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: 8236865
• 负责人: Michael Scott
• 金额: $ 23.86万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236865
• 关键词: Addictive Behavior; Address; Adult; Alleles; Behavior; Behavioral; Biological Assay; Brain; Cocaine; Complex; Consumption; Cues; Data; Development; Diet; Drug Addiction; Drug usage; Eating; Employee Strikes; Environment; Fatty acid glycerol esters; Feeding behaviors; Food; Food Intake Regulation; Genetic Models; Homeostasis; Hyperphagia; Incidence; Individual; Instruction; 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; novel; obesity in children; obesity treatment; orexin 1 receptor; preference; psychostimulant; receptor; receptor expression; research study; response; restoration; therapeutic development; treatment strategy

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 prefr-ontal 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.

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 事实证明，肥胖症的高发病率是极其困难的。最近的证据表明，肥胖者的大脑 类似于滥用药物成瘾的人，多巴胺能神经传递发生变化，辩称 戒除暴饮暴食可能和戒毒一样困难。因此，阐明神经回路 与高卡路里食物和滥用药物的驱动力有关的因素在 开发治疗肥胖和药物成瘾的治疗策略。 拟议中的实验利用小鼠的遗传模型检验了两个强有力的代谢信号的直接作用。 腹侧被盖区(VTA)神经元上瘦素和食欲素的蛋白质及其对能量稳态和 调节食物和可卡因的增强特性。VTA多巴胺能神经元，投射到前脑 伏隔核和额叶前皮质等结构参与了许多行为的调节。 对滥用药物的反应。有趣的是，有证据表明，VTA多巴胺神经元由增食欲素和 被瘦素抑制。因此，这些代谢信号可能作用于VTA，以调节能量动态平衡 寻求药物和天然食物的奖励。 在目标1中，将使用Cre-lox系统从小鼠VTA神经元中删除Lepr，以测试Lepr的必要性 当在目标2中时，可以在VTA中的零LEPR背景上选择性地重新激活的LEPR等位基因将被 用来测试VTA瘦素信号在调节能量动态平衡中的充分性和增强 食物和可卡因。在目标3中，携带突变的增食欲素1受体等位基因的小鼠可以在VTA中重新激活 与瘦素可激活受体模型类似，增食欲素1受体无背景将被用来测试是否足够 VTA中食欲素在调节能量平衡以及增强食物和可卡因特性方面的作用。 综上所述，拟议的研究将全面测试增食欲素和瘦素在vta中的作用及其 对肥胖的发展和消费食物和精神刺激性可卡因的驱动力的后续影响。