A molecular and functional dissection of the vagal heart-to-brain physiological circuits

迷走神经心脑生理回路的分子和功能解剖

• 批准号: 10314071
• 负责人: RUI CHANG
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314071
• 关键词: Afferent Neurons; Anatomy; Architecture; Area; Brain; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cells; Computational Biology; Cues; Data; Detection; Development; Disease; Dissection; Esthesia; Flowers; Foundations; Gene Expression Profile; Genetic; Genetic Identity; Genetic Techniques; Goals; Health; Heart; Homeostasis; Immune; Inflammation; Intervention; Ischemia; Knowledge; Label; Link; Mediating; Molecular; Molecular Genetics; Monitor; Neurons; Neurosciences; Organ; Outcome; Pathologic; Peptides; Perception; Peripheral; Physiological; Physiology; Piezo 2 ion channel; Population; Prevention; Process; Property; Reflex action; Regulation; Research; Respiratory System; Role; Sensory; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Stimulus; Testing; Tissues; Vagus nerve structure; Visceral; aortic arch; base; brain pathway; cardiovascular health; cell type; electrical property; gastrointestinal system; genetic approach; improved; innovation; innovative technologies; neural circuit; neuromechanism; neuroregulation; novel; pressure; respiratory; response; sensory mechanism; therapeutic target; tool

Project Summary/Abstract The heart is extensively innervated by the vagus nerve, and numerous vital heart-derived cues are actively sensed, including pressure fluctuations associated with every heartbeat, secreted peptides and signaling molecules, and pathological changes such as tissue damage, ischemia, and inflammation. Appropriate detection of heart signals is a first and key process in cardiovascular reflexes; however, the mechanisms by which the brain receives messages from the heart via the vagus nerve are still mysterious, and many essential questions about this heart-to-brain interface remain to be answered. Are different heart signals detected by different sensory neurons? What are the anatomical and molecular basis for sensing diverse cardiac inputs? How do distinct heart changes differentially regulate cardiovascular physiology? Here, we propose to bring knowledge and innovative technologies in neuroscience, physiology, genetics, and computational biology to this important interdisciplinary area to better understand the neural mechanisms that control cardiovascular functions. In preliminary studies, we identified two genetically distinct vagal sensory neurons subtypes marked by Npy2r and Piezo2 that both innervate the heart. Vagal Npy2r and Piezo2 neurons have fundamentally different gene expression patterns, electrical properties, and anatomical features and physiological roles in visceral organs other than the heart, suggesting they represent two distinct heart-to-brain pathways. Previously, we have developed a number of novel molecular and genetic techniques in the vagus nerve to enable cell-type specific studies for anatomy, neuronal activity, and physiological function of genetically defined vagal neuron populations. Here we will employ these powerful tools to determine, through three specific aims, whether vagal Npy2r and Piezo2 heart-to-brain neurons display distinct anatomical architectures, respond to different cardiac inputs, and differentially regulate a diversity of cardiovascular functions. We expect that studies proposed here will reveal many important details for two distinct vagal heart-to- brain circuits. We believe the proposed project will provide not only a critical foundation for delineating the underlying sensory mechanisms but also genetic access for charting distinct heart-to-brain neural circuits and precise modulation of cardiovascular functions. A molecular and functional dissection of the heart-to-brain axis will open up new vistas in this important area of neural control of the cardiovascular system and may bring novel concepts and therapeutic targets into the field of cardiovascular disease intervention and prevention.

项目摘要/摘要 心脏神经广泛支配了心脏，许多重要的心脏提示是 积极感知，包括与每个心跳相关的压力波动，分泌的肽和 信号分子和病理变化，例如组织损伤，缺血和炎症。 心脏信号的适当检测是心血管反射的第一个和关键过程。然而， 大脑通过迷走神经从心脏接收信息的机制仍然是 神秘，以及有关这种心脏界面界面的许多基本问题仍有待回答。 不同的感觉神经元检测到不同的心脏信号吗？什么是解剖学和 感测多种心脏输入的分子基础？不同的心脏如何变化差异调节 心血管生理学？在这里，我们建议将知识和创新技术带入 对这个重要的跨学科领域的神经科学，生理，遗传学和计算生物学 更好地了解控制心血管功能的神经机制。在初步研究中， 我们确定了由NPY2R和Piezo2标记的两个遗传上不同的迷走神经元亚型 两者都支配心脏。迷走神经NPY2R和压电2神经元具有根本不同的基因 表达模式，电性能以及内脏的解剖学特征和生理作用 除心脏以外的器官，这表明它们代表了两种不同的心对脑途径。之前， 我们已经在迷走神经中开发了许多新颖的分子和遗传技术以实现 细胞类型的解剖学，神经元活性和遗传学定义的生理功能的研究 迷走神经元种群。在这里，我们将采用这些强大的工具来确定三个特定的 目的，无论是迷走神经NPY2R和PIEZO2心对脑神经元都会显示出独特的解剖体系结构， 响应不同的心脏输入，并差异地调节了多种心血管功能。 我们预计，这里提出的研究将揭示两个不同的迷走神经对象的重要细节 脑电路。我们认为，拟议的项目不仅将为划定的关键基础 潜在的感官机制，也是为绘制独特心脏神经的遗传访问 电路和心血管功能的精确调制。分子和功能解剖 心对脑轴将在这个重要的神经控制区域开放新的远景 心血管系统，可能将新颖的概念和治疗靶标带入领域 心血管疾病干预和预防。