VTA MC3R neurons in the control of feeding and body weight

VTA MC3R 神经元控制摄食和体重

• 批准号: 10341086
• 负责人: Aaron G Roseberry
• 金额: $ 37.88万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10341086
• 关键词: ART protein; Affect; Anatomy; Behavior; Body Weight; Brain region; Disease; Dopamine; Eating; Electrophysiology (science); Fatty acid glycerol esters; Food; Future; Glutamates; Goals; Human; In Vitro; Incidence; Injections; Intake; Knowledge; Mediating; Medical Care Costs; Melanocortin 3 Receptor; Motivation; Neurons; Neuropeptides; Neurotransmitters; Obesity; Overweight; Pathway interactions; Play; Population; Pro-Opiomelanocortin; Regulation; Rewards; Role; Site; System; Testing; United States; Ventral Tegmental Area; alpha-Melanocyte stimulating hormone; antagonist; combat; designer receptors exclusively activated by designer drugs; dopamine system; economic cost; effective therapy; feeding; fighting; gamma-Aminobutyric Acid; hedonic; in vivo; integration site; mesolimbic system; neural circuit; neuromechanism; neuropeptide Y; neurotransmitter release; obesity development; obesity prevention; optogenetics; patch clamp; prevent; receptor; sugar

PROJECT SUMMARY/ABSTRACT: Obesity is a significant problem, with ~70% of the US population considered overweight or obese and estimated annual medical and economic costs >100 billion, yet there are few effective therapies currently available to combat obesity. The intake of appetizing high fat/high sugar foods has increased in parallel to the increased incidence of obesity, suggesting that targeting the pathways controlling the intake of these foods may be a viable mechanism for combating obesity. The mesolimbic dopamine system is the primary neural circuit controlling motivation and reward-related behavior, including the motivational and rewarding aspects of high fat/high sugar foods, and changes in dopamine circuits have been implicated in obesity. The melanocortin system is a neural circuit that plays in important role in controlling feeding and body weight, and it appears to interact with dopamine circuits to control feeding, in part through actions on MC3Rs in the ventral tegmental area (VTA). Overall, we have a poor understanding of how dopamine circuits control feeding however, including how melanocortin circuits and MC3Rs interact with dopamine circuits to control feeding and body weight. As both dopamine circuits and MC3Rs have been implicated in human obesity, these combined circuits may be an excellent target for potential future approaches to combat obesity. Therefore, increasing our currently limited understanding of how MC3Rs and VTA MC3R neurons interact with dopamine circuits to control feeding will greatly advance our ability to combat obesity. The central hypothesis of this proposal is that VTA MC3R neurons integrate information from multiple different neurotransmitters released from proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons to decrease feeding through the combined release of dopamine and glutamate in a restricted set of efferent target regions. This hypothesis will be tested in two specific aims. In Aim 1, advanced anatomical and electrophysiological approaches will be combined with in vivo optogenetics to test the hypothesis that POMC and AgRP neurons act in the VTA to control feeding and body weight by releasing multiple neurotransmitters that regulate the activity of VTA MC3R neurons. In Aim 2, anatomical approaches will be combined with in vivo optogenetics and DREADDs to test the hypothesis that VTA MC3R neurons directly control feeding through the combined release of dopamine and glutamate in specific efferent target regions. This project will significantly advance our understanding of the neural mechanisms controlling feeding and body weight and the development of obesity, and ultimately, this knowledge may allow for the identification of new strategies to treat and/or prevent obesity.

项目摘要/摘要： 肥胖是一个重大问题，约有70％的美国人口被认为超重或肥胖， 估计年度医疗和经济成本> 1000亿，但目前几乎没有有效的疗法 可用于对抗肥胖。与高脂肪/高糖食品开胃的摄入量与 肥胖的发生率增加，表明针对控制这些食物摄入的途径 可能是打击肥胖症的可行机制。中唇多巴胺系统是主要神经 控制动机和奖励相关行为的电路，包括 高脂肪/高糖食品以及多巴胺回路的变化与肥胖有关。这 黑素皮质素系统是一种神经回路，在控制喂养和体重中起着重要作用，并且 似乎与多巴胺电路相互作用以控制进食，部分通过腹侧MC3R的动作 段区域（VTA）。总体而言，我们对多巴胺电路如何控制进食的理解很差 但是，包括黑色皮质素电路和MC3RS与多巴胺电路相互作用以控制进食和 体重。由于多巴胺电路和MC3R都与人肥胖有关，因此这些结合了 电路可能是对抗肥胖的未来方法的绝佳目标。因此，增加我们的 当前对MC3RS和VTA MC3R神经元如何与多巴胺电路相互作用的了解有限 控制喂养将大大提高我们对抗肥胖的能力。该提议的核心假设是 VTA MC3R神经元整合了来自多种不同神经递质的信息 蛋白酶素皮质（POMC）和与Agouti相关蛋白（AGRP）神经元，以减少通过 多巴胺和谷氨酸的合并释放在受限的传出靶区域中。这个假设将会 在两个具体目标中进行测试。在AIM 1中，先进的解剖学和电生理方法将是 结合体内光遗传学，以检验pOMC和AGRP神经元在VTA中作用于TO的假设 通过释放多个调节VTA MC3R活性的神经递质来控制喂养和体重 神经元。在AIM 2中，解剖方法将与体内光遗传学和可怕的测试相结合 VTA MC3R神经元直接通过多巴胺释放直接控制进食的假设 和特定传出目标区域中的谷氨酸。这个项目将大大提高我们对 控制喂养和体重的神经机制以及肥胖的发展，最终 这些知识可能允许确定治疗和/或预防肥胖症的新策略。

项目成果

Whole-brain efferent and afferent connectivity of mouse ventral tegmental area melanocortin-3 receptor neurons.

• DOI: 10.1002/cne.25013
• 发表时间: 2021-04-15
• 期刊: The Journal of comparative neurology
• 作者: Dunigan AI;Swanson AM;Olson DP;Roseberry AG
• 通讯作者: Roseberry AG

Amphetamine Dose-Dependently Decreases and Increases Binge Intake of Fat and Sucrose Independent of Sex.

安非他明剂量依赖性地减少和增加脂肪和蔗糖的暴饮暴食，与性别无关。

• DOI: 10.1002/oby.22636
• 发表时间: 2019
• 期刊: Obesity (Silver Spring, Md.)
• 作者: West,KatherineStuhrman;Lawson,Valen;Swanson,AndrewM;Dunigan,AnnaI;Roseberry,AaronG
• 通讯作者: Roseberry,AaronG

Actions of feeding-related peptides on the mesolimbic dopamine system in regulation of natural and drug rewards.

• DOI: 10.1016/j.addicn.2022.100011
• 发表时间: 2022-06-01
• 期刊: Addiction neuroscience
• 作者: Dunigan, Anna I;Roseberry, Aaron G
• 通讯作者: Roseberry, Aaron G