Chemogenetic Inhibition of the Ventrolateral Orbitofrontal Cortex Disrupts Prediction Error and Salience-Guided Memory-Updating at the Hippocampal Engram Level

Rationale: Adaptive behavior requires revising existing memories when outcomes deviate from expectations. The orbitofrontal cortex (OFC) is implicated in representing outcome expectancies, but its role in memory-updating, beyond value-based learning, remains unclear. Objectives: Here, we tested whether the ventrolateral OFC (VLO) contributes to hippocampal-dependent memory-updating in the Objects in Updated Locations (OUL) task, where novelty-driven exploration signals successful updating of spatial information. Methods: Using inhibitory DREADDs, in male and female (Swiss Webster and C57BL/6) mice, we suppressed VLO activity during the Updating session, when new object-location information was presented. Results: Control mice preferentially explored the newly updated location whereas VLO-inhibited mice failed to show this preference during Updating and again at Test. Critically, VLO inhibition when no updating demand was present did not impair novelty preference or memory for original spatial configurations at Test, indicating preserved novelty detection and retrieval abilities. Conclusions: These results demonstrate that VLO activity is selectively required when novelty must be interpreted relative to prior experience, further implicating this region in evaluating change rather than detecting it. To determine whether these impairments reflected a deficit in memory-updating beyond altered salience attribution, we tagged neuronal ensembles in the dorsal dentate gyrus recruited during Updating, followed by quantification of overlap between Updating-tagged cells and ensembles reactivated at Test. We found that behavioral deficits were correlated with reduced ensemble overlap, indicating that VLO activity supports memory-updating at the hippocampal engram level. These findings extend OFC models beyond reward contexts and identify a cortical contribution to predictive spatial memory processes.