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

Summary Neocortical memory engrams are thought to stabilize and mature via enhanced interconnectivity during the so-called systems-consolidation process 1,2 . While synaptic plasticity of these engram connections is considered an important mechanism for storing memories 3,4 , it cannot fully account for the dynamic vividness of remote, cortically-based memories. Indeed, cell-intrinsic plasticity has been touted as the crucial early priming mechanism that renders nascent engram neurons susceptible to ongoing plastic processes while providing flexibility for later encoding events 5–7 . Here, we reveal that learning-related neuron-wide intrinsic excitability (IE) plasticity of nascent cortical engram neurons is a permissive mechanism for the formation and specificity of remote associative memories. Using a c-fos -dependent genetic and viral system for the targeted labeling of engram neurons in the anterior cingulate cortex (ACC) combined with ex vivo electrophysiology, we found that contextual fear learning triggered a time-dependent increase in their IE signature expressed over days during the early, but not late, phase of memory formation. Remarkably, chemogenetically hyperpolarizing engram neurons during this early plastic phase enhanced their maturation, increasing the strength and context-precision of consolidated memories and preventing memory disturbance caused by an interference event. Altogether, our findings identify cell-intrinsic plasticity within nascent ACC engram neurons as an essential tagging mechanism whose features determine the fate and dynamic content of remote memories.