Role of Neurotensin Neurons in Coordinating Adaptive Energy Balance

 描述(申请人提供)：肥胖大流行使数百万人易患2型糖尿病。然而，肥胖症治疗方法的发展一直受到对控制能量平衡的神经元回路的不完全理解的限制。下丘脑外侧区(LHA)通过适当的适应行为(包括进食、饮水和运动行为)协调不同的生理刺激来调节体重。许多LHA神经元表达厌食神经肽神经降压素(NTS)，并被抑制摄食和促进运动活动的刺激激活，包括脱水、炎症和激素瘦素。这些线索激活的LHA NTS神经元投射到中脑，在那里NTS已被证明激活多巴胺(DA)神经元，减少摄食和增加运动活动。我假设LHA NTS神经元协调厌食信号和中脑边缘多巴胺系统来促进体重减轻，而通过这些神经元失去作用会促进肥胖。在目标1中，我将选择性地消融LHA NTS神经元，以确定它们协调能量平衡的需求。在目标2中，我将确定LHA NTS神经元亚群将厌食线索传递到中脑的神经机制。为了实现这些目标，我的赞助人吉娜·莱宁格博士将培训我使用新的遗传试剂和代谢表型来检查肥胖的发病机制。我的共同赞助人，詹姆斯·加里根博士将培训我，以确定炎症信号如何调节LHA NTS神经元，并有助于能量平衡。总的来说，他们在连接神经科学、毒理学和新陈代谢的最先进技术方面的培训将使我能够完成这些研究，并发展成为一名多产的、研究肥胖的独立研究员。

 DESCRIPTION (provided by applicant): The obesity pandemic predisposes millions to develop type-2 diabetes. Development of therapies for obesity, however, has been limited by incomplete understanding of the neuronal circuits that control energy balance. The lateral hypothalamic area (LHA) coordinates diverse physiologic stimuli with appropriate adaptive behaviors (including feeding, drinking and locomotor behavior) to modulate body weight. Many LHA neurons express the anorectic neuropeptide neurotensin (Nts) and are activated by stimuli that suppress feeding and promote locomotor activity, including dehydration, inflammation and the hormone leptin. These cue-activated LHA Nts neurons project into the midbrain, where Nts has been shown to activate dopamine (DA) neurons, decrease feeding and increase locomotor activity. I hypothesize that LHA Nts neurons coordinate anorectic signals and the mesolimbic dopamine system to promote weight loss, and loss of action via these neurons promotes obesity. In Aim 1 I will selectively ablate LHA Nts neurons to define their requirement for coordinating energy balance. In Aim 2 I will determine the neural mechanisms by which subpopulations of LHA Nts neurons transduce anorectic cues to the midbrain. To accomplish these aims my Sponsor, Dr. Gina Leinninger, will train me to use novel genetic reagents and metabolic phenotyping to examine the pathogenesis of obesity. My Co-Sponsor, Dr. James Galligan will train me in paradigms to determine how inflammatory signaling regulates LHA Nts neurons and contributes to energy balance. Collectively, their training in state-of-the art techniques bridging neuroscience, toxicology and metabolism will enable me to complete these studies and develop into a productive, independent researcher studying obesity.