GLP1R neurons in the subfornical organ and integration of thirst and satiety cues

穹窿下器官中的 GLP1R 神经元以及口渴和饱腹感信号的整合

• 批准号: 9893863
• 负责人: RUI CHANG
• 金额: $ 15.66万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893863
• 关键词: Acute; Agonist; Anatomy; Attenuated; Behavior; Behavioral; Biology; Blood - brain barrier anatomy; Blood Circulation; Blood Glucose; Blood Pressure; Body Fluids; Brain; Brain region; Breathing; Calcium; Cells; Chemical Stimulation; Cues; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dependovirus; Digestion; Disease; Drug Design; Electric Stimulation; Electrolytes; Electrophysiology (science); Excretory function; Experimental Water Deprivation; Feeding behaviors; GLP-I receptor; GPCR Signaling Pathway; Generations; Genetic; Glucose; Goals; Health; Homeostasis; Hormones; Human; Hypothalamic structure; Image; Infusion procedures; Injections; Insulin; Intake; Kidney; Knock-in Mouse; Knowledge; Label; Learning; Lesion; Life; Ligands; Light; Liquid substance; MAPK3 gene; Maps; Measures; Mediating; Mentors; Molecular; Mus; Neuraxis; Neuroanatomy; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Organ; Osmolar Concentration; Output; Pathway interactions; Pharmacologic Substance; Physiology; Polydipsia; Rabies virus; Receptor Activation; Receptor Signaling; Research; Rodent; Role; Satiation; Sensory; Shapes; Signal Pathway; Signal Transduction; Site; Slice; Sodium; Specificity; Structure of area postrema; Subfornical Organ; System; Techniques; Testing; Thirst; Training; Vagus nerve structure; Water consumption; analog; anatomical tracing; base; blood pressure regulation; brain surgery; career; design; designer receptors exclusively activated by designer drugs; diabetic patient; drinking behavior; experience; experimental study; genetic approach; glucagon-like peptide 1; improved; incretin hormone; inhibitory neuron; insight; member; mimicry; neural circuit; neuroregulation; optogenetics; relating to nervous system; remote control; sensory input; skills; tool; treatment strategy

Project Summary Discoveries made in sensory biology not only shape the way we live, but also have important repercussions for human health. My long-term career goal is to better understand how environmental cues are detected and encoded in the periphery, and communicated with the brain to control physiology and behavior in health and disease. My current objective described in this proposal is to investigate how GLP-1 communicates centrally with the subfornical organ to control water intake and body fluid homeostasis. Maintaining fluid homeostasis is crucial for health and disease. Elevation of circulatory osmolarity by high glucose causes polydipsia in diabetic patients. Incretin therapies that involve mimicry or stabilization of glucagon-like peptide 1 (GLP-1) provide a strategy for treatment of type 2 diabetes. As an incretin, GLP-1 not only controls insulin release and feeding behavior but also regulates blood pressure, renal excretion of sodium, and fluid intake to coordinately promote digestion at a systematic level after meal. Intriguingly, acute GLP-1 administration elicits hypodipsia and effectively reduces water consumption in both healthy subjects and diabetic patients, suggesting an alternative strategy for alleviating polydipsia in diabetic patients. Among the many sites that express the receptor for GLP- 1 (GLP1R), the subfornical organ is a major brain center that controls water intake and fluid homeostasis. My central hypothesis is that SFO GLP1R neurons integrate satiety signals after meal to control fluid intake through specific signaling cascades and central neural circuits. I will test this hypothesis through three specific aims: to determine the effect of SFO GLP1R neuron stimulation on fluid intake (Specific Aim 1), to decipher GLP1R signaling pathways in these cells (Specific Aim 2), and to scrutinize their anatomical and functional connectivity (Specific Aim 3). For the training necessary for Specific Aim 2, I will continue to greatly benefit from the guidance of my mentor Prof. Liberles, who has incredible knowledge and understanding in GPCR signaling pathways. To carry out Specific Aim 1 and 3, I will also need to broaden my knowledge and skills to include mouse behavior and neurocircuit mapping, such as stereotaxic brain surgeries, brain slice electrophysiology, and chemogenetics. Such knowledge and skills will be obtained from training with my co- mentor, Prof. Bradford Lowell. I have received tremendous guidance from Prof. Lowell and his lab members in the past, with generation of Glp1r-ires-Cre mice and brain stereotaxic injection. I will continue to learn brain slice recording, rabies virus-based tracing, channelrhodopsin-assisted circuit mapping (CRACM), and DREADD-involved behavioral experiments under the guidance of Prof. Lowell. Particularly regarding the anatomical tracing of SFO GLP1R neurons (Specific Aim 3) that requires very extensive knowledge of brain anatomy, I will collaborate with Prof. Clifford Saper, who is an expert in neuroanatomy more than 40 years experience. Together, these studies will greatly expand our knowledge on how GLP-1 signal is integrated in the brain to coordinately control physiology and shed light on GLP-1 based drug design.

