Molecular, anatomical, and functional organization of lung interoceptors

Interoceptors are the sensory neurons that monitor internal organs and states, essential for physiological homeostasis and generating interoception.Here, we describe a comprehensive, high-quality molecular atlas of interoceptors of the mouse lung, identifing 10 molecular subtypes, which differ in developmental origin, myelination, receptive fields, and cell contacts in the organ. Each subtype expresses a unique but overlapping combination of sensory receptors that detect diverse physiological and pathological stimuli, and each can signal to distinct sets of lung cells including immune cells, forming an intricate local neuroimmune interaction network. Functional interrogation of two mechanosensory subtypes reveals exquisitely-specific homeostatic roles in breathing, one regulating inspiratory time and the other inspiratory flow. These suggest that lung interoceptors encode diverse and dynamic sensory information rivaling that of canonical exteroceptors, and this information is used to drive myriad local cellular interactions and enable precision control of breathing, while providing only vague perceptions of oragn states. Overall design: Vagal ganglia from adult mice instilled with fluorescent conjugated wheat germ agglutinin into the lung were dissociated, and single labeled sensory neurons were mannually picked and analyzed by single-cell RNA sequencing using SmartSeq2 method.