Editorial Focus on “Role of the Kölliker-Fuse/Parabrachial Complex in the generation of post-inspiratory vagal and sympathetic nerve activities and their recruitment by hypoxemic stimuli in the rat”

The original description of postinspiration attributed exhalation to the conversion of stored potential energy, in the lungs, to mechanical energy (1). Years later, postinspiration was suggested to be its own purposeful movement where laryngeal activation increased airway resistance, combined with post-inspiratory diaphragm contraction, to act as an expiratory breaking mechanism, slowing the flow of air, creating a fluid movement (2). While postinspiration is thought to play an essential role in the central rhythmogenesis of respiration (3), cardiorespiratory efficiency (4), and coordination for swallowing, vocalization, and airway protection (5), the mechanism and importance remains controversial.

Scientific evidence indicates the central regulation of postinspiration is located in the intermediate reticular nucleus (IRt) by a group of neurons that co-express both cholinergic (ChAT) and glutamatergic (Vglut2) neurotransmitters, named the postinspiratory complex (PiCo) (6, 7) and in a more rostral pontine region, the Kölliker-Fuse nucleus (KF) (8). Pharmacological inhibition of the IRt silenced vagal related postinspiratory and swallow activity, though in the presence of acute hypoxia vagal and sympathetic activity was still recruited (7). Cardiorespiratory sympathetic coupling is crucial in gas exchange and tissue oxygenation. Therefore, the recruitment of postinspiration during hypoxia led the authors to explore another pathway responsible for postinspiratory cardiorespiratory control (9).

The study by Toor et al. (2024), published in the Journal of Neurophysiology, pharmacologically silenced the Kölliker-Fuse/Parabrachial nuclei (KF-PBN) using a GABA_A receptor agonist, isoguvacine, to test the hypothesis the KF-PBN is a source of postinspiratory drive for respiratory-sympathetic coupling in anesthetized artificially ventilated rats. They found under normal oxygen conditions, bilateral inhibition of the KF-PBN decreased eupneic phrenic nerve amplitude, and respiratory frequency due to an increase in inspiratory duration, and increased breath to breath variability. Vagal postinspiratory amplitude was abolished and renal sympathetic postinspiratory amplitude significantly reduced. According to the authors, in the presence of hypoxemia, inhibition of the KF-PBN resulted in no change to phrenic nerve amplitude, while vagal postinspiratory activity was abolished. However, during this increase in respiratory drive, there was a graded recruitment of sympathetic postinspiratory activity. Upon reoxygenation of the system there is a known post-hypoxic respiratory frequency decline, particular to this study, about a 30% decrease in respiratory frequency. However, after inhibition of the KF-PBN, the post-hypoxic frequency decline was blunted, with only an 8% decrease in respiratory frequency.

This study suggests that in a paralyzed and vagotomized rodent model, the KF-PBN is essential for vagal postinspiratory activity and partially modulates the sympathetic postinspiratory activity. The authors point out that the phrenic inspiratory and vagal postinspiratory activity uncouples, where the former is unchanged, and the latter is abolished when the KF-PBN is silenced during hypoxic conditions. Suppression of ChAT PiCo neurons via somatostatin and DAMGO reduced the duration and amplitude of vagal postinspiratory activity, suggesting PiCo is necessary for vagal postinspiration (6). It is plausible that both the PiCo neurons located in the IRt and the KF-PBN are essential for vagal postinspiratory activity. However, it is important these mechanisms are further tested in intact rodent models, since anesthesia, vagotomy, and artificial ventilation create an autonomic imbalance resulting in restricted finds. Using chemogenetic techniques, targeting specific cell types, in an awake and alert rodent model would be ideal, however recording postinspiratory activity in this approach becomes difficult.

The authors found a reduction, not abolishment, in postinspiratory renal sympathetic activity when the IRt and the KF-PBN were inhibited during normal oxygen conditions (7, 9). Interestingly, optogenetic stimulation of PiCo neurons during postinspiration evoked cervical sympathetic activity (4) introducing a new role in sympathetic modulation, likely related to upper airway behaviors. The rostral ventrolateral medulla (RVLM) is the primary generator for sympathetic activity, and presympathetic neuronal discharge is determined by excitatory and inhibitory synaptic connections from different brain regions and peripheral afferences (10). The authors suggest sympathetic postinspiration outflow is likely modulated by multiple independent pathways: 1) originating in the KF-PBN and relaying through pre-motoneurons in the IRt. 2) Direct interactions between medullary respiratory (preBötzinger and Bötzinger complex) and pre-sympathetic neurons in the RVLM, as demonstrated by other studies. 3) Barosensitive neurons in the caudal ventrolateral medulla phasically inhibit RVLM presympathetic neurons which is also modulated by respiratory drive (9).

Chronic intermittent hypoxia, the process of hypoxic bouts followed by reoxygenation, is the physiological act that occurs during obstructive sleep apnea (OSA). Understanding neurophysiologic changes during acute hypoxia and the complex interactions between cell signaling cascade promoted by reoxygenation, including the production of reactive oxygen/nitrogen species are important in understanding OSA. The authors noted that during hypoxemia vagal postinspiratory activity was not abolished when the IRt was silenced but was abolished when the KF-PBN was silenced, suggesting KF-PBN plays a fundamental role in generating postinspiratory vagal activity in conditions of enhanced peripheral chemoreceptor drive (7, 9). During reoxygenation, the post-hypoxic respiratory frequency decline was blunted and postinspiratory sympathetic activity was partially blocked when KF-PBN was silenced. The authors provided information about the KF-BPN playing a role in cardiorespiratory control, however other systems likely regulate postinspiratory sympathetic activity. While these studies have significantly advanced our understanding of postinspiration’s role in respiratory rhythmogeneis, cardiorespiratory control, and upper airway behaviors, further research is needed to fully elucidate its mechanisms in mediating homeostasis.