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

Associative recognition memory is essential for our everyday lives, allowing us to form cognitive representations of and remember relationships between things we encounter and their environments, such as where we left our keys or parked the car. Evidence suggests that these 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 representations of object-associations react to changes in the environment are not understood. Here we use transgenic mice to label associative recognition memory engrams in mice, finding that memory recall reactivates engram cells in multiple cortical regions, but that engram cell reactivation only correlates with behavioural performance in the dorsolateral entorhinal cortex, where reactivation was highest in layer 5/6. Chemogenetic inhibition of engram cells in lateral entorhinal cortex impaired memory retrieval. Electrophysiology from e x vivo slices following memory recall demonstrated that engram cells in lateral entorhinal cortex layer 5, but not other cortices or layers, showed increased excitability only when the engram-specific objects had been reconfigured. These data collectively identify neurons in deep layers of lateral entorhinal cortex as probable loci of object-place associations and propose a mechanism by which new information is incorporated into pre-existing neural representations.