Heart rate at rest, its variability during breathing, and its suppression during cardiac reflexes is chiefly controlled by the parasympathetic nervous system, which connects to the heart through the vagus nerve. Vagal nerve activity is a robust indicator of cardiac health and key predictor of mortality and morbidity. A loss of vagal nerve activity is a common feature of many cardiovascular diseases, including heart failure/arrhythmia, sudden cardiac death, and cardiac autonomic neuropathy in diabetes. Vagus nerve stimulation has emerged as a promising treatment for heart disease but is limited by off-target effects and infection risk during implant surgery. One way around these limitations would be to increase cardiovagal tone by specifically targeting the cardiovagal neurons or their signaling pathways. However, the nature of these neurons and their signaling pathways is not well understood.

The main objective of this project is to define the molecular, anatomical, and functional organization of cardiovagal neurons, in order to reveal how they control heart rate and how to target them for therapeutic intervention. The vast majority of cardiovagal neurons(CVNs) reside in the nucleus ambiguus (nAmb), where they physically intermingle with parasympathetic pulmonary neurons as well as upper airway and esophageal motor neurons. This cellular heterogeneity presents a significant technical challenge to characterizing CVNs. In essence, the field is held back by (1) a lack of tractable definitions of CVNs and other nAmb neuron subtypes and (2) an inability to specifically access each nAmb neuron subtype. Our work is overcoming these barriers by identifying unique genetic markers of CVNs and then leveraging this information to determine CVN anatomy and function.