Rapamycin attenuates reconsolidation of a backwards-conditioned aversive stimuli in female mice

Abstract

Rationale: The mammalian target of rapamycin (mTOR) kinase is known to mediate consolidation and reconsolidation of aversive memories. Most studies in this area use a forward conditioning paradigm in which the conditioned stimulus (CS) precedes the unconditioned stimulus (US). Little is known, however, about the neurobiological underpinnings of backwards (BW) conditioning paradigms, particularly in female mice. In BW conditioning, the CS does not become directly associated with the US; it instead evokes conditioned fear by reactivating a memory of the conditioning context and indirectly retrieving a memory of the aversive US.

Objectives: We sought to examine BW conditioned fear memory processes in female mice. First, we examined whether freezing to a BW CS is mediated by fear to the conditioning context. Second, we tested whether blocking consolidation of a BW CS attenuated memory of the CS and conditioning context. Finally, we tested whether blocking reconsolidation of a BW CS attenuated memory of the conditioning context.

Results: We show that conditioned freezing to a BW CS is mediated by fear to the conditioning context. Furthermore, rapamycin-an mTOR inhibitor, when given immediately following BW conditioning, impairs consolidation of both cued and contextual fear memory. Similarly, rapamycin given following retrieval of a BW CS blocks context recall. Rapamycin is acting on reconsolidation as CS retrieval is necessary to see the effects of rapamycin on context memory recall.

Conclusions: Our study provides novel evidence that indirect retrieval cues are sensitive to rapamycin in female mice. The capacity to indirectly reactivate memories and render them susceptible to disruption is critical in the translation of reconsolidation-based approaches to the clinic.

Keywords: Backwards conditioning; Consolidation; Extinction; Fear memory; Female; Mice; Rapamycin; Reconsolidation.