Early Tagging of Cortical Networks Is Required for the Formation of Enduring Associative Memory

TLDR

Long‑lasting associative memories depend on time‑dependent hippocampal‑cortical interactions, yet the underlying mechanisms remain unclear. The study demonstrates that cortical neurons must undergo a tagging process during encoding to enable hippocampal‑driven rewiring that supports remote memory storage. This tagging process relies on AMPA and NMDA receptors, is information‑specific, and modulates remote memory persistence by altering the temporal dynamics of hippocampal‑cortical interactions. Reinforcing the tagging process after learning with brief epigenetic modifications improves remote memory retrieval, showing that early cortical tagging is essential for remote memory formation and fits the extended timescale of systems‑level consolidation.

Abstract

Although formation and stabilization of long-lasting associative memories are thought to require time-dependent coordinated hippocampal-cortical interactions, the underlying mechanisms remain unclear. Here, we present evidence that neurons in the rat cortex must undergo a "tagging process" upon encoding to ensure the progressive hippocampal-driven rewiring of cortical networks that support remote memory storage. This process was AMPA- and N-methyl-D-aspartate receptor-dependent, information-specific, and capable of modulating remote memory persistence by affecting the temporal dynamics of hippocampal-cortical interactions. Post-learning reinforcement of the tagging process via time-limited epigenetic modifications resulted in improved remote memory retrieval. Thus, early tagging of cortical networks is a crucial neurobiological process for remote memory formation whose functional properties fit the requirements imposed by the extended time scale of systems-level memory consolidation.