Psychopharmacology · 2026
Chemogenetic inhibition of the ventrolateral orbitofrontal cortex disrupts novelty-guided updating of spatial memories and alters hippocampal engram reactivation.
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Kim K, Yu D, Wade W F, Zdziarski-West R, Ahmad Z, Cutler M, Romanelli G, Daki A, Grella S L
Аннотация
RATIONALE: Adaptive behavior requires revising 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: 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 provides a behavioral readout consistent with 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 introduced.
RESULTS: Control mice preferentially explored the updated object-location configuration during Updating and discriminated between updated and novel object-location configurations at Test, whereas VLO-inhibited mice did not. VLO inhibition when no updating demand was present did not alter exploration of novel object-location configurations or memory for the original spatial configuration at Test.
CONCLUSIONS: These results indicate that VLO activity is selectively required when novelty must be interpreted relative to prior experience, implicating this region in evaluating change rather than detecting it. To assess hippocampal ensemble dynamics, we tagged neuronal ensembles, in the dorsal dentate gyrus (dDG) recruited during Updating, followed by quantification of overlap between Updating-tagged cells and ensembles reactivated at Test. We found that VLO inhibition reduced reactivation of Updating-tagged dDG ensembles, paralleling the behavioral impairments observed in the OUL task. These findings support a role for the VLO in hippocampal-dependent memory-updating and extend OFC models beyond reward contexts to include predictive updating of spatial memory representations.
CLINICAL TRIAL: Not applicable.
OBJECTIVES: 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 provides a behavioral readout consistent with 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 introduced.
RESULTS: Control mice preferentially explored the updated object-location configuration during Updating and discriminated between updated and novel object-location configurations at Test, whereas VLO-inhibited mice did not. VLO inhibition when no updating demand was present did not alter exploration of novel object-location configurations or memory for the original spatial configuration at Test.
CONCLUSIONS: These results indicate that VLO activity is selectively required when novelty must be interpreted relative to prior experience, implicating this region in evaluating change rather than detecting it. To assess hippocampal ensemble dynamics, we tagged neuronal ensembles, in the dorsal dentate gyrus (dDG) recruited during Updating, followed by quantification of overlap between Updating-tagged cells and ensembles reactivated at Test. We found that VLO inhibition reduced reactivation of Updating-tagged dDG ensembles, paralleling the behavioral impairments observed in the OUL task. These findings support a role for the VLO in hippocampal-dependent memory-updating and extend OFC models beyond reward contexts to include predictive updating of spatial memory representations.
CLINICAL TRIAL: Not applicable.