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

项目摘要/摘要 心脏广泛地被迷走神经支配，许多重要的心脏起源的线索是 主动感知，包括与每一次心跳相关的压力波动，分泌肽和 信号分子，以及组织损伤、缺血和炎症等病理变化。 心脏信号的适当检测是心血管反射的第一个也是关键的过程；然而， 大脑通过迷走神经从心脏接收信息的机制仍然是 关于这种心与脑的接口，许多神秘的、本质的问题仍有待解答。 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 感知不同心脏输入的分子基础？不同的心脏变化是如何区别调节的 心血管生理学？在这里，我们建议将知识和创新技术引入 神经科学、生理学、遗传学和计算生物学到这一重要的交叉学科领域 以更好地了解控制心血管功能的神经机制。在初步研究中， 我们鉴定了两种遗传上不同的迷走神经感觉神经元亚型，分别由NPY2R和Piezo2标记 两者都对心脏起着神经作用。迷走神经NPY2R和Piezo2神经元具有根本不同的基因 内脏的表达模式、电学特性、解剖特征和生理作用 心脏以外的器官，这表明它们代表了两条截然不同的心到脑的通路。此前， 我们已经在迷走神经中开发了许多新的分子和基因技术，以使 对基因定义的神经细胞的解剖学、神经元活动和生理功能的特殊细胞类型的研究 迷走神经元群。在这里，我们将使用这些强大的工具来确定，通过三个具体的 目的，迷走神经NPY2R和Piezo2心脑神经元是否显示出不同的解剖结构， 对不同的心脏输入做出反应，并对多种心血管功能进行差异化调节。 我们预计，这里提出的研究将揭示两种截然不同的迷走神经心脏对心的许多重要细节。 大脑回路。我们相信，拟议的项目不仅将为划定 潜在的感觉机制，以及绘制不同的心脑神经的遗传通路 循环和心血管功能的精确调节。的分子和功能解剖 心-脑轴将在这一重要的神经控制领域开辟新的前景 心血管系统，并可能将新的概念和治疗靶点带入 心血管疾病干预和预防。

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.