Molecular and Functional Taxonomy of Cardiovagal Neurons

项目总结 心率是使用最广泛、信息量最大的健康指标之一。然而，这些神经回路 确定心率的方法只有一部分是已知的。一个多世纪的研究表明，心率与 由自主神经系统的两个分支控制，这两个分支增加(交感)或减少 (副交感神经)对身体不断变化的循环需求作出反应的心率。副交感神经输入到 心脏通过迷走神经发生，迷走神经是一种从后脑副交感神经输送轴突的脑神经 神经细胞，称为心脏迷走神经细胞，连接到心脏神经节的下游神经元。绝大多数人 心迷走神经元位于后脑疑核(NAMB)。然而，Namb也是它的家 ，这给研究心脏迷走神经带来了重大的技术挑战 子集。例如，与Namb的心脏迷走神经混合在一起的是副交感神经元，它 调节肺功能(支气管收缩、支气管排泄)和运动神经元控制上 呼吸道和食道肌。无法访问心脏迷走神经亚群极大地限制了我们 了解它们的突触电路、基因表达以及在心脏功能中的具体作用。因此，有很多事情可以做 了解这些重要神经元的性质，它们是如何发挥作用的，以及它们如何被靶向治疗 心脏病。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 建立小鼠模型，根据基因表达对神经元亚型进行全面分类。然后，利用基因 NAMB神经元亚型之间的差异为了获得信息，我们将追踪每个亚型的突触输入 和输出使用病毒载体，然后激活和灭活每个亚型以揭示其特异性 生理角色。初步研究确定了NAMB神经元的三种亚型，其中一种 支配心脏中的多个部位，并展示了我们绘制和操纵地图的可行性 特定的神经回路。拟议的研究结果将定义分子和功能 NAMB的组织和对神经元、神经回路和信号的前所未有的洞察 控制心率的途径。

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.