eNeuro. 2022 Mar 31. pii: ENEURO.0026-22.2022. [Epub ahead of print]
The airways are densely innervated by sensory afferent nerves, whose activation regulates respiration and triggers defensive reflexes (e.g. cough, bronchospasm). Airway innervation is heterogeneous, and distinct afferent subsets have distinct functional responses. However, little is known of the innervation patterns of subsets within the lung. A neuroanatomical map is critical for understanding afferent activation under physiological and pathophysiological conditions. Here, we quantified the innervation of the mouse lung by vagal and dorsal root ganglion (DRG) sensory subsets defined by the expression of Pirt (all afferents), 5HT3 (vagal nodose afferents), Tac1 (tachykinergic afferents) and TRPV1 (defensive/nociceptive afferents) using Cre-mediated reporter expression. We found that vagal afferents innervate almost all conducting airways and project into the alveolar region, whereas DRG afferents only innervate large airways. Of the two vagal ganglia, only nodose afferents project into the alveolar region, but both nodose and jugular afferents innervate conducting airways throughout the lung. Many afferents that project into the alveolar region express TRPV1. Few DRG afferents expressed TRPV1. ∼25% of blood vessels were innervated by vagal afferents (many were Tac1+). ∼10% of blood vessels had DRG afferents (some were Tac1+), but this was restricted to large vessels. Lastly, innervation of neuroepithelial bodies correlated with the cell number within the bodies. In conclusion, functionally distinct sensory subsets have distinct innervation patterns within the conducting airways, alveoli and blood vessels. Physiological (e.g. stretch) and pathophysiological (e.g. inflammation, edema) stimuli likely vary throughout these regions. Our data provide a neuroanatomical basis for understanding afferent responses in vivo.Significance StatementActivation of airway sensory afferent nerves by physical and chemical stimuli evokes reflex changes in respiratory function. Multiple afferent subsets exist, including those activated by noxious stimuli (so-called "nociceptors"), which have distinct functions. The inappropriate activation of airway afferents, especially nociceptors, in inflammatory/infectious disease contributes to morbidity (e.g. bronchospasm, mucus secretion, cough). Despite extensive electrophysiological characterization of airway afferent subsets, little is known of their innervation patterns. To date, afferent subsets have been qualitatively identified in airway tissue, mostly using immunohistochemistry (which often lacks specificity and signal strength). Here, we have used Cre-dependent reporter expression to quantify genetically-defined afferent subsets. Thus, we provide a neuroanatomical map of the sensory innervation of conducting airways, alveoli and blood vessels throughout the lung.
Keywords: DRG; lung; mapping; nociceptor; sensory nerve; vagal ganglia