Role of Neurotensin Neurons in Coordinating Adaptive Energy Balance

神经降压素神经元在协调适应性能量平衡中的作用

• 批准号: 9205459
• 负责人: Juliette Anne Brown
• 金额: $ 2.68万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205459
• 关键词: Acute; Adaptive Behaviors; Adult; American; Appetite Depressants; Appetite Stimulants; Behavior; Biological; Body Weight; Body Weight decreased; Brain; Calories; Comorbidity; Consumption; Corpus striatum structure; Coupled; Cues; Data; Dehydration; Development; Disease; Dopamine; Energy Metabolism; Epidemic; Food; Genetic; Glutamates; Hormones; Inflammation; Inflammatory; Intake; Lateral Hypothalamic Area; Leptin; Mediating; Metabolism; Midbrain structure; Motor Activity; Movement; Mus; Neurons; Neuropeptides; Neurosciences; Neurotensin; Neurotensin Receptors; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome Study; Palate; Pathogenesis; Pharmacology; Physical activity; Physiological; Population; Reagent; Research; Research Personnel; Risk; Role; Signal Transduction; Stimulus; System; Techniques; Testing; Toxicology; Training; Weight; dopamine system; dopaminergic neuron; drinking; effective therapy; energy balance; feeding; gamma-Aminobutyric Acid; hedonic; in vivo; mesolimbic system; metabolic phenotype; mouse model; neuromechanism; neuronal circuitry; novel; pandemic disease; prevent; public health relevance; recombinase; response; therapy development

 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.

 描述（由申请人提供）：肥胖流行使数百万人容易患上 2 型糖尿病。然而，由于对控制能量平衡的神经元回路的不完全了解，肥胖疗法的发展受到限制。下丘脑外侧区（LHA）协调不同的生理刺激和适当的适应性行为（包括进食、饮水和运动行为）以调节体重。许多 LHA 神经元表达厌食神经肽神经降压素 (Nts)，并被抑制进食和促进运动活动的刺激激活，包括脱水、炎症和瘦素激素。这些线索激活的 LHA Nts 神经元投射到中脑，其中 Nts 已被证明可以激活多巴胺 (DA) 神经元、减少进食并增加运动活动。我假设 LHA Nts 神经元协调厌食信号和中脑边缘多巴胺系统以促进体重减轻，而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要求。在目标 2 中，我将确定 LHA Nts 神经元亚群将厌食信号转导至中脑的神经机制。为了实现这些目标，我的赞助商 Gina Leinninger 博士将培训我使用新型遗传试剂和代谢表型来检查肥胖的发病机制。我的共同发起人 James Galligan 博士将在范例中对我进行培训，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，并发展成为一名富有成效的、独立的肥胖研究人员。