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

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，解决肥胖的高发问题被证明是极其困难的。最近的证据表明，肥胖个体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，这表明停止暴饮暴食可能和戒断吸毒一样困难。因此，阐明与消耗高热量食物和滥用药物的驱动有关的神经回路对肥胖和药物成瘾治疗策略的发展至关重要。本实验利用小鼠遗传模型，研究了瘦素和食欲素这两种有效的代谢信号蛋白对腹侧被盖区（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强化特性的调节。VTA多巴胺能神经元，投射到前脑结构，如伏隔核和前额皮质，参与调解许多滥用药物的行为反应。有趣的是，有证据表明VTA多巴胺神经元被食欲素激发，被瘦素抑制。因此，这些代谢信号可能在VTA中起作用，调节能量稳态，同时寻求药物和天然食物奖励。在实验1中，使用Cre-lox系统将麻风基因从小鼠VTA神经元中删除，以测试麻风基因信号的必要性；而在实验2中，一个麻风基因等位基因可以在VTA无麻风背景下选择性地重新激活，以测试VTA瘦素信号在调节能量稳态和增强食物和可卡因特性方面的充分性。在Aim 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受体缺失的背景下在VTA中被重新激活，类似于瘦素可重新激活受体模型，将被用来测试食欲素在VTA中调节能量稳态和增强食物和可卡因特性的充充性。总之，拟议的研究将全面测试食欲素和瘦素在VTA中的作用，以及它们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动力。公共卫生相关性：拟议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。研究结果将为制定预防吸毒和摄入高热量食物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.