Memory destabilization is critical for the success of the reactivation–extinction procedure

Abstract

It has been suggested that, unlike pure extinction which typically results in the return of the fear response under a variety of circumstances, memory reactivation followed by extinction can attenuate the reemergence of conditioned fear. The reactivation-extinction procedure has attracted the attention of basic and clinical researchers due to its potential clinical value for the treatment of psychiatric conditions, such as anxiety and drug abuse disorders. However, mixed results have been achieved so far in replicating and understanding this paradigm. It has been proposed that memory destabilization could be critical in this sense. Using contextual fear conditioning in rats and midazolam as an amnesic agent, we first determined what reactivation conditions are necessary to destabilize the mnemonic trace. After establishing the conditions for memory destabilization, a series of experiments was conducted to determine if destabilization is critical for the success of the reactivation-extinction procedure. Data confirmed the importance of memory destabilization prior to extinction inside the reconsolidation window to attenuate spontaneous recovery and retard reacquisition of conditioned fear. The present report offers a candidate explanation of the discrepancy in results obtained with the reactivation -extinction procedure by different laboratories.

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

“…When reviewing the literature to better understand these seemingly contradictory outcomes, a pattern is seen: for example, Pedreira and Maldonado (2003) (also see Eisenberg et al 2003) observed that reactivation duration influences in part which process takes place. This pattern has been replicated by other groups that further found that short presentations only produce memory retrieval, intermediate reactivations destabilize the memory and long reactivations generate extinction learning (Suzuki et al 2004;Bustos et al 2009;Piñeyro et al 2013).…”

“…It has been reported by several laboratories (Eisenberg et al 2003;Pedreira and Maldonado 2003;Suzuki et al 2004;Bustos et al 2009) that a short memory reactivation only produces memory retrieval (with or without CR expression). In a recent study (Piñeyro et al 2013; Exp. 1) we also observed in this preparation that a short reactivation did not result in memory destabilization Therefore, we predicted that a 30-sec reactivation session (without shock) in the conditioned context would not allow animals to detect any discrepancy with the already encoded information about US arrival, since in both single-event training conditions the US arrived at later time points (60 sec for the 1-min condition, 300 sec for the 5-min condition).…”

“…Based on previous studies, we expected that 15 min should induce extinction learning (which would be blocked by MDZ) for animals trained under the 1-min condition (see Piñeyro et al 2013). For animals trained in the 5-min condition, two possible outcomes were expected: the transitional insensitive period as observed in the 1-min condition (Experiment 6), particularly operationalized in the lack of MDZ amnesic effects and intact CR expression for SAL group, or extinction (reduced CR expression for SAL group, which would be blocked by MDZ).…”

“…However, a large body of evidence in experimental psychology suggested malleability for previously stored memories through different manipulations (e.g., Misanin et al 1968), and this issue has recently regained interest (Nader et al 2000;Nader 2013). Data from a variety of experimental preparations has firmly established that consolidated memories become vulnerable to amnestics (i.e., sensitive to different manipulations), if reactivated under appropriate conditions (Piñeyro et al 2013). 5 Understanding the dynamics of memory reactivation and extinction has strong theoretical and clinical value, offering avenues to advance translatable knowledge on how human and nonhuman animals use stored information and pointing to potential therapeutic targets for the treatment of pathogenic memories (Urcelay 2012).…”

Prediction error demarcates the transition from retrieval, to reconsolidation, to new learning

“…We showed that memory reactivation induces simple retrieval, reconsolidation or new learning (Osan et al 2011;Piñeyro et al 2014), as a function of the number of reactivation trials. Our data showed that in the absence of PE, the retrieved memory remained intact, although a single PE was required for memory destabilization.…”