Covert capture and attenuation of a hippocampus-dependent fear memory.

Abstract

Reconsolidation may be a viable therapeutic target to inhibit pathological fear memories. In the clinic, incidental or imaginal reminders are used to safely retrieve traumatic memories of experiences that occurred elsewhere. However, it is unknown whether indirectly retrieved traumatic memories are sensitive to disruption. Here we used a backward conditioning procedure to indirectly retrieve and manipulate a hippocampus-dependent contextual fear engram in male rats. We show that conditioned freezing to a backward conditioned stimulus is mediated by fear to the conditioning context, activates hippocampal ensembles that can be covertly captured and chemogenetically activated to drive fear, and is impaired by post-retrieval protein synthesis inhibition. These results reveal that indirectly retrieved contextual fear memories reactivate hippocampal ensembles and undergo protein synthesis-dependent reconsolidation. Clinical interventions that rely on indirect retrieval of traumatic memories, such as imaginal exposure, may open a window for editing or erasing neural representations that drive pathological fear.