Molecular and Neural Mechanisms regulating Foraging and Food Intake

摘要 在正常个体中，食物摄入受到感觉、稳态和享乐神经回路的严格调节， 平衡能量摄入与能量消耗。未能调节食物感知和食欲会导致 适应不良的饮食行为以及代谢综合征和饮食失调的发生率增加。 调节食物摄入的神经回路已在啮齿动物模型中得到广泛研究。然而， 哺乳动物大脑的复杂性使得解释其潜在的分子机制变得非常具有挑战性 和控制食物摄入的电路动力学。我建议使用一种遗传上易于处理的模型生物，即苍蝇 （黑腹果蝇），了解大脑如何整合感觉的基本原理 通过饥饿感对食物的感知，在分子、细胞和回路水平上调节食物摄入量。 果蝇是研究这些过程的绝佳模型，因为它们的神经元数量少了 1000 倍。 大脑比老鼠差，但它们仍然表现出饥饿状态和特定的食物摄入控制与老鼠非常相似 在脊椎动物中。此外，果蝇神经系统更容易进行基因改造、解剖学改造 研究和监测行为动物中大量神经元的活动。之前我已经展示过 苍蝇和人类一样，通过将食物的味道和营养价值与饥饿感相结合来调节食物摄入量 神经系统的感觉。我在果蝇大脑中发现了一类新型兴奋性中间神经元（IN1） 调节食物摄入。在这个项目中，我们将首先使用光遗传学和 顺行突触回路追踪。接下来，我们将揭示IN1神经元和下游电路如何变化 使用双光子显微镜进行虚拟现实觅食测定中食物搜索过程中的活动。最后，使用切割—— 边缘三光子技术，我们将像果蝇一样长期捕获完整果蝇中 IN1 神经元的活动 被剥夺食物。 IN1 电路的功能剖析将引导我们了解神经系统的基本原理 系统用于调节食物摄入量。在我们的食物摄入回路解剖工作的同时，我们还确定了 8 对24岁后未能表现出补偿性摄食的果蝇进行大型遗传筛选中的进化保守基因 数小时的食物匮乏。我们将从解剖学和功能上剖析这些基因和神经元的作用 它们控制调节食物摄入的回路。最后，我们将测试候选食物摄入量的相互作用 基因和 IN1 电路调节食物感知和食欲控制。模拟食物摄入量和 在遗传易驯化的有机体中系统地控制食欲使我们能够揭示新的分子和神经 控制机制。一旦我们发现了食物摄入和食欲的关键机制，我们就可以搜索 在更复杂的哺乳动物模型以及患有肥胖或饮食的患者中进行类似的过程 制定治疗策略，干预这些危及生命的疾病的发病机制 疾病。

ABSTRACT In normal individuals, food intake is strictly regulated by sensory, homeostatic and hedonic neural circuits, which balance energy intake with energy expenditure. Failure to regulate food perception and appetite result in maladaptive eating behaviors and an increase in the occurrence of metabolic syndromes and eating disorders. Neural circuits that regulate food intake have been extensively investigated in rodent models. However, the complexity of the mammalian brain makes it very challenging to explain the underlying molecular mechanisms and circuit dynamics controlling food intake. I propose to use a genetically tractable model organism, the fly (Drosophila melanogaster), to understand the fundamental principles of how the brain integrates the sensory percept of food with the sensation of hunger to regulate food intake on the level of molecules, cells and circuits. Flies are an excellent model to investigate these processes because they have 1000-fold fewer neurons in the brain than mice, and yet they still show hunger states and specific food intake control remarkably similar to those in vertebrates. Furthermore, the fly nervous system is more accessible for genetic modifications, anatomical studies and monitoring the activity of large populations of neurons in behaving animals. Previously, I have shown that flies, like humans, regulate their food intake by integrating the taste and nutrient value of food with hunger sensation in the nervous system. I identified a novel class of excitatory interneurons (IN1) in the fly brain that regulate food ingestion. In this project, we will first identify the IN1 food intake circuitry using optogenetics and anterograde transsynaptic circuit tracing. Next, we will reveal how IN1 neurons and downstream circuitry change activity during food search in a virtual reality foraging assay using two-photon microscopy. Finally, using cutting- edge three-photon technology, we will capture the activity of IN1 neurons chronically in an intact fly as flies are being food deprived. Functional dissection of IN1 circuitry will lead us to fundamental principles that the nervous system uses to regulate food intake. In parallel with our food intake circuit dissection efforts, we also identified 8 evolutionary conserved genes in a large genetic screen for flies that fail to show compensatory feeding after 24 hours of food deprivation. We will anatomically and functionally dissect the role of these genes and the neural circuits they control in regulating food intake. Finally, we will test the interaction of the candidate food intake genes and the IN1 circuitry in regulating food perception and appetite control. Modelling the food intake and appetite control systematically in a genetically tractable organism allows us to reveal new molecular and neural control mechanisms. Once, we discover key mechanisms underlying food intake and appetite, we can search for similar processes in more complex mammalian models and in patients suffering from obesity or eating disorders to develop treatment strategies that will intervene with the pathogenesis of these life threating diseases.