Molecular and Neural Mechanisms regulating Foraging and Food Intake

调节觅食和食物摄入的分子和神经机制

• 批准号: 10454362
• 负责人: Nilay Yapici
• 金额: $ 40.14万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-07 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454362
• 关键词: Anatomy; Animal Model; Animals; Behavior; Biological Assay; Brain; Cells; Chronic; Complex; Desire for food; Disease; Dissection; Drosophila melanogaster; Eating; Eating Behavior; Eating Disorders; Energy Intake; Energy Metabolism; Esthesia; Failure; Food; Food deprivation (experimental); Genes; Genetic; Genetic Models; Genetic Screening; Hour; Human; Hunger; Individual; Ingestion; Interneurons; Knowledge; Lead; Life; Metabolic syndrome; Modeling; Modification; Molecular; Monitor; Mus; Nervous system structure; Neurons; Nutrient; Obesity; Organism; Pathogenesis; Patients; Perception; Photons; Population; Process; Research; Rodent Model; Role; Sensory; Taste Perception; Technology; Testing; Therapeutic; Vertebrates; energy balance; feeding; fly; hedonic; insight; mind control; neural circuit; neuromechanism; neuroregulation; novel; optogenetics; treatment strategy; two photon microscopy; virtual reality

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.

摘要 在正常人中，食物摄入受到感觉、自我平衡和享乐神经回路的严格调节， 平衡能量摄入和能量消耗。无法调节食物感知和食欲， 不适应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经在啮齿动物模型中得到了广泛的研究。但 哺乳动物大脑的复杂性使得解释潜在的分子机制非常具有挑战性 和控制食物摄入的电路动力学。我建议用一种遗传学上易于处理的模式生物， （果蝇），了解大脑如何整合感觉的基本原则， 通过饥饿感来调节分子、细胞和电路水平上的食物摄入量。 苍蝇是研究这些过程的一个很好的模型，因为它们的大脑中的神经元要少1000倍。 然而，它们仍然显示出饥饿状态和特定的食物摄入控制， 在脊椎动物中。此外，苍蝇神经系统更容易进行遗传修饰，解剖学修饰， 研究和监测行为动物中大量神经元的活动。此前，我曾表示 苍蝇和人类一样，通过将食物的味道和营养价值与饥饿相结合来调节食物的摄入量， 神经系统中的感觉。我在果蝇大脑中发现了一类新的兴奋性中间神经元（IN 1）， 调节食物摄入。在这个项目中，我们将首先使用光遗传学识别IN 1食物摄入回路， 顺行跨突触回路描记。接下来，我们将揭示IN 1神经元和下游电路如何改变 在使用双光子显微镜的虚拟现实觅食测定中，在食物搜索期间的活动。最后，使用切割- 利用先进的三光子技术，我们将在一只完整的苍蝇中长期捕获IN 1神经元的活动，就像苍蝇一样。 被剥夺食物。IN 1回路的功能解剖将引导我们了解神经系统的基本原理， 系统用来调节食物摄入量。在我们的食物摄入回路解剖工作的同时，我们还确定了8个 进化保守基因在一个大的遗传筛选苍蝇，未能显示补偿喂养后24 几个小时的食物匮乏我们将从解剖学和功能上剖析这些基因的作用， 它们控制的调节食物摄入的回路。最后，我们将测试候选人食物摄入量的相互作用 基因和IN 1电路调节食物感知和食欲控制。模拟食物摄入量， 在遗传上易于控制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系统， 控制机制。一旦我们发现了食物摄入和食欲的关键机制， 在更复杂的哺乳动物模型和患有肥胖或进食障碍的患者中进行类似的过程 疾病，以制定治疗策略，将干预这些生命威胁的发病机制 疾病