The Role of the Paratrigeminal Nucleus in Vagal Afferent Evoked Respiratory Reflexes: A Neuroanatomical and Functional Study in Guinea Pigs

Abstract

The respiratory tree receives sensory innervation from the jugular and nodose vagal sensory ganglia. Neurons of these ganglia are derived from embryologically distinct origins and as such demonstrate differing molecular, neurochemical and physiological phenotypes. Furthermore, whereas nodose afferent neurons project to the nucleus of the solitary tract (nTS), recent neuroanatomical studies in rats suggest that jugular neurons have their central terminations in the paratrigeminal nucleus (Pa5). In the present study we confirm that guinea pigs demonstrate a comparable distinction between the brainstem terminations of nodose and jugular ganglia afferents. Thus, microinjection of fluorescently conjugated cholera toxin B (CT-B) neural tracers into the caudal nTS and Pa5 resulted in highly specific retrograde labeling of neurons in the nodose and jugular ganglia, respectively. Whereas, nodose neurons more often expressed 160 KD neurofilament proteins and the alpha3 subunit of Na+/K+ ATPase, significantly more jugular neurons expressed the neuropeptides substance P (SP) and, especially, Calcitonin Gene-Related Peptide (CGRP). Indeed, terminal fibers in the Pa5 compared to the nTS were characterized by their significantly greater expression of CGRP, further supporting the notion that jugular afferents project to trigeminal-related brainstem regions. Electrical stimulation of the guinea pig larynx following selective surgical denervation of the nodose afferent innervation to the larynx (leaving intact the jugular innervation) resulted in stimulus dependent respiratory slowing and eventual apnea. This jugular ganglia neuron mediated response was unaffected by bilateral microinjections of the GABAA agonist muscimol into the nTS, but was abolished by muscimol injected into the Pa5. Taken together these data confirm that jugular and nodose vagal ganglia afferent neurons innervate distinct central circuits and support the notion that multiple peripheral and central pathways mediate sensory responses associated with airway irritations.

Piezo2 senses airway stretch and mediates lung inflation-induced apnoea

“…d , tdTomato epifluorescence in adult thoracic DRG. e, f , tdTomato epifluorescence in adult nucleus of the solitary tract (NTS) ( e ) and in adult spinal trigeminal nucleus (Sp5) ( f ), where axons of nodose and jugular/trigeminal sensory neurons project, respectively 52,53 . Smaller panels on right in f show a magnified view of Sp5 with Nefh staining.…”

“…It has been widely reported that nodose sensory neurons contain low-threshold mechanosensors innervating the lower airway tract including the lungs, while jugular sensory neurons contain high-threshold mechanosensors that innervate the upper airway tract, such as the larynx and the trachea. In addition, nodose sensory neurons project to the NTS 6,53 , a synaptic station required for the Hering–Breuer reflex in the brainstem 54 . Consistent with these findings, Piezo2 expression is detected in the jugular–nodose ganglia complex, and Piezo2 + nerve fibres project to the NTS.…”

Role of reactive oxygen species and TRP channels in the cough reflex

“…However, selective stimulation of nodose C fibers fails to evoke cough [44]. The mechanisms underlying this disparity are unknown, although recent evidence suggests that jugular and nodose C fibers modulate distinct brainstem networks [50, 51]. …”

Brainstem mechanisms underlying the cough reflex and its regulation

“…Mazzone and Undem 2016). This nucleus is certainly involved in respiratory reflexes other than cough, such as respiratory slowing and apnea (Chou et al, 2008;Driessen et al, 2015). However, its possible role, if any, in the genesis of the cough motor pattern or of the "urge-tocough" remains to be ascertained.…”