Locus coeruleus input-modulated reactivation of dentate gyrus opioid-withdrawal engrams promotes extinction

Extinction training during the reconsolidation window following memory recall is an effective behavioral pattern for promoting the extinction of pathological memory. However, promoted extinction by recall-extinction procedure has not been universally replicated in different studies. One potential reason for this may relate to whether initially acquired memory is successfully activated. Thus, the methods for inducing the memory into an active or plastic condition may contribute to promoting its extinction. The aim of this study is to find and demonstrate a manipulatable neural circuit that engages in the memory recall process and where its activation improves the extinction process through recall-extinction procedure. Here, naloxone-precipitated conditioned place aversion (CPA) in morphine-dependent mice was mainly used as a pathological memory model. We found that the locus coeruleus (LC)-dentate gyrus (DG) circuit was necessary for CPA memory recall and that artificial activation of LC inputs to the DG just prior to initiating a recall-extinction procedure significantly promoted extinction learning. We also found that activating this circuit caused an increase in the ensemble size of DG engram cells activated during the extinction, which was confirmed by a cFos targeted strategy to label cells combined with immunohistochemical and in vivo calcium imaging techniques. Collectively, our data uncover that the recall experience is important for updating the memory during the reconsolidation window; they also suggest a promising neural circuit or target based on the recall-extinction procedure for weakening pathological aversion memory, such as opioid withdrawal memory and fear memory.