Molecular and Genetic Analysis of the Vagus Nerve

Abstract

The vagus nerve serves as a primary neural link between the brain and internal organs, detecting a variety of physiological stimuli and controlling a range of autonomic functions essential to homeostatic regulation. However, despite its fundamental importance, little is known about the repertoire of sensory mechanisms residing in vagal afferents, the cellular logic of information coding within the vagus nerve, and the central representation of internal physiological states. To dissect the neural circuits underlying viscerosensation, we adopted a genome-guided strategy to classify vagal sensory neurons based on G-protein-coupled receptor (GPCR) expression. We identified 5 principal cell types and obtained genetic access to these neurons in vivo using GPCR-ires-cre mouse strains. Using a combination of approaches that support cell-type specific analysis, we investigated the anatomical projections, response profiles, and physiological function of discrete vagal sensory subtypes. Within the respiratory system, we identified two vagal sensory populations that exert powerful and opposing effects on breathing. P2ry1- and Npy2r-expressing neurons innervate distinct anatomical structures in the lung and send projections to different brainstem targets. Npy2r neurons are largely slow-conducting C fibers while P2ry1 neurons are fast conducting A fibers. Optogenetic activation of Npy2r neurons induces rapid and shallow breathing whereas activating P2ry1 neurons acutely silences respiration, trapping animals in exhalation. Furthermore, activating P2ry1 neurons had no effect on heart rate or gastric pressure, other autonomic functions under vagal control. Thus, the vagus nerve contains intermingled sensory neurons constituting genetically definable labeled lines with different anatomical connections and physiological roles.