Feeding behavior is influenced by multiple factors including food palatability and nutritional needs. Peripheral chemosensory taste neurons primarily detect palatable food, but animals lacking these taste neurons can still develop a preference to sugars on the basis of their nutritional value. My laboratory previously determined that dSLC5A11+, EB R4d neurons in the Drosophila brain are required for the selection of nutritive D- glucose over nonnutritive L-glucose after periods of starvation. dSLC5A11 (or cupcake) acts on approximately 12 pairs of EB R4d neurons to trigger the selection of nutritive sugars, but the mechanism underlying this process is not understood. We previously proposed two possible mechanisms by which EB R4 neurons may mediate the selection of nutritive sugars: (1) by detecting the nutritional value of sugar through direct activation or (2) monitoring the internal energy reserves of the fly with a direct nutrient sensor located elsewhere; starved flies lacking functional EB R4d neurons cannot sense the deprived metabolic state and, thus, would not select nutritive sugars. Through calcium imaging and a more-sensitive electrophysiology approach, we tested whether EB R4d neurons respond to nutritive sugars, but failed to observe any responses to glucose or any other sugars. Instead, the activity of EB R4d neurons and the expression of dSLC5A11 transcript increase significantly following periods of starvation. Furthermore, the increased dSLC5A11 suppresses dKCNQ currents, thereby increasing the activity of EB R4d neurons during starvation. Recently, we found that EB R4d neurons are robustly activated by serotonin, which is apparently secreted by the neurons labeled by R50H05-GAL4. These R50H05+ neurons were shown to promote food intake, similar to EB R4d neurons. We also found that another population of the EB Ring neurons, apparently the neighboring EB R4m neurons, suppress food intake. In this renewal application, we propose to study the following questions based on our published and preliminary results.
In Aim 1, we will determine the mechanisms by which EB R4d neurons are activated. We will further elucidate the dSLC5A11/dKCNQ- mediated mechanism, but also investigate the dSLC5A11?independent mechanism in which serotonin plays critical roles in stimulating the activity of EB R4d neurons and the expression of dSLC5A11 transcript.
In Aim 2, we will determine whether EB R4d neurons function downstream of R50H05+ neurons.
In Aim 3, we will validate that the recently identified EB R4m neurons suppress food intake and characterize the interactions between EB R4m and EB R4d neurons, and between EB R4d or EB R4m neurons, and the sleep-promoting EB R2 neurons.
and Relevance The obesity pandemic is no longer considered as just a major health problem, but also as an economic predicament that places an enormous financial burden on family and society for the care and treatment of patients. The obese patients often suffer from its associated illnesses such as diabetes, hypertension, dyslipidemia and cardiovascular diseases. The healthcare costs attributed to the obesity related illnesses have significantly increased in the past decades and will continue to rise in the next 20 years. The continued rise of this epidemic is largely due to the availability of highly dense, caloric food, and poor eating habit. The central circuit regulating food intake such as the melanocortin system in the mammalian hypothalamus has been identified and studied, but we still do not have clear understanding of how these orexigenic and anorexigenic neurons in the melanocortin system are regulated by hunger or satiety, whether these neurons respond to any or specific macronutrients, whether the intimately interwoven orexigenic and anorexigenic neurons exists in invertebrate, and how these neurons regulating feeding behavior interact with other circuits mediating related behaviors. In this renewal application, we will investigate the functions of the recently identified orexigenic and anorexigenic neurons in the Drosophila brain and determine the mechanisms by which feeding is regulated by these neurons using genetic, molecular, physiology tools, and behavior assays readily available in Drosophila. It is also easier to conduct a large number of trials in behavior testing and other experiments using flies to accelerate our understanding of feeding behavior. These would not only provide a valuable conceptual framework, but could also lead to development of therapeutic application to treat obesity and eating disorders.
|Abu, Farhan; Wang, Justin G; Oh, Yangkyun et al. (2018) Communicating the nutritional value of sugar in Drosophila. Proc Natl Acad Sci U S A 115:E2829-E2838|