Propofol Modulates Fear Memory Reconsolidation by Inhibiting D2 Receptor‐Expressing Neurons in the Medial Prefrontal Cortex

ABSTRACT Fear memory reconsolidation provides a temporal window for modifying established fear memories, yet the underlying cellular and neural circuit mechanisms remain incompletely understood. Using in vivo fiber photometry and chemogenetic approaches in freely moving mice, we show that propofol modulates fear memory reconsolidation by inhibiting D2 receptor‐expressing neurons in the medial prefrontal cortex (mPFC). These neurons exhibit heightened activity during fear memory reconsolidation and project prominently to the basolateral amygdala (BLA). Notably, local pharmacological activation of D2 receptors in the mPFC recapitulates the fear‐attenuating effect of propofol when administered during the reconsolidation window. Circuit‐level investigations further show that propofol suppresses the reconsolidation‐associated enhancement of the mPFC D2 ‐BLA synaptic transmission, and chemogenetic activation of this projection counteracts the effect of propofol on fear memory reconsolidation. Moreover, selective knockdown of D2 receptors in BLA‐projecting mPFC neurons diminishes the effect of propofol, supporting a critical role for D2 receptor signaling within this projection‐defined circuit. Together, these findings identify the mPFC D2 ‐BLA circuit as a key neural substrate through which propofol modulates fear memory reconsolidation and highlight prefrontal D2 receptor signaling as a potential target for reconsolidation‐based interventions aimed at maladaptive fear memories.