Many neuroactive peptides, acting at hypothalamic nuclei, are critically important central regulators of food intake via the gut-(blood)-brain axis. Oxytocin is a potent anorexigenic peptide that plays a key role at hypothalamic and hindbrain centers that regulate appetite, satiety and ingestion. Taste strongly influences food selection. Yet, the role of taste has not been integrated into models of appetite and satiety. The premise of this application is that oxytocin, in addition to its central effects, also modulates the peripheral taste signal. Oxytocin knockout mice show altered taste sensitivity and preference, specifically for sweeteners. Our preliminary data show that a membrane receptor for Oxytocin (OxtR) is expressed in a discrete subset of cells within the taste bud, and responds to physiological concentrations of Oxytocin. Based on published reports and our preliminary data, we hypothesize that oxytocin acts on glial-like cells within taste buds, and secondarily alters the sweet-selective sensitivity and output of taste buds. We will test this hypothesis through the following Specific Aims: 1: Which taste cells express oxytocin receptor? Using single cell gene expression profiling and immunocytochemistry, we will test this because cell type has implications for function. We will conduct these analyses in wild-type and transgenic mice, PLC22-GFP, GAD-GFP and OxtR-YFP. 2: Is OxtR functional in taste buds and does it influence taste-evoked responses? We will extend our preliminary Ca2+ imaging experiments on taste cells from OxtR-YFP reporter mice. Using laser scanning confocal Ca2+ imaging on a lingual slice preparation, we will evoke responses to taste compounds, and ask whether oxytocin modulates sweet (or other) taste evoked responses. We will also examine if taste-evoked secretion of the afferent transmitter, ATP, is modulated by exposure to oxytocin. These experiments will be carried out on taste tissue from OxtR-YFP and PLC22-GFP. All proposed methodologies to achieve these aims, although highly technical, are routinely performed in our laboratories, and are in our publications. This assures the feasibility of the project. We intend to use this Exploratory Research grant (R21) to launch a new area of investigation that may have significant translational impact. Understanding how peptides (especially those implicated in central pathways for satiety) influence the peripheral taste signal may suggest new avenues to address eating disorders. PUBLIC HEALTH RELEVANCE: Several peptides in the brain and gut regulate food intake and are intensely researched. Their malfunction results in overeating or anorexic behaviors, and/or changes in body weight. Ironically, the most intuitive driver of feeding, taste, has not been investigated as a contributor to appetite regulation. We present evidence and propose to study further, how the taste system may be modulated by at least two of the same peptides that control satiety in the brain. This understanding would suggest new pharmacological possibilities to address eating disorders.