Differential modulation of aversive signaling by expectation across the cingulate cortex

Abstract

Pain-related aversion is an affective-motivational state driven by sensory experience that promotes learning and recruits widespread cortical networks, yet how distinct cingulate subregions contribute to its adaptive utility remains poorly understood. Here we used longitudinal one-photon calcium imaging in mice to compare dynamics in the anterior cingulate cortex (ACC) and retrosplenial cortex (RSC) across repeated unsignaled foot-shocks and fear conditioning and extinction paradigm. Both regions contained relatively stable ensembles that responded robustly to shocks, indicating shared encoding of acute nociceptive events. However, only the RSC flexibly re-organized its population activity when shocks were preceded by predictive cues. These anticipatory dynamics in the RSC predicted the rate of fear learning across individuals and subsequent extinction. By contrast, the ACC maintained shock-responsive ensembles with limited cue modulation. Instead, its dynamics encoded decisions to freeze, aligning with its role in encoding ongoing nociception and driving immediate defensive behavior. Together, these results reveal a division of labor in which the ACC emphasizes ongoing nociceptive processing, while the RSC transforms sensory signals into predictive codes that shape learning and memory. This specialization highlights how distributed cortical computations cooperate to generate the adaptive value of aversion. More broadly, our findings suggest that these regions assume complementary roles to address immediate sensory-motivational responses while flexibly reconfiguring to support long-term behavioral adaptation. Significance statementPain engages widespread cortical circuits, yet how distinct cingulate subregions collaborate to shape its experience and utility remains unknown. Using longitudinal calcium imaging in mice, we demonstrate that both the anterior cingulate and retrosplenial cortex contain stable shock-responsive ensembles, but only the retrosplenial cortex flexibly remodels its activity when shocks are predicted by cues. These anticipatory dynamics not only predict fear learning but influence extinction. Our findings uncover a division of labor in which the anterior cingulate encodes ongoing nociception and immediate defensive actions, while the retrosplenial cortex transforms these signals into temporally structured representations that support learning and memory. This work highlights how specialized cortical computations interact to generate the adaptive value of pain.