Molecular mechanisms underpinning deconditioning‐update in fear memory

Abstract Traumatic experiences are closely associated with some psychiatric conditions such as post‐traumatic stress disorder. Deconditioning‐update promotes robust and long‐lasting attenuation of aversive memories. The deconditioning protocol consists of applying weak/neutral footshocks during reactivations, so that the original tone‐shock association is replaced by an innocuous stimulus that does not produce significant fear response. Here, we present the molecular bases that can support this mechanism. To this end, we used pharmacological tools to inhibit the activity of ionotropic glutamate receptors (NMDA‐GluN2B and CP‐AMPA), the activity of proteases (calpains), and the receptors that control intracellular calcium storage (IP3 receptors), as well as the endocannabinoid system (CB1). Our results indicate that blocking these molecular targets prevents fear memory update by deconditioning. Therefore, this study uncovered the molecular substrate of deconditioning‐update strategy, and, broadly, shed new light on the traumatic memory destabilization mechanisms that might be used to break the boundaries regarding reconsolidation‐based approaches to deal with maladaptive memories.