Neural Mechanisms by which Lateral Hypothalamic Neurotensin Neurons Regulate Energy Balance

 描述（由申请人提供）：三分之一的美国成年人肥胖，有患2型糖尿病的风险，但几乎没有有效的治疗方法可以促进健康的体重。需要对控制能量平衡的生理机制有更好的理解，以开发肥胖症的治疗方法。大脑下丘脑外侧区（LHA）的神经元通过与腹侧被盖区（VTA）的多巴胺（DA）神经元接合来对摄食和能量平衡进行相反的控制。腹侧被盖区的DA释放调节目标驱动的身体活动和可口的食物寻求，这些行为被破坏并导致肥胖。Leinninger实验室已经开始表征表达神经降压素（Nts）的LHA神经元群体，神经降压素是一种促进DA释放、抑制进食和增加运动活性的神经肽。LHA Nts神经元投射到VTA，其中许多DA神经元表达神经降压素受体1（NtsR1）。与其他促进进食的LHA神经元亚型相反，LHA Nts神经元对厌食提示做出反应，并准备抑制进食。因此，我假设LHA Nts神经元参与中脑边缘DA系统，以抑制食物摄入和增加体力活动，从而有利于负能量平衡。在目标1中，我将定义Nts和NtsR1神经元参与DA系统的神经回路。在目标2中，我将选择性地激活LHA Nts神经元以测试以下假设：通过LHA Nts神经元回路的作用抑制食物摄入并促进自发活动以诱导体重减轻。通过我的共同赞助人吉娜·莱宁格博士和谢丽尔·西斯克博士，我将学习结合联合收割机新型遗传试剂、药物遗传学、代谢表型和神经行为范例来确定LHA Nts神经元回路在能量平衡中的作用。这些连接新陈代谢和神经科学的最先进技术的培训将使我能够完成这份提案，并且是促进我成为研究和治疗肥胖的医生科学家的基本技能。

 DESCRIPTION (provided by applicant): One third of U.S. adults are obese and at risk to develop type-2 diabetes, yet few effective treatments exist to promote healthy body weight. Improved understanding of the physiologic mechanisms that control energy balance is needed to develop treatments for obesity. Neurons in the lateral hypothalamic area (LHA) of the brain exert opposing control of feeding and energy balance by engaging dopamine (DA) neurons in the ventral tegmental area (VTA). DA release from the VTA regulates goal-driven physical activity and palatable food- seeking, behaviors that are disrupted in, and contribute to obesity. The Leinninger lab has begun to characterize a population of LHA neurons that expresses neurotensin (Nts), a neuropeptide that promotes DA release, suppresses feeding and increases locomotor activity. LHA Nts neurons project to the VTA, where many DA neurons express neurotensin receptor-1 (NtsR1). In contrast to other LHA neuronal sub-types that promote feeding, LHA Nts neurons respond to anorectic cues and are poised to suppress feeding. I therefore hypothesize that LHA Nts neurons engage the mesolimbic DA system to restrain food intake and increase physical activity, thus favoring negative energy balance. In Aim 1, I will define the neuronal circuit by which Nts and NtsR1 neurons engage the DA system. In Aim 2, I will selectively activate LHA Nts neurons to test the hypothesis that action via the LHA Nts neuronal circuit suppresses food intake and promotes locomotor activity to induce weight loss. Via my co-sponsors Dr. Gina Leinninger and Dr. Cheryl Sisk, I will learn to combine novel genetic reagents, pharmacogenetics, metabolic phenotyping and neurobehavioral paradigms to determine the role of the LHA Nts neuronal circuit in energy balance. Training in these state-of- the-art techniques that bridge metabolism and neuroscience will enable me to complete this proposal and are essential skills to promote my development into a physician-scientist studying and treating obesity.