Reorganization of lateral orbitofrontal neuronal ensembles underlies pain-related impairment of delayed gratification

Abstract Chronic pain is associated with impaired decision-making, increased impulsivity, and a reduced ability to pursue long-term rewards. However, the neural mechanisms by which chronic inflammatory pain alters lateral orbitofrontal cortex (lOFC) activity during time-reward associations remain poorly understood. To address this question, we used one-photon miniscope calcium imaging to monitor lOFC neuronal activity in adult male CD rats performing a delayed gratification task (DGt). lOFC neuronal activity was monitored using the genetically encoded calcium indicator GCaMP8f. Behavioral performance was assessed following the induction of persistent inflammatory pain using the complete Freund's adjuvant (CFA) model. Our results demonstrated that inflammatory pain significantly increased impulsive choice, shifting behavioral preference toward immediate rewards at the expense of delayed larger rewards. Calcium imaging revealed that CFA-treated rats exhibited attenuated lOFC neuronal responses, particularly during rewarded trials surrounding lever press. Despite minimal changes in overall neuronal response magnitude across behavioral contingencies, hierarchical clustering revealed a marked reorganization of functional neuronal ensembles in CFA-treated animals. Inflammatory pain altered the relationships between distinct neuronal clusters, indicating that persistent pain reshapes the population coding of time-reward information rather than producing a uniform change in neuronal activity. Together, these findings demonstrate that chronic inflammatory pain reorganizes lOFC neuronal ensembles, identifying population-level network reorganization as a potential mechanism underlying impaired delayed gratification and cognitive dysfunction.