NEURAL MECHANISMS OF TASTE-IMMUNE ASSOCIATIVE LEARNING: BRAINSTEM AND INSULAR CONTRIBUTIONS TO EXTINCTION OF CONDITIONED IMMUNE RESPONSES

Immunological responses can be learned and memorized by associative learning. When the administration of an immunosuppressive drug is paired with a novel taste, subsequent re-exposure to that taste elicits conditioned taste avoidance (CTA) and a conditioned suppression of specific T cell functions, mimicking the drugs’ effects. Such conditioning paradigms have been proposed as clinically relevant strategies to enhance therapeutic efficacy while reducing drug dosage, adverse effects, and treatment costs. However, to provide a basis for implementing this phenomenon in clinical situations, it is essential to clarify the mechanisms governing extinction of learned taste-immune responses. Using a validated conditioning paradigm, neuronal tracing and c-Fos immunohistochemistry revealed critical involvement of the reciprocally connected insular cortex (IC) and the nucleus of the solitary tract (NTS) during extinction of taste-immune associations. To test functional relevance of these structures and connection, chemogenetic approaches were used to transiently manipulate neuronal activity during memory retrieval. Silencing either the IC or NTS alone did not affect the extinction process. In contrast, simultaneous inhibition of CaMKIIα-positive neurons in both regions accelerated extinction of CTA, while preserving the previously learned immunosuppressive response. Our findings demonstrate that extinction of taste-immune engrams depends on coordinated processing within a cortical-brainstem network comprising the IC and NTS. Moreover, these results suggest that during retrieval of taste-immune associations behavioral extinction can occur independently of immunopharmacological extinction.