A Critical Time Window of Neocortex Modulation for Remote Fear Memory in Rats and Humans

ABSTRACT Persistent fear memories, central to trauma‐related psychopathology, rely on long‐term consolidation. While initial encoding involves subcortical circuits, the precise timing and necessity of neocortical engagement for remote fear memory expression remain elusive. In the present translational study from rats to humans, we identified a late consolidation phase in the medial prefrontal cortex (mPFC) that occurs around 18 h after fear conditioning, a phase essential for remote memory. Neuronal ensembles in the mPFC activated during this phase mediate the expression of remote fear memory in rats. Critically, dopaminergic signaling in the mPFC modulated by ventral tegmental area (VTA) projections specifically during this delayed phase is required for remote fear memory maintenance. Consistent with these findings in humans, non‐invasive stimulation of homologous mPFC regions during this temporal window selectively reduced remote fear memory retrieval without affecting recent memory. These findings reveal an evolutionarily conserved temporal window for remote fear memory and identify novel time‐specific targets for clinical intervention in fear‐ and trauma‐related disorders.