Deconstructing the Neural Control of Food Seeking

解构寻找食物的神经控制

基本信息

批准号：
9363470
负责人：
John Nicholas Betley
金额：
$ 40.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-17 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9363470
关键词：
ART protein Accelerometer Acute Affective Anatomy Animals Axon Behavior Behavior Control Behavioral Body Weight decreased Brain Brain region Caloric Restriction Cessation of life Comorbidity Consumption Cues Data Development Diet Eating Feeling Food Human Hunger Hypothalamic structure Individual Intake Learning Mediating Medical Motivation Negative Valence Neurons Neurosciences Obese Mice Obesity Pattern Pharmacology Physiological Public Health Recruitment Activity Role Signal Transduction Structure of nucleus infundibularis hypothalami Techniques Testing Thinness United States Weight Gain Work awake cost design experimental study improved in vivo calcium imaging negative affect neuromechanism neuroregulation neurotransmission novel obesity treatment optogenetics preference recidivism reduced food intake relating to nervous system translational impact

项目摘要

Summary. The dramatic increase in obesity and associated comorbidities in the United States is a major public health concern. While weight loss improves these conditions, widespread difficulty in implementing successful diets and high recidivism are major barriers to effective obesity treatments. The objective of this proposal is to identify neuron subpopulations and define neural mechanisms that impede weight loss. Agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus are activated by energy deficit and motivate food seeking and consumption. We have demonstrated that AgRP neurons transmit a negative valence signal that may underlie the negative affect often associated with hunger and weight loss. Thus, there is a critical need to identify how AgRP neurons communicate with other brain regions to drive negative valence, food seeking, and consumption. AgRP neurons can be divided into distinct subpopulations that project to one of several target brain regions, but our understanding of the distinct AgRP projection subpopulations that mediate the physiological and affective consequences of AgRP neural activity remains incomplete. To this end, the complementary aims in this proposal use state-of-the-art techniques to characterize, with unprecedented levels of detail, the AgRP neuron projection subpopulations and circuit mechanisms that drive food intake. Specifically, our experiments will (1) identify the distinct AgRP projection subpopulation(s) that mediate the negative valence associated with hunger, (2) determine the endogenous activity patterns of AgRP subpopulations during the transition between replete and deprived physiological states, (3) examine how AgRP subpopulation activity changes with obesity, and (4) determine the AgRP projection subpopulations that contribute to the motivation to work for food. Overall, results from these experiments will identify brain regions that are physiologically and functionally recruited by AgRP neuron activity, providing novel neural substrate targets that can be leveraged to develop potent therapies for obesity.

概括。在美国，肥胖和相关合并症的急剧增加是一个重大的公共卫生问题忧虑。虽然减肥改善了这些状况，但实施成功的饮食普遍存在困难和高累犯率是有效治疗肥胖症的主要障碍。该提案的目的是识别神经元亚群并定义阻碍减肥的神经机制。刺鼠相关蛋白下丘脑弓状核中表达 AgRP 的神经元因能量不足而被激活，激发食物寻找和消费。我们已经证明 AgRP 神经元传递负信号价信号可能是通常与饥饿和体重减轻相关的负面影响的基础。因此，有迫切需要确定 AgRP 神经元如何与其他大脑区域通信以驱动负性价、食物寻找和消耗。 AgRP 神经元可分为不同的亚群投射到几个目标大脑区域之一，但我们对不同 AgRP 投射的理解介导 AgRP 神经活动的生理和情感后果的亚群仍然存在不完整。为此，本提案中的补充目标使用最先进的技术来以前所未有的详细程度描述 AgRP 神经元投射亚群和电路驱动食物摄入的机制。具体来说，我们的实验将 (1) 识别不同的 AgRP 投影介导与饥饿相关的负价的亚群，（2）决定内源性 AgRP 亚群在生理充足和生理匮乏之间过渡期间的活动模式状态，(3) 检查 AgRP 亚群活性如何随肥胖而变化，以及 (4) 确定 AgRP 预测有助于为食物而工作的动机的亚人群。总体而言，这些结果实验将确定 AgRP 神经元在生理和功能上招募的大脑区域活性，提供新的神经底物靶标，可用于开发有效的肥胖疗法。