Orexin and Leptin Regulation of Feeding and Addictive Behavior in the VTA

食欲素和瘦素对 VTA 中进食和成瘾行为的调节

• 批准号: 7739920
• 负责人: Michael Scott
• 金额: $ 8.87万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739920
• 关键词: Addictive Behavior; Address; Adult; Alleles; Animals; Behavior; Behavioral; Biological Assay; Brain; Cocaine; Complex; Consumption; Cues; Development; Diet; Drug Addiction; Drug usage; Eating; Employee Strikes; Energy Metabolism; Environment; Fatty acid glycerol esters; Food; Food Intake Regulation; Genetic Models; Homeostasis; Incidence; Individual; Intake; Knockout Mice; Leptin; Mammals; Mediating; Metabolic; Modeling; Mus; Nature; Neurons; Nucleus Accumbens; Nutrient; Obesity; Pharmaceutical Preparations; Phenotype; Predisposition; Prefrontal Cortex; Property; Prosencephalon; Public Health; Regulation; Relative (related person); Rewards; Signal Transduction; Signaling Protein; Structure; System; Testing; Ventral Tegmental Area; design; dopaminergic neuron; drug abuse prevention; drug of abuse; drug reward; feeding; hypocretin; leptin receptor; motivated behavior; mouse model; mutant; neural circuit; neurotransmission; obesity in children; obesity treatment; orexin 1 receptor; preference; psychostimulant; public health relevance; receptor; receptor expression; research study; response; restoration; therapeutic development; treatment strategy

DESCRIPTION (provided by applicant): Obesity has become one of the most pressing public health issues of the current century. Unfortunately, tackling the high incidence of obesity is proving to be extremely difficult. Recent evidence suggests the brains of obese individuals resemble those of people addicted to drugs of abuse, with alterations in dopaminergic neurotransmission, arguing that cessation of over eating may be as difficult as abstaining from drug use. Consequently, elucidating the neural circuits that are involved in both the drive to consume high calorie foods and drugs of abuse is extremely important in the development of therapeutic strategies in the treatment of obesity and drug addiction. The proposed experiments examine, using mouse genetic models, the direct action of two potent metabolic signaling proteins, leptin and orexin, on neurons of the ventral tegmental area (VTA) and their control of energy homeostasis and modulation of the reinforcing properties of food and cocaine. VTA dopaminergic neurons, projecting to forebrain structures such as the nucleus accumbens and prefrontal cortex, are involved in mediating many of the behavioral responses to drugs of abuse. Interestingly, evidence suggests that VTA dopamine neurons are excited by orexin and inhibited by leptin. Thus, these metabolic signals may act in the VTA to modulate energy homeostasis along with the seeking of both drug and natural food rewards. In Aim 1, lepr will be deleted from mouse VTA neurons, using the Cre-lox system, to test the necessity of lepr signalling while in aim 2, a lepr allele that can be selectively reactivated on a null lepr background in the VTA will be used to test the sufficiency of VTA leptin signalling in regulating energy homeostasis and the reinforcing properties of food and cocaine. In Aim 3, mice carrying a mutant orexin 1 receptor allele that can be reactivated in the VTA on an orexin 1 receptor null background, similar to the leptin reactivatable receptor model, will be used to test the sufficency of orexin action in the VTA in modulating both energy homeostasis and the reinforcing properties of food and cocaine. In summary, the proposed studies will comprehensively test the action of orexin and leptin in the VTA and their subsequent effect on the development of obesity and the drive to consume both food and the psychostimulant cocaine. PUBLIC HEALTH RELEVANCE: The proposed studies will greatly increase our understanding of the mechanisms underlying drug addiction and the drive to consume calorie dense food. The study findings will provide valuble information with which to develop treatment strategies for the prevention of drug use and consumption of calorie dense food.

描述（由申请人提供）：肥胖已成为本世纪最紧迫的公共卫生问题之一。不幸的是，解决肥胖症的高发率被证明是极其困难的。最近的证据表明，肥胖者的大脑与滥用药物成瘾者的大脑相似，多巴胺能神经传递发生了变化，认为停止过度进食可能与戒断药物使用一样困难。因此，阐明参与消耗高热量食物和滥用药物的驱动的神经回路在治疗肥胖和药物成瘾的治疗策略的开发中是极其重要的。拟议的实验研究，使用小鼠遗传模型，两个有效的代谢信号蛋白，瘦素和食欲素，对腹侧被盖区（VTA）的神经元和它们的能量稳态控制和食物和可卡因的强化性能的调制的直接作用。腹侧被盖区的多巴胺能神经元投射到前脑结构，如丘脑核和前额皮质，参与介导许多对滥用药物的行为反应。有趣的是，有证据表明腹侧被盖区多巴胺神经元被食欲素兴奋，被瘦素抑制。因此，这些代谢信号可能在腹侧被盖区起作用，以调节能量稳态沿着寻求药物和天然食物奖励。在目标1中，使用Cre-lox系统将lepr从小鼠VTA神经元中删除，以测试lepr信号传导的必要性，而在目标2中，可以在VTA中的空lepr背景上选择性地再激活的lepr等位基因将用于测试VTA瘦素信号传导在调节能量稳态和食物和可卡因的增强特性中的充分性。在目的3中，携带突变的食欲素1受体等位基因的小鼠将用于测试食欲素在VTA中的作用在调节能量稳态和食物和可卡因的增强性质中的充分性，所述突变的食欲素1受体等位基因可以在食欲素1受体无效背景下在VTA中被再激活，类似于瘦素可再激活受体模型。总之，拟议的研究将全面测试食欲素和瘦素在腹侧被盖区的作用及其对肥胖发展的后续影响，以及消耗食物和精神兴奋剂可卡因的驱动力。 公共卫生相关性：拟议中的研究将大大增加我们对药物成瘾和消耗高热量食物的驱动机制的理解。研究结果将提供有价值的信息，以制定预防药物使用和高热量食物消费的治疗策略。