Retrieval of conditioned immune response in male mice is mediated by an anterior–posterior insula circuit

To protect the body from infections, the brain has evolved the ability to coordinate behavioral and immunological responses. The conditioned immune response (CIR) is a form of Pavlovian conditioning wherein a sensory (for example, taste) stimulus, when paired with an immunomodulatory agent, evokes aversive behavior and an anticipatory immune response after re-experiencing the taste. Although taste and its valence are represented in the anterior insular cortex and immune response in the posterior insula and although the insula is pivotal for CIRs, the precise circuitry underlying CIRs remains unknown. Here, we demonstrated that a bidirectional circuit connecting the anterior and posterior (aIC–pIC) insula mediates the CIR in male mice. Retrieving the behavioral dimension of the association requires activity of aIC-to-pIC neurons, whereas modulating the anticipatory immunological dimension requires bidirectional projections. These results illuminate a mechanism by which experience shapes interactions between sensory internal representations and the immune system. Moreover, this newly described intrainsular circuit contributes to the preservation of brain-dependent immune homeostasis.