Molecular and Functional Taxonomy of Cardiovagal Neurons

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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.