Mapping of the Sensory Innervation of the Mouse Lung by Specific Vagal and Dorsal Root Ganglion Neuronal Subsets

Abstract

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), 5HT 3 (vagal nodose afferents), Tac1 (tachykinergic afferents), and transient receptor potential vanilloid 1 channel (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. Approximately 25% of blood vessels were innervated by vagal afferents (many were Tac1+). Approximately 10% of blood vessels had DRG afferents (some were Tac1+), but this was restricted to large vessels. Lastly, innervation of neuroepithelial bodies (NEBs) 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. Physiologic (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 .

Evidence for vagal sensory neural involvement in influenza pathogenesis and disease

“…Following 4 weeks recovery, we observed a significantly lower number of mCherry expressing neurons in Phox2B-Cre + mice compared to the Phox2B-Cre - littermates (13.2 ± 4.0 and 90.1 ± 32.0 mCherry neurons, respectively; p = 0.0058; Fig 1K and K’). We also observed less mCherry-expressing nerve fibers in the nucleus of the solitary tract (NTS), the brainstem location where nodose afferents centrally project [15, 16, 29] in Phox2B-Cre + mice compared to Phox2B-Cre - mice (Fig 1K”) indicative of correct AAVrg mCh-FLEX-DTA functionality. Similar to surgical vagotomy, Phox2B-Cre + mice receiving intrapulmonary injection of AAVrg mCh-FLEX-DTA lost significantly more body weight compared to the Phox2B-Cre - AAVrg mCh-FLEX-DTA group following IAV infection (Fig 1L).…”

Sensory neurons regulate stimulus-dependent humoral immunity

“…RTX, administered by subcutaneous injection, induces global ablation of TRPV1+ neurons, thus blocking sensory neuron vesicle emission of neuropeptides and rendering them ineffective/atrophied 2,44,45 . Although there are indications that dorsal root ganglia (distal site, primarily innervate skin and visceral organs 46 ) provide some innervation of the lungs 47 , recent tracer studies have demonstrated sparse innervation with an overwhelming majority of lung sensory neuron innervation provided by the vagal ganglia 48 .…”

The Coding Logic of Interoception

“…They sense ingested water and acids indirectly from laryngeal taste receptor cells via ATP signaling and trigger swallowing ( 80 ). Sensory fibers from the DRG neurons mainly innervate the large airways and are absent from the alveolar region ( 100 ). How DRG and vagal sensory neurons differentially contribute to interoception in the respiratory system remains to be elucidated.…”