Molecular and Functional Taxonomy of Cardiovagal Neurons

项目摘要 心率是最广泛使用和信息量最大的健康指标之一。然而，神经回路， 确定心率仅部分已知。超过世纪的研究表明， 由自主神经系统的两个分支控制，增加（交感神经）或减少 （副交感神经）心率响应身体对循环的需求变化。副交感神经输入 心脏通过迷走神经发生，迷走神经是一种脑神经，它携带来自后脑副交感神经的轴突。 神经元，称为心迷走神经元，到心脏神经节中的下游神经元。绝大多数 心迷走神经元位于后脑的疑核（nAmb）中。然而，nAmb也是家庭 这对研究心迷走神经的功能提出了重大的技术挑战。 子集例如，与nAmb的心迷走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）和运动神经元控制上 气道和食道肌肉。无法进入心迷走神经亚群极大地限制了我们 了解它们的突触回路、基因表达和在心脏功能中的特定作用。因此， 了解这些重要神经元的性质，它们如何发挥作用，以及如何靶向治疗 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， 小鼠模型，通过基因表达对神经元亚型进行全面分类。然后，利用遗传 为了了解nAmb神经元亚型之间的差异，我们将跟踪每个亚型的突触输入 并使用病毒载体输出，然后激活和复制每个亚型，以揭示其特定的 生理作用。初步研究已经确定了nAmb神经元的三种亚型，其中一种是 支配心脏的多个部位，并显示了我们的方法映射和操纵的可行性。 特定的神经回路拟议研究的结果将确定分子和功能 组织的nAmb和产生前所未有的洞察神经元，神经回路，和信号 控制心率的通路

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.