Early intrinsic excitability plasticity of neocortical engram neurons defines memory formation and precision

Neocortical memory engrams are thought to mature via strengthened interconnectivity, yet synaptic plasticity alone cannot explain the dynamic vividness of enduring memories. Neuronal intrinsic excitability (IE) plasticity has been touted as an early priming mechanism that renders engram neurons susceptible to ongoing plastic processes and later encoding events. Here, we reveal that learning-induced IE plasticity of nascent anterior cingulate cortex (ACC) engram neurons is a permissive mechanism for the formation and specificity of remote memories. Using c-fos-dependent genetic/viral targeting in mice, we found that contextual fear learning triggered a time-limited increase in ACC engram IE during the early phase of memory formation. Remarkably, chemogenetically hyperpolarizing these neurons within—but not outside—the IE plasticity window strengthened consolidated memories, enhanced their context-precision, and prevented interference-induced engram reallocation. Thus, IE plasticity in nascent ACC engram neurons acts as an essential tagging mechanism that determines the fate and dynamic content of remote memories. In this study, the authors present that a learning-induced enhancement of the intrinsic excitability of nascent anterior cingulate “engram” neurons in mice tags memories for long-term storage and proves crucial for the maturation, precision, and protection of enduring memories.