Distributed encoding of natural and drug-induced physiological states in the insular cortex

Abstract

Interoception—the sensing of internal bodily signals—is crucial for maintaining homeostasis and plays a significant role in pathological states including drug addiction. Both the rewarding aspects of drug consumption and the aversive effects of withdrawal are experienced as salient body states. The insular cortex (InsCtx) is a key interoceptive region that integrates external sensory, visceral, and limbic information, and has been implicated in the maintenance of nicotine dependence. Here, we combine chronic two-photon imaging of hundreds of InsCtx neurons with physiological recordings of heart rate, pupil area, and body temperature during repeated nicotine exposure. We find that InsCtx neurons exhibit stable, distributed encoding of natural physiological states, enabling accurate predictions of arousal and cardiovascular variables across days. Nicotine administration triggers unique, centrally mediated physiological changes, which are reflected in distinct patterns of InsCtx activity. Longitudinal nicotine administration resulted in physiological tolerance, which contrasts with nicotine-evoked InsCtx neural responses that did not adapt across days. This study highlights the InsCtx’s role in tracking and distinguishing between natural and drug-induced states, and offers insight into the neural basis of tolerance -- a core feature of addiction.