项目摘要 在感觉生物学中创造的发现不仅会塑造我们的生活方式，而且对 人类健康。我的长期职业目标是更好地了解如何检测到环境线索和 在外围编码，并与大脑进行交流，以控制健康中的生理和行为 疾病。我目前在此提案中描述的目前的目标是调查GLP-1如何中心交流 用副骨骼器官控制水的摄入量和体液稳态。保持流体稳态是 对于健康和疾病至关重要。高葡萄糖通过高葡萄糖抬高循环渗透性会导致多次糖尿病患者 患者。涉及模仿或稳定胰高血糖素样肽1（GLP-1）的肠直直染素疗法提供了A 治疗2型糖尿病的策略。作为肠静脉素，GLP-1不仅控制胰岛素释放和进食 行为，但还调节血压，钠的肾脏排泄和液体摄入以协调促进 进餐后在系统水平上消化。有趣的是，急性GLP-1给药会引起速度和 有效地降低了健康受试者和糖尿病患者的用水量，这表明了另一种 减轻糖尿病患者多次多次的策略。在表达GLP受体的许多位点中 1（GLP1R），副脱机器官是控制摄入量和液体稳态的主要大脑中心。我的 中心假设是SFO GLP1R神经元在进餐后整合饱腹感以控制液体摄入量 通过特定的信号级联和中央神经回路。我将通过三个特定的特定来检验这一假设 目的：确定SFO GLP1R神经元刺激对液体摄入的影响（特定目标1） 这些细胞中的GLP1R信号通路（特定目标2），并仔细检查其解剖学和功能 连接性（特定目标3）。对于特定目标2所需的培训，我将继续大大受益 从我的导师Libleles教授的指导下，他在GPCR中具有令人难以置信的知识和理解 信号通路。要执行特定的目标1和3，我还需要扩大我的知识和技能 包括鼠标行为和神经回路映射，例如立体定位脑手术，脑切片 电生理学和化学遗传学。这些知识和技能将通过与我的共同培训获得 导师，布拉德福德·洛厄尔教授。我收到了洛厄尔教授及其实验室成员的巨大指导 过去，随着GLP1R-IRES-CRE小鼠和脑立体定位注射的产生。我将继续学习大脑 切片记录，基于狂犬病病毒的追踪，通道旋转辅助电路映射（CRACM）和 在洛厄尔教授的指导下进行了涉及Dreadd的行为实验。特别是关于 SFO GLP1R神经元的解剖学跟踪（特定目标3），需要对大脑非常广泛的了解 解剖学，我将与克利福德·萨珀（Clifford Saper）教授合作，他是40多年的神经解剖学专家 经验。这些研究一起将大大扩展我们对GLP-1信号如何集成到中的知识 大脑协调地控制生理学并阐明基于GLP-1的药物设计。