Molecular and Functional Taxonomy of Cardiovagal Neurons

心脏迷走神经元的分子和功能分类学

基本信息

批准号：
10211852
负责人：
John N Campbell
金额：
$ 58.5万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211852
关键词：
3-Dimensional Acute Address Anatomy Anus Arrhythmia Atlases Autonomic nervous system Axon Back Baroreflex Blood Circulation Blood Pressure Breathing Bronchoconstriction Cardiac Cardiac health Cardiovascular Diseases Cells Chest Chronic Contracts Cranial Nerves Data Deglutition Diabetes Mellitus Esophagus Ganglia Gene Expression Genes Genetic Genetic Markers Health Heart Heart Diseases Heart Rate Heart failure Heterogeneity Home Human Hypertension Image Implant Label Larynx Lead Learning Lung Measures Mediating Modeling Molecular Monitor Morbidity - disease rate Motor Neurons Mus Muscle Myocardial Infarction Nature Nerve Nervous System control Neurobiology Neurons Neuropeptide Gene Operative Surgical Procedures Optics Organ Output Parasympathetic Nervous System Pharyngeal structure Physiological Play Proteins Rabies Receptor Gene Reflex action Research Research Proposals Resources Rest Role Signal Pathway Signal Transduction Site Smooth Muscle Specificity Striated Muscles Synapses Taxonomy Therapeutic Intervention Trachea Transgenic Mice Vagus nerve structure Viral Vector autonomic neuropathy base heart function heart rate variability hindbrain infection risk insight mortality mouse model neural circuit new therapeutic target novel marker nucleus ambiguus optogenetics pre-clinical pulmonary function response single-cell RNA sequencing sudden cardiac death therapeutic target transcriptomics vagus nerve stimulation vector

项目摘要

PROJECT SUMMARY Heart rate is one of the most widely used and informative metrics of health. Yet, the neural circuits which determine heart rate are only partly known. Over a century of research has shown that heart rate is oppositely controlled by the two branches of the autonomic nervous system, which increase (sympathetic) or decrease (parasympathetic) heart rate in response to the body’s changing needs for circulation. Parasympathetic input to the heart occurs through the vagus nerve, a cranial nerve which carries axons from hindbrain parasympathetic neurons, known as cardiovagal neurons, to downstream neurons in the cardiac ganglia. The vast majority of cardiovagal neurons reside in the nucleus ambiguus (nAmb) of the hindbrain. However, the nAmb is also home to a variety of other neurons, which presents significant technical challenges to studying the cardiovagal subset. For instance, intermingled with the nAmb’s cardiovagal neurons are parasympathetic neurons which mediate pulmonary function (bronchoconstriction, bronchosecretion) and motor neurons controlling upper airway and esophageal muscles. The inability to access the cardiovagal subset has greatly limited what we know about their synaptic circuitry, gene expression, and specific roles in heart function. Thus, there is much to learn about the nature of these important neurons, how they function, and how they can be targeted to treat heart disease. To address these issues, our proposal will leverage the molecular diversity of nAmb neurons in mouse models to comprehensively classify neuron subtypes by their gene expression. Then, utilizing genetic differences between the nAmb neuron subtypes to gain access, we will trace each subtype’s synaptic inputs and outputs using viral vectors, and then activate and inactivate each subtype to reveal their specific physiological roles. Preliminary studies have identified three subtypes of nAmb neurons, one of which innervates multiple sites in the heart, and shown the feasibility of our approach to mapping and manipulating specific neural circuits. The results of the proposed studies will define the molecular and functional organization of the nAmb and yield unprecedented insight into the neurons, neural circuit, and signaling pathways that control heart rate.

项目概要心率是最广泛使用且信息丰富的健康指标之一，然而，神经回路却影响着健康。一个多世纪的研究表明，心率是相反的。由自主神经系统的两个分支控制，这两个分支增加（交感神经）或减少（副交感神经）心率响应身体副交感神经输入变化的需求。心脏通过迷走神经发生，迷走神经是一种脑神经，携带来自后脑副交感神经的轴突神经元，称为心脏迷走神经元，占心脏神经节下游神经元的绝大多数。心脏迷走神经元位于后脑的疑核 (nAmb)，然而，nAmb 也是它的家。对各种其他神经元的影响，这对研究心血管迷走神经系统提出了重大的技术挑战例如，与 nAmb 的心血管神经元混合的是副交感神经元。介导肺功能（支气管收缩、支气管分泌）和控制上呼吸道的运动神经元气道和食管肌肉的无法进入心血管子集极大地限制了我们的能力。了解它们的突触回路、基因表达以及在心脏功能中的具体作用因此，还有很多事情要做。了解这些重要神经元的性质、它们的功能以及如何针对它们进行治疗为了解决这些问题，我们的建议将利用 nAmb 神经元的分子多样性。小鼠模型根据基因表达对神经亚型进行全面分类，然后利用遗传。为了获得访问权，nAmb 神经元亚型之间存在差异，我们将追踪每个亚型的突触输入并使用病毒载体进行输出，然后激活和灭活每个亚型以揭示其特定的初步研究已经确定了 nAmb 神经元的三种亚型，其中之一。神经支配心脏的多个部位，并展示了我们绘制和操纵方法的可行性所提出的研究结果将定义分子和功能。 nAmb 的组织并对神经元、神经回路和信号传导产生前所未有的见解控制心率的途径。