Novel object-place configurations increase excitability of layer 5 lateral entorhinal cortex engram cells

Associative recognition memory is essential for everyday life, forming cognitive representations of and recalling relationships between things we encounter and their environments. Object-place associations are represented in the lateral entorhinal and medial prefrontal cortices, however the identity of neurons in which these associations are formed, the cellular mechanisms supporting them, and how these representations react to change are not understood. Here we labelled associative recognition memory engrams, finding that engram neuron reactivation by memory recall correlated with behavioural performance only in the dorsolateral subregion of entorhinal cortex, where reactivation was overrepresented in layer 5/6. Electrophysiology from ex vivo slices prepared directly following memory recall revealed increased excitability in layer 5 lateral entorhinal cortex engram cells, which only occurred when engram-specific objects were reconfigured. These data identify deep layer lateral entorhinal cortex neurons as key loci of object-place associations and proposes a plastic mechanism by which pre-existing neural representations are updated. Significance statementAssociative recognition memory is key to our normal everyday lives, but how these memories are updated and which neurons support these memories remain poorly understood. We identify a population of neurons in the deep-layers of lateral entorhinal cortex which are activated by memory encoding and whose reactivation is correlated with, and necessary for, memory retrieval, thus identifying them as engram neurons. These entorhinal neurons demonstrate increased firing following presentation of familiar cues in a novel configuration, revealing a mechanism for integrating new information into existing memories. By identifying a specific cell type and plasticity process underlying memory updating, this work advances understanding of how flexible object-place representations are maintained in the brain.