From Forgetting to Remembering: Context-Dependent Memory Recovery after Post-Retrieval Disruption

Memories are dynamic and can be made vulnerable to disruption upon reactivation, resulting in a long-lasting attenuation of conditioned responses (i.e., cue-dependent amnesia). Traditionally, cue-dependent amnesia has been studied using AAA between-subjects designs, where a memory is trained for context A, reactivated, and tested with the same context. Using contextual fear conditioning in rats and midazolam as the amnestic agent, we have recently observed that amnesia can be observed when memories are reactivated by a generalization stimulus (context B) and tested with the same generalization stimulus (ABB design). However, this amnestic intervention does not affect fear expression when animals are tested with the original stimulus (ABA design) or a novel generalization stimulus (ABC design). Methodologically, however, evaluating whether amnesia is reversed, rather than simply not expressed, requires tracking changes in responding within the same individuals across contexts and time. This avoids the ambiguity inherent to between-group comparisons, which may confound memory retention with retrieval differences driven by contextual or procedural variability. Here, using an ABB, ABA, and ABC within-subjects design, and employing a gold standard amnestic manipulation - protein synthesis inhibition via Cycloheximide (CHX) - the interplay between memory retention and amnesia expression in different contexts was assessed. The results indicate that amnesia is expressed only when CHX-animals are re-exposed to the reactivation context, regardless of when this re-exposure occurs within the experimental timeline. The implications of these findings for a reconsolidation-based account of post-reactivation amnesia are discussed.