Dysregulation of the fear system is at the core of many psychiatric disorders. Much progress has been made in uncovering the neural basis of fear learning through studies in which associative emotional memories are formed by pairing an initially neutral stimulus (conditioned stimulus, CS; e.g., a tone) to an unconditioned stimulus (US; e.g., a shock). Despite significant recent advances, the question of how to persistently weaken aversive CS-US associations, or dampen traumatic memories in pathological cases, remains a major dilemma. Two paradigms (blockade of reconsolidation and extinction) have been used in the laboratory to reduce acquired fear. Unfortunately, their clinical efficacy is limited: reconsolidation blockade typically requires potentially toxic drugs and extinction is not permanent. Here we describe a novel behavioral design, in rats, in which a fear memory is destabilized and reinterpretated as safe by presenting an isolated retrieval trial prior to an extinction session. This procedure permanently attenuates the fear memory without the use of drugs.
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