Central integration of swallow and airway-protective reflexes.

The relationship between the timing of respiration and swallowing has been proven not to be random. Using pseudorabies virus (PRV) as a transsynaptic neural tracer, a basis for the central integration of swallowing and airway-protective reflexes can be located in the neural circuits projecting to swallowing-related muscles. The premotor neurons (PMNs) that constitute the swallowing central pattern generators, interneuronal networks able to initiate repetitive rhythmic muscle activity independent of sensory feedback, connect with multiple areas of the brainstem and other areas of the central nervous system. Those PMNs that project to muscles used in swallowing have been localized within the nucleus of the solitary tract (NTS) and its adjacent reticular formation, and they are synaptically linked both to peripheral afferents and to cortical swallowing areas. Bartha PRV, an attenuated vaccine strain of swine alpha-herpesvirus with a long postinjection survival rate and the ability to produce controlled infections that spread in a hierarchical manner within synaptically linked neurons, can specifically label neurons projecting to PMNs of a given circuit. Thus, it has been used to isolate two neuroanatomically distinct subnetworks of PMNs involved in the buccopharyngeal and esophageal phases of swallowing. Use of PRV as a neural tracer shows that during the buccopharyngeal phase of swallowing, vagal afferents from the pharynx and larynx and from the superior laryngeal nerve terminate in the intermediate and interstitial subnuclei of the NTS. Motoneurons projecting to the pharynx and larynx are located in the semicompact and loose formations of the nucleus ambiguus (NA). Neural tracing with PRV also shows that esophageal PMNs have direct synaptic contact with esophageal motoneurons in the compact formation of the NA. Moreover, esophageal PMNs are localized exclusively to the central subnucleus of the NTS, a site that also is the sole point of termination of esophageal vagal afferents. Using PRV, one can identify third-order (neurons projecting to PMNs) esophageal neurons in sites where pharyngeal PMNs have been noted. Injection of PRV into the esophagus and subsequent detection using immunofluorescence found a subpopulation of neurons in the intermediate and interstitial subnuclei of the NTS. This subpopulation projects to pharyngeal motoneurons and buccopharyngeal PMNs, and it is synaptically linked to esophageal PMNs. The synaptic link between buccopharyngeal and esophageal PMNs provides a potential anatomic substrate within the NTS for the central integration of esophageal peristalsis with the pharyngeal phase of swallowing and airway-protective reflexes. Human studies and animal models investigating esophagoglottal closure and pharyngo-upper esophageal sphincter (pharyngo-UES) contractile reflexes have located the neural pathways that mediate airway-protective reflexes. Similar studies and models using two PRV strains injected simultaneously into different swallowing and respiration-related muscle groups may identify synaptic connectivity between laryngeal, esophageal, and pharyngeal PMNs and, thus, may help to demonstrate the central integration of swallowing and airway-protective reflexes.