enhancer, it can enhance both fear learning and extinction learning (Lee et al 2006); thus, if the exposure session is unsuccessful in promoting extinction, it could instead promote reconsolidation (i.e., strengthening of conditioned fear to trauma memories and cues) that is then increased by DCS treatment. Thus far, however, predicting a "successful" session versus an unsuccessful one has been elusive.…”