Characterization of Taste-independent Sugar Sensor in the Brain

描述(申请人提供)：饮食行为受到多种因素的影响，如营养需求和食物适口性，这使得很难调查这种行为是如何被调节的。外周化学感受器神经元，如糖感受器神经元，赋予动物检测美味食物的能力。将有更多的机制来检测满足营养需求的食品。事实上，我的实验室表明，对糖的味道不敏感的果蝇突变体--GR5a、GR64a和POX-NERO突变体--在长时间的食物匮乏后，仍然根据糖液的营养价值产生了对糖液的偏好。具体地说，这些饥饿的糖盲或味盲的果蝇能够区分营养的D-葡萄糖和零卡路里的L葡萄糖，对果蝇来说，后者的味道几乎与D-葡萄糖相同。这些发现表明，存在一种不依赖味道的内部糖传感器，可以检测其卡路里含量。使用双选择偏好试验(D-葡萄糖和L-葡萄糖)，我们对内部糖传感器进行了小规模筛选，发现了钠/葡萄糖共转运体dSGLT3的一个突变，该突变对糖的热量含量完全不敏感，而只对糖的浓度--“甜度”--做出反应。令人惊讶的是，dSGLT3在大脑中10对神经元中表达，这些神经元是内部糖感所必需的。在这项研究中，我们将通过对果蝇进行行为学、电生理学和钙成像实验，研究dSGLT3基因和dSGLT3+表达神经元在介导内源性糖感觉中的作用。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、肥胖和进食障碍患者的代谢需求调节食欲的机制提供一个有价值的框架。

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.