Sugar in the natural environment can be detected through taste-independent and taste-dependent modalities. Taste-independent modalities consist mainly of peripheral chemosensory neurons such as sweet taste receptors, which primarily detect the orosensory value of sugar (i.e. sweetness). My laboratory and others have shown that there exist taste-independent, internal sensors that detect the nutritional value of sugar in Drosophila and rodents. In this proposal, we will test a hypothesis that six neurons in the fly brain that produce diuretic hormone (Dh44), a homologue of the mammalian corticotropin-releasing hormone (CRH), directly detects the nutritional content of sugar in a fast time scale. Our preliminary results indicate that DH44 neurons are required for the selection of nutritive sugars in the two-choice assay and are activated by nutritive D-glucose, but not by nonnutritive L-glucose in calcium imaging experiment. Furthermore, we made a surprising observation that artificial activation of DH44 pathway resulted in rapid extensions of the mouthpart, and frequent episodes of excretion. These actions would facilitate the ingestion and digestion of nutritive foods. In the proposal, we will also determine the mechanism by which the activation of DH44 pathway leads to a rapid increase of ingestion and digestion through a positive feedback loop to continue consumption of nutritive foods. Identification and characterization of the taste-independent sugar sensor in Drosophila would provide a framework to understand how appetite is regulated by energy need in normal and eating disorder patients. Given its strong sequence homology, CRH and its neurons in the hypothalamus may offer similar functions in mammals. RELEVANCE: The proposed study to investigate the function of six neurons in the Drosophila brain that produce diuretic hormone (Dh44), a homologue of the mammalian corticotropin-releasing hormone (CRH), suggests a hypothesis that CRH neurons in the hypothalamus function as internal sensors that detect the nutritional value of sugar. Indeed, CRH was shown to play a significant role in the regulation of feeding and food intake, but the exact nature of it role is controversial. The homology between Drosophila DH44 and mammalian CRH is approximately 30% and between Drosophila and mammalian receptors is approximately 40%. Similar to Drosophila DH44, mammalian CRH regulates gastric and colonic movements, and stimulates defecation in rodents. CRH also mediates glucose homeostasis by regulating hypoglycemia-induced counterregulation. It was suggested that the function of glucose-sensing neurons is to generate neuroendocrine stress responses to the hypoglycemic challenge, but the identity of these neurons is unknown. It is possible that CRH neurons in the hypothalamus are glucose-sensing neurons as in the Drosophila brain and are capable of mediating starvation-induced behavioral responses to the nutritional value of sugar in mammals. Mice with compromised CRH function are indeed obese or anorexic. It is intriguing to speculate that obese individuals may be insensitive to the heightened circulating sugar levels after meals and therefore, continues to eat. By contrast, anorexic individuals may be too sensitive to circulating sugar levels and therefore, feel satiated and are reluctant to eat. The proposed research using the Drosophila model would provide a foundation for understanding the mechanisms by which internal sensors respond to the nutritional value of sugar in normal and obese individuals.