Dissecting the Role of the Lateral Entorhinal Cortex in Memory Interference

Memory interference occurs when an older memory competes with a newer memory that shares similar features ¹ . The hippocampal–entorhinal system is essential for memory ^2,3 , and the entorhinal cortex has been implicated in interference using the latent inhibition paradigm ⁴ . In latent inhibition, prior non-reinforced exposure to a stimulus reduces the conditioned response later elicited when that same stimulus is paired with an aversive or appetitive outcome ⁵ . Competition-based models propose that latent inhibition arises because the memory that the pre-exposed stimulus was inconsequential competes during retrieval with the memory that the same stimulus predicts an unconditioned stimulus ⁶ . Although entorhinal cortex lesions or inactivation impair latent inhibition ^7–10 , the specific contribution of the lateral entorhinal cortex (LEC) remains unclear. The LEC provides non-spatial and cue-related input to the hippocampus ¹¹ and has been implicated in associative memory ^12,13 . LEC function also declines with age ^14,15 , a period when memory interference increases ¹⁶ . Here, we used chemogenetics to transiently inhibit excitatory neurons in the LEC during retrieval in a latent inhibition paradigm. LEC inhibition did not impair conditioned fear responses to a non-pre-exposed tone, indicating that retrieval of the tone–shock association remained intact. However, LEC inhibition attenuated latent inhibition by increasing conditioned fear responses to a pre-exposed tone. Together, these findings suggest that the LEC supports retrieval of prior inconsequential stimulus memories that compete with newer conditioned associations, providing a potential mechanism by which age-related LEC dysfunction may contribute to increased memory interference.