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

基本信息

批准号：
10670270
负责人：
Nilay Yapici
金额：
$ 40.14万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
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/10670270
关键词：
Anatomy 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 Life Metabolic syndrome Modeling Modification Molecular Monitor Mus Nervous System 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 gene conservation hedonic insight mind control model organism neural circuit neuromechanism neuroregulation novel optogenetics sensory integration treatment strategy two photon microscopy virtual reality

项目摘要

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.

抽象的在普通人中，食物摄入严格受到感觉，体内平衡和享乐神经回路的调节，平衡能量摄入量与能量消耗。无法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的增加。调节食物摄入的神经回路已在啮齿动物模型中得到了广泛的研究。但是，哺乳动物大脑的复杂性使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。我建议使用遗传上可牵引的模型生物，苍蝇（果蝇Melanogaster），了解大脑如何整合感觉的基本原理对食物的感知饥饿感在分子，细胞和电路水平上调节食物摄入量。苍蝇是研究这些过程的绝佳模型，因为它们的神经元少1000倍大脑比小鼠，但它们仍然显示出饥饿状态和特定的食物摄入控制，与那些的食物摄入量非常相似在脊椎动物中。此外，蝇神经系统更容易进行遗传修饰，解剖学研究和监测行为动物中大量神经元种群的活性。以前，我已经表明像人类一样，飞翔通过将食物的口味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。我确定了一类新颖的兴奋性中间神经元（in1），在苍蝇大脑中调节食物摄入。在这个项目中，我们将首先使用光遗传学和顺行透射电路跟踪。接下来，我们将揭示IN1神经元和下游电路的变化使用两光子显微镜在虚拟现实觅食测定中进行食物搜索过程中的活动。最后，使用剪裁 - 边缘三光子技术，我们将在完整的苍蝇中捕获1个神经元的活动，因为苍蝇是被剥夺了食物。 In1电路的功能解剖将使我们达到紧张的基本原则系统用于调节食物摄入量。与我们的食物摄入电路解剖工作同时，我们还确定了8 果蝇的大遗传筛选中的进化保守基因，这些果蝇未能在24之后表现出代偿喂养食物剥夺时间。我们将在解剖和功能上剖析这些基因和神经的作用他们控制着调节食物摄入的电路。最后，我们将测试候选食物摄入的相互作用基因和IN1电路调节食物感知和食欲控制。建模食物摄入量和在遗传诱导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。有一次，我们发现食物摄入和食欲的基础的关键机制，我们可以搜索对于更复杂的哺乳动物模型和患有肥胖或进食的患者的类似过程制定治疗策略的疾病，这些策略将干预这些威胁这些生命的发病机理疾病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Of flies, mice and neural control of food intake: lessons to learn from both models.

DOI：
10.1016/j.conb.2022.102531
发表时间：
2022-04
期刊：
Current opinion in neurobiology
影响因子：
5.7
作者：
通讯作者：

Spatially resolved measurements of ballistic and total transmission in microscale tissue samples from 450 nm to 1624 nm

对 450 nm 至 1624 nm 范围内的微型组织样品中的弹道和总透射率进行空间分辨测量

DOI：
10.1364/boe.441844
发表时间：
2021
期刊：
Biomedical Optics Express
影响因子：
3.4
作者：
Mok, Aaron T.;Shea, Jamien;Wu, Chunyan;Xia, Fei;Tatarsky, Rose;Yapici, Nilay;Xu, Chris
通讯作者：
Xu, Chris