Project Summary/Abstract The main goal of this proposal is to elucidate how cortex-brainstem interactions shape the neural representations of taste to drive avoidance behavior during conditioned taste aversion (CTA) in mice. Taste perception guides appropriate food choices. While animals display innate preferences for sweet tastes associated with calorically dense foods, new learned associations can reverse these preferences to protect against consumption of potentially toxic or harmful foods. For example, CTA occurs when visceral illness (unconditioned stimulus, US) follows consumption of a novel taste (conditioned stimulus, CS), which leads to a robust and long-lasting avoidance of the CS, even after only a single taste-illness (CS-US) pairing. However, the neural circuit mechanisms underlying CTA remain poorly understood. Prior work has implicated the insular cortex (InsCtx), which encompasses primary gustatory and visceral cortex, and the brainstem lateral parabrachial nucleus (LPBN), which integrates multimodal sensory input from the body, as key brain regions for the learning and retrieval of CTA in rodents. It was long known that LPBN neurons respond to and are necessary for the transmission of visceral malaise signals during acquisition of CTA. In addition, recent work has demonstrated that a specific population of LPBN neurons, those expressing calcitonin gene-related peptide (CGRP), develop learned responses to the CS after CTA and are necessary for CTA retrieval. Likewise, InsCtx contains representations of both taste and malaise, and its CS-evoked population activity shifts after CTA, leading to the question of whether a functional interaction between InsCtx and LPBN may drive the neural and behavioral response to CTA. Indeed, InsCtx sends a dense excitatory projection to LPBN (InsCtxLPBN), the function of which is entirely unknown. I will test the hypothesis that upon re-exposure to the CS during CTA expression, InsCtxLPBN neurons drive activity patterns in LPBN that simulate and reinstate feelings of malaise, leading to avoidance of the CS. In Aim 1, I will use two-photon calcium imaging to determine how LPBN neurons and InsCtxLPBN axons represent the CS and US, and how representations of the CS shift after CTA learning. Preliminary studies show that CTA dramatically shifts the CS-evoked pattern of activity in LPBN, and that this new pattern may resemble that of LiCl-induced malaise. In Aim 2, I will investigate the influence of InsCtxLPBN axons on LPBN activity and on avoidance behavior during the expression of CTA. These studies will elucidate the neural circuit mechanisms underlying CTA with important clinical applications for understanding maladaptive taste learning, which can occur during treatment with nausea-inducing medications or chronic gastrointestinal illnesses. Furthermore, these studies will advance our broader understanding of how cortex-brainstem interactions can shape taste perception, with implications for sensory ...