Selective Modulation of Fear Memory in Non‐Rapid Eye Movement Sleep

Abstract Sleep stabilizes memories for their consolidation, but how to modify specific fear memory during sleep remains unclear. Here, it is reported that using targeted memory reactivation (TMR) to reactivate prior fear learning experience in non‐slow wave sleep (NS) inhibits fear memory consolidation, while TMR during slow wave sleep (SWS) enhances fear memory in mice. Replaying conditioned stimulus (CS) during sleep affects sleep spindle occurrence, leading to the reduction or enhancement of slow oscillation‐spindle (SO‐spindle) coupling in NS and SWS, respectively. Optogenetic inhibition of pyramidal neurons in the frontal association cortex (FrA) during TMR abolishes the behavioral effects of NS‐TMR and SWS‐TMR by modulating SO‐spindle coupling. Notably, calcium imaging of the L2/3 pyramidal neurons in the FrA shows that CS during SWS selectively enhances the activity of neurons previously activated during fear conditioning (FC+ neurons), which significantly correlates with CS‐elicited spindle power spectrum density. Intriguingly, these TMR‐induced calcium activity changes of FC+ neurons further correlate with mice freezing behavior, suggesting their contributions to the consolidation of fear memories. The findings indicate that TMR can selectively weaken or strengthen fear memory, in correlation with modulating SO‐spindle coupling and the reactivation of FC+ neurons during substages of non‐rapid eye movement (NREM) sleep.