A prelimbic molecular clock of protein synthesis for memory persistence

Abstract

Emotionally salient associative memories can endure for long periods, yet the mechanisms that determine their long-term stability remain unclear. Here we show that the prelimbic (PL) cortex integrates temporally structured translational programs to control both the consolidation and reconsolidation of cued threat memories. Using Pavlovian threat conditioning with in vivo fiber photometry, we found that PL calcium dynamics tightly track memory strength: discrete threat-predictive cues evoked robust activity during recent and single-timepoint remote retrieval, whereas prior retrieval selectively weakened remote expression, independent of contextual influences. Translational profiling of PL Camk2a cells uncovered a biphasic consolidation program, with an early phase characterized by ER stress-linked translational repression and robust oligodendrocyte plasticity, followed by a delayed phase engaging synaptic growth pathways. Loss- and gain-of-function approaches demonstrated that eIF2-regulated, cap-independent translation is essential for recent consolidation and for the enduring stabilization of remote memory, whereas retrieval-induced destabilization engages a mechanistically distinct, eIF4E-dependent translational pathway required for reconsolidation. These findings identify the PL cortex as a dynamic node in which discrete modes of translational control govern the long-term persistence of emotional memories.