Disruptive Effect of Midazolam on Fear Memory Reconsolidation: Decisive Influence of Reactivation Time Span and Memory Age

Abstract

Benzodiazepine (BDZ) administered shortly after retrieval disrupts the reconsolidation of fear memory. In this research, we explored the way in which different factors that limit the emergence of such process may affect BDZ's disruptive effect on fear memory reconsolidation. Animals were conditioned in a contextual fear paradigm; the consolidated memory was reactivated by exposure to the associated context for different periods of time that were followed by midazolam (MDZ) administration. We also studied MDZ amnesic effect after reactivating fear memories of several ages. We finally analyzed the effectiveness of different MDZ doses in preventing the reconsolidation of different age fear memories. The memory trace was disrupted following MDZ when the reactivation session lasted 3-5 min but it was not after a briefer 1-min reactivation period. Over a 10-min reactivation session, all animals gradually reduced their fear response, which indicates the emergence of the extinction process. When tested, MDZ rats exhibited a robust fear, suggesting that MDZ impaired the consolidation of extinction. In a 3-min reactivation session, MDZ (1-1.5 mg/kg) prevented the reconsolidation of recently acquired memories. A 21-day-old fear memory was only vulnerable to MDZ at a 1.5 mg/kg dose with a reactivation session of 5 and not 3 min, whereas a 36-day-old memory was only disrupted with a higher MDZ dose (3 mg/kg) regardless of the reactivation trial's duration. This study demonstrated MDZ's interference on fear-memory reconsolidation within a relatively short reactivation period in recently acquired memories. Over longer reexposure, MDZ disrupts the consolidation of extinction. A longer duration of the reexposure session, as well as higher MDZ doses, is required to prevent the reconsolidation process of remote fear memories.

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

“…This was due to the SAL group expressing increased freezing from test to retest (P , 0.01; Cohen's f ¼ 3.71) suggesting spontaneous recovery, which is consistent with the typical pattern of extinction learning (Bouton 2004). The MDZ group, however, showed intact CR expression, a consequence of the amnesic agent over the consolidation of extinction memory, as previously reported with MDZ (Bustos et al 2009) hypothermia (Briggs and Riccio 2007), and other pharmacological agents (Eiserberg et al 2003;Pedreira and Maldonado 2003;Suzuki et al 2004). Figure 7A shows the course of extinction minute by minute over the 15 min of reactivation time.…”

“…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).…”

“…3). 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.…”

“…The total volume of drug or equivalent amount of SAL was 1.0 mL/ kg in all cases. This dose of MDZ was selected on the basis of previous reports demonstrating its ability to block contextual fear memory reconsolidation in Wistar rats (Bustos et al 2006(Bustos et al , 2009.…”

Previous Stress Attenuates the Susceptibility to Midazolam's Disruptive Effect on Fear Memory Reconsolidation: Influence of Pre-Reactivation D-Cycloserine Administration

“…Moreover, there are boundary conditions that place constraints on the onset of both the labile phase and the re-stabilization process (Tronson and Taylor, 2007). For instance, memory age, the duration of the reactivation period, and the interaction between these two factors have a decisive influence on the susceptibility to disruption after memory reactivation (Bustos et al, 2009;Suzuki et al, 2004). As memory ages, it is more difficult to induce post-retrieval retrograde amnesia by pharmacological intervention as compared with newer memories (Frankland et al, 2006;Milekic and Alberini, 2002;Suzuki et al, 2004).…”