The Norepinephrine‐dependent ‘Postinspiratory Complex’ is NOT an Autonomous Generator of the Postinspiratory Rhythm

Previous studies have identified a defined population of postinspiratory (post‐I) driver neurons in pontine Kölliker‐Fuse nucleus which send an excitatory input to post‐I interneurons and motoneurons in medulla 1 . In contrast, a recent report 2 suggests that a group of norepinephrine (NE)‐dependent cholinergic neurons localized within a medullary area dubbed the ‘post‐I complex’ (PiCo) may produce post‐I bursts as well as ectopic bursts that outpace the inspiratory rhythm in vitro . Because the inspiratory and post‐I rhythms are always phase‐locked in vivo , we tested whether the spontaneous post‐I rhythm was dependent on NE by injecting i.v. in rats an α 1 ‐adrenergic receptor antagonist known to block the excitatory effect of NE on respiratory‐related neurons. Remarkably, systemic α 1 ‐adrenergic blockade resulted in a significant decrease of arterial blood pressure but postinspiration at rest and during hypoxic chemostimulation persisted. Next, we suppressed NE facilitation of respiratory‐related neurons by injecting i.v. an α 2 ‐adrenergic receptor agonist known to block the release of NE from pontine noradrenergic neurons. Systemic α 2 ‐adrenergic blockade resulted in a significant decrease of hypoglossal nerve activity but postinspiration at rest and during hypoxic chemostimulation again persisted, indeed with a significant prolongation of the post‐I period. These data strongly suggest that NE‐facilitated PiCo neurons are not necessary for generating post‐I activity, although other NE‐inhibited neurocircuits could play a role. This is in contrast to the reported suppression of vagal post‐I activity after bilateral injections of the peptide somatostatin or the μ‐opioid receptor agonist DAMGO into the mouse PiCo in vivo 2 . This discrepancy may be attributed to the excessively large volume of injection (reportedly 250 nl) in mice 2 —which would inevitably invade the neighboring Bötzinger complex where similar injections at a much smaller volume (20–50 nl) has been shown sufficient to produce similar effects in rats. Interestingly, post‐I PiCo neurons are phenotypically akin to post‐I laryngeal motoneurons which (1) are cholinergic; (2) receive catecholamine inputs; (3) receive simultaneous excitatory and GABA A receptor‐mediated inhibitory inputs during inspiration followed by a postinhibitory rebound postinspiration; (4) mediate the laryngeal adductor reflex resetting of inspiratory rhythm; (5) do not generate the post‐I rhythm. The NE‐dependent ectopic PiCo neuronal bursts in vitro are reminiscent of fictive rhythmic bursting in motoneurons and are non‐autonomous and nonphysiologic. Finally, available functional and histologic data do not support the notion that cholinergic PiCo neurons are also glutamatergic. Support or Funding Information HL093225, HL127258 and NS094178