Apparent Reconsolidation Interference Without Generalized Amnesia

Memories remain dynamic after consolidation, and when reactivated, they can be rendered vulnerable to various pharmacological agents that disrupt the later expression of memory (i.e., amnesia). Such drug-induced post-reactivation amnesia has traditionally been studied in AAA experimental designs, where a memory is initially created for a stimulus A (be it a singular cue or a context) and later reactivated and tested through exposure to the exact same stimulus. Using a contextual fear conditioning procedure in rats and midazolam as amnestic agent, we recently demonstrated that drug-induced amnesia can also be obtained when memories are reactivated through exposure to a generalization stimulus (GS, context B) and later tested for that same generalization stimulus (ABB design). However, this amnestic intervention leaves fear expression intact when at test animals are instead presented with the original training stimulus (ABA design) or a novel generalization stimulus (ABC design). The underlying mechanisms of post-reactivation memory malleability and of MDZ-induced amnesia for a generalization context remain largely unknown. Here, we evaluated whether, like typical CS-mediated (or AAA) post-reactivation amnesia, GS-mediated (ABB) post-reactivation amnesia displays key features of a destabilization-based phenomenon. We first show that ABB post-reactivation amnesia is critically dependent on prediction error at the time of memory reactivation and provide evidence for its temporally graded nature. In line with the known role of GluN2B-NMDA receptor activation in memory destabilization, we further demonstrate that pre-reactivation administration of ifenprodil, a selective antagonist of GluN2B-NMDA receptors, prevents MDZ-induced ABB amnesia. In sum, our data reveal that ABB MDZ-induced post-reactivation amnesia exhibits the hallmark features of a destabilization-dependent phenomenon. Implication of our findings for a reconsolidation-based account of post-reactivation amnesia are discussed.

Transitions from avoidance: Reinforcing competing behaviors reduces generalized avoidance in new contexts

Generalized avoidance behaviors are a common diagnostic feature of anxiety-related disorders and a barrier to affecting changes in anxiety during therapy. However, strategies to mitigate generalized avoidance are under-investigated. Even less attention is given to reducing the category-based generalization of avoidance. We therefore investigated the potential of an operant-based approach. Specifically, it was examined if reinforcing competing (non-avoidance) behaviors to threat-predictive cues would interfere with expression of generalized avoidance. Using a matching-to-sample task, artificial stimulus categories were established using physically dissimilar nonsense shapes. A member of one category (conditioned stimulus; CS1) was then associated with an aversive outcome in an Acquisition context, unless an avoidance response was made. Next, competing behaviors were reinforced in response to the CS1 in new contexts. Lastly, we tested for the generalization of avoidance to another member of the stimulus category (generalization stimulus; GS1) in both a Novel context and the Acquisition context. The selective generalization of avoidance to GS1 was observed, but only in the Acquisition context. In the Novel context, the generalization of avoidance to GSs was significantly reduced. A comparison group (Experiment 2), which did not learn any competing behaviors, avoided GS1 in both contexts. These findings suggest that reinforcing competing behavioral responses to threat-predictive cues can lead to reductions in generalized avoidance. This study is among the first study to demonstrate sustained reductions in generalized avoidance resulting from operant-based protocols, and the clinical and research implications are discussed.

Generalization Gradients for Acquisition and Extinction in Human Contingency Learning

Two experiments investigated the perceptual generalization of acquisition and extinction in human contingency learning. In Experiment 1, the degree of perceptual similarity between the acquisition stimulus and the generalization stimulus was manipulated over five groups. This successfully generated a generalization gradient of acquisition. In the subsequent phase, the response to the generalization stimulus was extinguished in each group. Finally, the acquisition stimulus was presented again. The response recovered differently over groups, thereby establishing the generalization gradient of extinction. In Experiment 2, the acquisition stimulus itself was extinguished before the set of generalization stimuli was tested between groups. One group evidenced a response recovery at test, which suggests that the gradient of acquisition is somewhat broader than the gradient of extinction.