Central infusion of prostaglandin E2 reveals a unified representation of sickness in the mouse insular cortex

During infections, vertebrates develop stereotypic symptoms such as elevated body temperature, reduced appetite, and lethargy. These changes, collectively known as sickness syndrome, are orchestrated by the brain in response to immune mediators released during systemic inflammation. While the roles of subcortical regions, including the hypothalamus and brainstem, in regulating sickness symptoms are well established, the contribution of the neocortex to the encoding and modulation of sickness remains less well understood. We examined the neuronal correlates of sickness in the neocortex of awake mice following a single intracerebroventricular (i.c.v.) injection of prostaglandin E2 (PGE2), a well-characterized sickness mediator. Behavioral analysis revealed that PGE2 elicits a rapid and robust sickness response, characterized by fever, slower locomotion, quiescence, anorexia, and eye squinting. Whole-brain Fos mapping showed that PGE2 generates a distinct neural activation pattern encompassing much of the interoceptive network. Electrophysiological recordings in awake mice revealed that neuronal population dynamics in the antero-mid insular cortex (IC) and the primary somatosensory cortex (SSp), two regions involved in body-state representation, encode sickness-related information, such as body temperature, walking velocity, grooming, and eye squinting. However, unlike SSp, ongoing neuronal activity in IC exhibited better decoding performance for a multidimensional measure of sickness than for individual sickness traits. Together, these results suggest that PGE2 induces a coordinated physiological and behavioral response akin to a sick state, which is preferentially encoded in the IC, providing a conceptual framework for studying interactions between the immune system and the brain.