Neural determinants on meal size in invertebrate models of obesity

无脊椎动物肥胖模型中膳食量的神经决定因素

• 批准号: 10518734
• 负责人: Monica Dus
• 金额: $ 39.07万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518734
• 关键词: Address; Affect; American; Animals; Appetitive Behavior; Behavior; Behavioral Assay; Body Weight; Brain; Brain region; Calcium; Calories; Chronic Disease; Consumption; Cues; Data; Development; Diet; Dopamine; Eating; Environment; Etiology; Exposure to; Fatty acid glycerol esters; Feeding behaviors; Food; Functional Imaging; Future; Genetic; Goals; Human; Impairment; Intake; Invertebrates; Knowledge; Learning; Life Expectancy; Light; Link; Mammals; Measurement; Memory; Metabolic; Metabolic Diseases; Metabolic syndrome; Mission; Modeling; Mushroom Bodies; National Institute of Diabetes and Digestive and Kidney Diseases; Neurons; Nutrient; Obesity; Output; Play; Process; Property; Psychological reinforcement; Publishing; Research; Rewards; Role; Sensory; Signal Transduction; Sodium Chloride; System; Taste Perception; Testing; Transgenic Organisms; Vertebrates; Weight Gain; Work; base; classical conditioning; connectome; density; dietary; dopaminergic neuron; expectation; experience; experimental study; fly; food consumption; food environment; food quality; high body mass index; in vivo calcium imaging; in vivo imaging; learning network; neural circuit; neurochemistry; neurogenetics; neuromechanism; neuroregulation; obesogenic; optogenetics; prevent; recruit; relating to nervous system; sensor; sugar; tool; transmission process

PROJECT SUMMARY During eating animals modulate the size of meals by associating sensory cues with rewarding qualities of food. This process is central to the control of food intake and is impaired in humans and animals exposed to high fat and sugar diets. The neural mechanisms through which food associations 1) regulate meal size and 2) are perturbed by this dietary environment, however, remain poorly understood. This lack of knowledge has hindered progress in uncovering the underlying causes of obesity and, thus, in curbing the spread of metabolic disease. Here we propose to use the D. melanogaster model to address the need for mechanistic studies on the neural regulation and deregulation of meal size. A diet high in sugar promotes higher intake and obesity in flies, but unlike vertebrate models, the neural circuits involved in food associations converge onto a single brain region; further, transgenic tools to manipulate and visualize these circuits are publicly available, thanks to decades of research and the connectome. Our long term goal is to use the unique advantages of the fly model to uncover how food environments high in sugar and fat promote obesity and metabolic disease. Our central hypothesis is that diet-driven changes in dopamine transmission underlie the increase in meal size observed in animals fed high-calorie diets. This hypothesis is based on our published and unpublished data showing a causal link between the dopaminergic processing of taste and nutrient qualities, the formation of food associations, and intake. To test this idea we will use in vivo imaging of calcium and dopamine signals, behavioral assays, metabolic measurements, and optogenetic manipulations of dopaminergic, associative learning, and premotor circuits to define both the causes of impaired food associations (Aim 1) and their consequences on meal size (Aim 2). The successful completion of the proposed studies will define how food associations control intake and the extent through which diet-dependent alterations in DA signaling impact this process; this will illuminate the neural mechanisms that regulate meal size and uncover how they are deregulated by the food environment. Together, this will help advance our understanding of the causes of obesity, which is key to the NIDDK mission of decreasing the burden and spread of metabolic disease.

项目摘要 在吃动物期间，通过将感官提示与有意义的品质相关联，可以调节饭菜的大小 食物。这个过程是控制食物摄入量的核心，并且在人类和暴露于的动物中受到损害 高脂肪和糖饮食。食物关联的神经机制1）调节餐大小和2） 然而，这种饮食环境使人们感到厌烦。缺乏知识 妨碍了揭示肥胖的根本原因，从而阻碍了进步 疾病。在这里，我们建议使用D. melanogaster模型来满足对机械研究的需求 膳食大小的神经调节和放松管制。高糖的饮食可促进更高的摄入量和肥胖 苍蝇，但与脊椎动物模型不同，涉及食物关联的神经回路汇聚到一个 大脑区域；此外，要公开可用来操纵和可视化这些电路的转基因工具，这要归功于 数十年的研究和连接组。我们的长期目标是使用苍蝇模型的独特优势 揭示糖和脂肪含量高的食物环境如何促进肥胖和代谢疾病。我们的中心 假设是，多巴胺传播的饮食驱动的变化是观察到的进餐大小的增加 喂养高热量饮食的动物。该假设基于我们已发布且未发表的数据，显示 味道和营养品质的多巴胺能加工之间的因果关系，食物的形成 协会和进气。为了测试这个想法，我们将使用钙和多巴胺信号的体内成像， 行为测定，代谢测量和多巴胺能的光遗传操作 学习和前电路，以定义食物协会受损的原因（AIM 1）及其 进餐大小的后果（AIM 2）。拟议研究的成功完成将定义食物 关联控制摄入量以及DA信号中饮食依赖性改变的程度影响这一点 过程;这将阐明调节餐大小的神经机制，并发现它们的状态 食物环境放松管制。一起，这将有助于提高我们对 肥胖，这是减轻代谢疾病负担和传播的NIDDK使命的关键。