Kinnavane, L. | Search bioRxiv

bioRxiv2025

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.

neuroscience↗

bioRxiv2025

Medial prefrontal cortex input to lateral entorhinal cortex supports both encoding and retrieval of associative recognition memory

Associative recognition memory allows us to form representations of items and their environment and to judge the novelty of such representations. This memory is dependent on a brain circuit that includes interactions between medial prefrontal cortex (mPFC) and lateral entorhinal cortex (LEC); however it is unknown whether the interaction of these brain areas is required for memory encoding, retrieval or both processes. Furthermore, little is known as to whether indirect or direct mPFC-LEC connections are critical for associative recognition memory and, if the latter, in which direction information travels. To address these questions, we first performed pharmacological disconnection of mPFC and LEC, finding that mPFC-LEC interaction is required for both memory encoding and retrieval. Next, we optogenetically inhibited projections from mPFC to LEC, showing that this projection was crucial for both encoding and retrieval of both object-in-place and object-in-context recognition memory when a 1 h, but not a 5 min, memory retention delay was used. These data show that a direct connection from mPFC to LEC is critical for associative recognition memory, in a delay-dependent manner.

neuroscience↗