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. HighlightsO_LIPre-exposure to a tone attenuates retrieval of a tone-evoked conditioned fear response, revealing latent inhibition C_LIO_LILateral entorhinal cortex inhibition does not impair fear-memory retrieval in non-pre-exposed animals C_LIO_LIThe lateral entorhinal cortex is required for the expression of latent inhibition during retrieval C_LIO_LIThe lateral entorhinal cortex contributes to memory interference during retrieval of stimuli with conflicting associations C_LI In BriefGhazy et al. show that the lateral entorhinal cortex (LEC) is required for latent inhibition during retrieval, in which prior tone exposure attenuates later fear responding to that same tone. Because LEC inhibition does not impair tone-evoked conditioned fear responding, these findings indicate that the LEC contributes to memory interference when the same stimulus has conflicting associations.