Charting vagal circuits containing glucagon-like peptide 1 receptor

绘制含有胰高血糖素样肽 1 受体的迷走神经回路

• 批准号: 9095676
• 负责人: STEPHEN Daniel LIBERLES
• 金额: $ 38.14万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095676
• 关键词: Ablation; Afferent Neurons; Agonist; Anatomy; Axon; Behavioral; Biology; Blood Pressure; Body Weight; Brain; Brain Stem; Breathing; Cells; Cellular biology; Collection; Complex; Cre-LoxP; Cues; Data; Dependovirus; Desire for food; Diabetes Mellitus; Digestion; Diphtheria Toxin; Disease; Economic Inflation; Electric Stimulation; Feeding behaviors; Foundations; Future; GCG gene; Ganglia; Genetic; Genetic Identity; Genetic Techniques; Health; Heart; Heart Rate; Homeostasis; Hormones; Hypothalamic structure; Imaging Techniques; In Vitro; Infection; Insulin; Intake; Intestines; Irritants; Knock-in Mouse; Location; Lung; Maps; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methods; Molecular Genetics; Mus; Nausea; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Organ; Pattern; Peripheral; Physiological; Physiology; Procedures; Property; Resolution; Respiration; Role; Route; Satiation; Sensory; Specificity; Stimulus; Stomach; Stretching; Techniques; Technology; Therapeutic; Tissues; Tracer; Trachea; Vagotomy; Vagus nerve structure; Virus Diseases; aortic arch; base; blood glucose regulation; calcium indicator; cell type; cohort; diabetes control; drug development; feeding; genetic approach; glucagon-like peptide; improved; in vivo; in vivo imaging; insight; mimicry; neural circuit; neuroregulation; novel; optogenetics; public health relevance; receptor; relating to nervous system; response; sensory mechanism; sensory stimulus; therapy design; therapy development; tool; treatment strategy

 DESCRIPTION (provided by applicant): Glucagon-like peptide 1 (GLP1) is a hormone that controls energy homeostasis, insulin release, and feeding behavior. GLP1 activates a complex neuroendocrine axis that coordinates systemic behavioral and metabolic responses to nutrient intake, with GLP1 receptor (GLP1R) expressed in many locations, including the vagus nerve, brainstem, and hypothalamus. The roles of some GLP1-responsive neurons remain poorly defined, in part due to a lack of appropriate genetic tools. Understanding the roles of different GLP1-responsive neurons is imperative, as therapeutic strategies that involve mimicry or stabilization of GLP1 provide clinically important methods for control of diabetes and potentially other metabolic disorders. GLP1R is expressed in a cohort of vagal sensory neurons, although the roles of vagal GLP1R neurons in feeding behavior, metabolism, and nausea are highly controversial. Recent studies indicate that vagal GLP1R is not required for the effects of GLP1R agonists on body weight or diabetes resolution, raising basic questions about (1) where vagal GLP1R neurons project in the body and brain, (2) what they detect, and (3) what physiological responses they evoke, all of which are unknown. In preliminary data, we used a molecular and genetic approach to deconstruct the sensory vagus nerve into cellular components. We generated a collection of 'ires-Cre' knock-in mice, including Glp1r-ires-Cre mice, and adapted powerful genetic techniques for connectivity mapping, in vivo imaging, and optogenetic control of neural activity in the vagus nerve. Using these approaches, we identified two subtypes of vagal afferents that innervate the lung, and exert powerful and opposing effects on breathing (Cell, 2015), and here, will use related techniques to study the sensory biology of vagal GLP1R neurons. In Aim 1, we developed a strategy for introducing genetic tracers into vagal sensory neurons by adeno-associated virus infection, and will use this technique to map the projections of vagal GLP1R neurons in peripheral organs and the brainstem. In Aim 2, we developed a novel in vivo imaging paradigm in vagal ganglia that involves a genetically encoded calcium indicator, and will use this technique to query the specific response properties of vagal GLP1R neurons. In Aim 3, we will selectively activate or eliminate vagal GLP1R neurons using genetic approaches, and determine the impact on feeding behavior, metabolism, nausea, and other aspects of autonomic physiology. Together, these studies will provide needed information about the cell biology of vagal GLP1R neurons. Charting GLP1- responsive circuits at a cellular level will help reveal how GLP1 evokes diverse physiological responses in health and disease, and may provide an important foundation for future therapy development.

 描述（由申请人提供）：胰高血糖素样肽1（GLP 1）是一种控制能量稳态、胰岛素释放和进食行为的激素。GLP 1激活一个复杂的神经内分泌轴，协调营养摄入的全身行为和代谢反应，GLP 1受体（GLP 1 R）在许多位置表达，包括迷走神经，脑干和下丘脑。一些GLP 1反应神经元的作用仍然不清楚，部分原因是缺乏适当的遗传工具。了解不同GLP 1反应神经元的作用是必要的，因为涉及GLP 1模拟或稳定的治疗策略为控制糖尿病和潜在的其他代谢紊乱提供了临床重要方法。GLP 1 R在迷走神经感觉神经元群中表达，尽管迷走神经GLP 1 R神经元在摄食行为、代谢和恶心中的作用存在很大争议。最近的研究表明，迷走神经GLP 1 R不是GLP 1 R激动剂对体重或糖尿病消退的影响所必需的，这提出了关于以下的基本问题：（1）迷走神经GLP 1 R神经元在身体和大脑中投射的位置，（2）它们检测到什么，以及（3）它们引起什么生理反应，所有这些都是未知的。在初步数据中，我们使用分子和遗传方法将感觉迷走神经解构为细胞成分。我们产生了一组“ires-Cre”基因敲入小鼠，包括Glp 1 r-ires-Cre小鼠，并采用了强大的遗传技术进行连接映射，体内成像和迷走神经活动的光遗传学控制。使用这些方法，我们确定了迷走神经传入的两种亚型，它们支配肺，并对呼吸产生强大而相反的影响（Cell，2015），在这里，我们将使用相关技术来研究迷走神经GLP 1 R神经元的感觉生物学。在目标1中，我们开发了一种策略，通过腺相关病毒感染将遗传示踪剂引入迷走神经感觉神经元，并将使用这种技术来绘制迷走神经GLP 1 R神经元在外周器官和脑干中的投射。在目标2中，我们开发了一种新的在体成像范式迷走神经节，涉及遗传编码的钙指标，并将使用这种技术来查询迷走神经GLP 1 R神经元的特定响应特性。在目标3中，我们将使用遗传方法选择性地激活或消除迷走GLP 1 R神经元，并确定对摄食行为，代谢，恶心和自主生理学其他方面的影响。总之，这些研究将提供有关迷走神经GLP 1 R神经元的细胞生物学所需的信息。在细胞水平上绘制GLP 1响应电路将有助于揭示GLP 1如何在健康和疾病中引起不同的生理反应，并可能为未来的治疗开发提供重要基础。