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

Learning induces an early tag of prefrontal cortex neurons implicated in long-term memory storage, but this tag’s nature, functional role, and time course are unknown. Using a c-fos dependent genetic and viral system for the labeling and manipulation of putative engram neurons of the anterior cingulate cortex (ACC) together with behavior and in vitro electrophysiology, we found that contextual fear learning triggered an increase in the neuron-wide intrinsic excitability specifically of ACC engram neurons. This plasticity was expressed over several days during the early memory phase and required for enduring memory storage. Pharmacogenetic manipulation of the engram neurons’ intrinsic excitability during its plastic phase altered the strength and context-precision of enduring fear memories. Moreover, this manipulation prevented the memory decline usually caused by an interference event. In contrast, excitability manipulation or interference during remote memory phases did not influence long-term memory retrieval; their impact is thus strongly correlating with the time course of intrinsic plasticity. These findings shed light on the functional role of intrinsic plasticity of ACC engram neurons in long-term memory storage. Associative learning strongly engages ACC engram neurons and triggers neuron-wide intrinsic plasticity. This plasticity is transiently expressed and necessary for the consolidation and specificity of long-term memory.