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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

基本信息

批准号：
10526423
负责人：
RUI CHANG
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10526423
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 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 brain pathway cardiovascular health cell type electrical property gastrointestinal system genetic approach improved innovation innovative technologies neural circuit neuromechanism neuroregulation novel pressure respiratory response segregation sensory mechanism therapeutic target tool

项目摘要

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.

项目总结/摘要心脏广泛地受迷走神经支配，并且许多重要的心脏来源的线索是主动感知，包括与每次心跳相关的压力波动，分泌的肽，信号分子和病理变化，如组织损伤、局部缺血和炎症。心脏信号的适当检测是心血管反射的首要和关键过程;然而，大脑通过迷走神经接收来自心脏的信息的机制仍然是这是一个神秘的问题，关于这种心与脑的接口的许多基本问题仍然有待回答。不同的感觉神经元是否检测到不同的心脏信号？什么是解剖学和感知不同心脏输入的分子基础？不同的心脏变化如何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引入神经科学，生理学，遗传学和计算生物学，这一重要的跨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，标记为Npy 2 r和Piezo 2，两者都支配心脏。迷走神经Npy 2 r和Piezo 2神经元具有根本不同的基因表达模式，电特性，解剖特征和生理作用，在内脏这表明它们代表了两种不同的心脏到大脑的通路。在此之前，我们已经在迷走神经中开发了许多新的分子和遗传技术，细胞类型特异性研究解剖学，神经元活动，和生理功能的遗传定义迷走神经元群。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是，迷走神经Npy 2 r和Piezo 2心脑神经元是否显示出不同的解剖结构，对不同的心脏输入作出反应，并有差别地调节多种心血管功能。我们希望，这里提出的研究将揭示两个不同的迷走神经心脏的许多重要细节，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，以及绘制不同的心脏到大脑神经系统的遗传途径，循环和心血管功能的精确调节。从分子和功能上剖析了心脏-大脑轴将为大脑神经控制的这一重要领域开辟新的前景。心血管系统，并可能带来新的概念和治疗目标的领域，心血管疾病的干预和预防。