Characterization of Taste-independent Sugar Sensor in the Brain

描述（由申请人提供）：进食行为受多种因素影响，如营养需求和食物适口性，这使得很难研究这种行为是如何调节的。外周化学感受神经元，如糖受体神经元赋予动物检测可口的食物。还将有其他机制来检测满足营养需求的食物。事实上，我的实验室表明，对糖的味道不敏感的果蝇突变体--GR 5a、GR 64 a和痘神经突变体--在长时间的食物匮乏后，仍然对糖溶液产生了基于其营养价值的偏好。具体来说，这些饥饿的糖盲或味觉盲果蝇能够区分营养的D-葡萄糖和零卡路里的L-葡萄糖，后者的味道几乎与果蝇的D-葡萄糖相同。这些发现表明，存在一种与味道无关的内部糖传感器，可以检测其卡路里含量。使用两种选择偏好测定（D-葡萄糖与L-葡萄糖），我们对内部糖传感器进行了小规模筛选，并鉴定了钠/葡萄糖协同转运蛋白dSGLT 3的突变，该突变对糖的卡路里含量完全不敏感，而是仅对糖的浓度-“甜味”做出反应。令人惊讶的是，dSGLT 3在大脑中的10对神经元中表达，这些神经元是内部糖感知所需的。在本研究中，我们将通过果蝇的行为学、电生理学和钙离子成像实验来研究dSGLT 3基因和dSGLT 3+表达神经元在介导内部糖感受中的功能。这些研究不仅将从根本上改变我们对化学感觉生物学的理解，而且还将为理解正常，肥胖和饮食失调患者的代谢需求调节食欲的机制提供有价值的框架。

DESCRIPTION (provided by applicant): Eating behavior is influenced by multiple factors such as nutritional needs and food palatability, which makes it difficult to investigate how this behavior is regulated. Peripheral chemosensory neurons such as sugar receptor neurons endow animals to detect palatable food. Additional mechanisms would exist for the detection of foods that meet nutrient needs. Indeed, my laboratory showed that the Drosophila mutants - GR5a; GR64a and pox-neuro mutants - that are insensitive to the taste of sugar still developed a preference for a sugar solution based on its nutritional value after prolonged periods of food deprivation. Specifically, these starved sugar-blind or taste-blind flies were able to distinguish nutritious D-glucose from zero-calorie L-glucose, which tastes almost identical as D-glucose to flies. These findings suggest that there exists a taste-independent, internal sugar sensor that detects its caloric content. Using two-choice preference assay (D-glucose versus L-glucose), we carried out a small-scale screen for an internal sugar sensor and identified a mutation in a Sodium/Glucose co-transporter, dSGLT3, that was completely insensitive to the caloric content of sugar, but rather responded only to the concentration of sugar - the "sweetness". Surprisingly, dSGLT3 is expressed in 10 pairs of neurons in the brain that are required for internal sugar sensing. In this proposal, we will characterize the function of dSGLT3 gene and dSGLT3+ expressing neurons in mediating internal sugar sensing by conducting behavior, electrophysiology and calcium imaging experiments in Drosophila. These studies will not only fundamentally transform our understanding of chemosensory biology, but will also provide a valuable framework for understanding the mechanisms by which appetite is regulated by metabolic needs in normal, obese and eating disorder patients.