Dissociable memory modulation mechanisms facilitate fear amnesia at different timescales

Memory reactivation renders consolidated memory fragile and thereby opens the window for memory updates, such as memory reconsolidation. However, whether memory retrieval facilitates update mechanisms other than memory reconsolidation remains unclear. We tested this hypothesis in three experiments with healthy human participants. First, we demonstrate that memory retrieval-extinction protocol prevents the return of fear expression shortly after extinction training, and this short-term effect is memory reactivation dependent (Study 1, N=57 adults). Furthermore, across different timescales, the memory retrieval-extinction paradigm triggers distinct types of fear amnesia in terms of cue specificity and cognitive control ability dependence, suggesting that the short-term fear amnesia might be caused by different mechanisms from the cue-specific amnesia at a longer and separable timescale (Study 2, N=79 adults). Finally, using continuous theta-burst stimulation (Study 3, N=75 adults), we directly manipulated brain activity in the dorsolateral prefrontal cortex and found that both memory reactivation and intact prefrontal cortex function were necessary for the short-term fear amnesia after the retrieval-extinction protocol. The differences in temporal scale, cue specificity, and cognitive control ability dependence between the short- and long-term amnesia suggest that memory retrieval and extinction training trigger distinct underlying memory update mechanisms. These findings suggest the potential involvement of coordinated memory modulation processes upon memory retrieval and may inform clinical approaches for treating persistent maladaptive memories.