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

描述(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，事实证明，解决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上瘾的人，多巴胺能神经传递发生了变化，他们认为，戒除暴饮暴食可能与戒毒一样困难。因此，阐明与消耗高热量食物和滥用药物的驱动力有关的神经回路对于制定治疗肥胖症和药物成瘾的治疗策略极其重要。拟议的实验利用小鼠遗传模型，研究了两种强有力的代谢信号蛋白瘦素和食欲素对腹侧被盖区(VTA)神经元的直接作用，以及它们对能量稳态的控制和对食物和可卡因增强特性的调节。VTA多巴胺能神经元投射到伏隔核和前额叶皮质等前脑结构，参与调节对药物滥用的许多行为反应。有趣的是，有证据表明VTA多巴胺神经元被增食欲素兴奋，而被瘦素抑制。因此，这些代谢信号可能在VTA中起作用，调节能量平衡，同时寻求药物和天然食物奖励。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信号的必要性；而在目标2中，可以在VTA中Lepr为零的背景下选择性地重新激活的Lepr等位基因将被用于测试VTA Leptin信号在调节能量稳态以及食物和可卡因的增强特性方面的充分性。在目标3中，携带突变的食欲素1受体等位基因的小鼠，可以在食欲素1受体缺失背景下在VTA中重新激活，类似于瘦素可激活受体模型，将用于测试VTA中食欲素作用在调节能量平衡以及食物和可卡因的增强特性方面的充分性。总而言之，拟议的研究将全面测试增食欲素和瘦素在VTA中的作用，以及它们随后对肥胖发展和消费食物和精神刺激性可卡因的驱动力的影响。与公共健康相关：拟议的研究将极大地提高我们对药物成瘾的潜在机制的理解，以及对摄入高卡路里食物的驱动力。研究结果将为制定预防药物使用和高热量食物消耗的治疗策略提供有价值的信息。

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.