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

肥胖已成为本世纪最紧迫的公共卫生问题之一。不幸的是， 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 类似于那些滥用药物成瘾的人，多巴胺能神经传递的改变，认为， 停止暴饮暴食可能就像戒除毒品一样困难。因此，阐明神经回路 这些参与了高热量食物和药物滥用的驱动力， 开发治疗肥胖和药物成瘾的治疗策略。 拟议的实验研究，使用小鼠遗传模型，两个强大的代谢信号的直接作用 蛋白质，瘦素和食欲素，对腹侧被盖区（VTA）的神经元和它们的控制能量稳态， 调节食物和可卡因的强化特性。腹侧被盖区多巴胺能神经元，投射至前脑 神经核和前额叶皮层等结构参与调节许多行为， 对滥用药物的反应。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，这些代谢信号可以在VTA中起作用，以沿着调节能量稳态。 寻求药物和天然食物的回报。 目的1：利用Cre-lox系统，从小鼠VTA神经元中删除lepr，以检测lepr的必要性。 而在aim 2中，可以在VTA中的空lepr背景下选择性地再激活的lepr等位基因将被 用于测试腹侧被盖区瘦素信号传导在调节能量稳态中的充分性和 食物和可卡因在目标3中，携带突变的食欲素1受体等位基因的小鼠可以在VTA中重新激活， 食欲素1受体空背景，类似于瘦素可再活化受体模型，将用于测试足够性 食欲素在腹侧被盖区调节能量平衡和食物及可卡因的强化作用。 总之，所提出的研究将全面测试食欲素和瘦素在腹侧被盖区中的作用及其对腹侧被盖区的影响。 随后对肥胖症的发展以及消费食物和精神兴奋剂可卡因的驱动力的影响。

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.