Oxytocinergic signalling in the respiratory parafacial region increases the activity of chemosensitive neurons and respiratory output

The retrotrapezoid nucleus, located in the parafacial medullary region (RTN/pFRG), is crucial for respiratory activity and central chemoreception. Recent evidence suggests that neuromodulation, including peptidergic signalling, can influence the CO2/H+ sensitivity of RTN neurons. The paraventricular nucleus of the hypothalamus (PVN) projects to the ventral medullary surface, including the RTN, and is considered the primary source of oxytocin to the brainstem. However the physiological significance of oxytocin signalling in RTN neurons has not been determined. To investigate this further we employed neuroanatomical techniques, slice-patch electrophysiology and in vivo pharmacological and optogenetic tools to characterize the effects of oxytocin on breathing. We found that a subset of PVN excitatory neurons (VGlut2-positive) that project to the RTN (Ctb-positive) are also immunoreactive for oxytocin, suggesting the RTN is a downstream target of these neurons. Exogenous application of the selective oxytocin agonist (TGOT) activates RTN chemoreceptors in a dose-dependent manner (EC50 = 3 nm), and this response is blunted by the blockade of KCNQ channels (ML252; 10 µM). In urethane-anaesthetized mice pharmacological (TGOT) or optogenetic activation of oxytocinergic receptors/varicosities in the RTN increases breathing amplitude without changing respiratory frequency. These results identify oxytocin signalling to RTN neurons as a novel regulator of respiratory activity and further demonstrate the importance of KCNQ channels in the modulation of RTN neurons. KEY POINTS: Oxytocin is an important modulator of breathing, including at the level of the retrotrapezoid nucleus (RTN). The paraventricular nucleus of the hypothalamus (PVN), considered as the primary source of oxytocin in the brainstem, projects to the RTN. Selective oxytocin agonist (Thr4,Gly7-oxytocin, TGOT) activates RTN by a mechanism partly dependent on KCNQ channels. In vivo, selective activation of oxytocinergic signalling within the RTN increases breathing amplitude without changing respiratory frequency. Identifying components of the signalling pathway that couples oxytocin receptor activation to changes in chemoreceptor activity may provide new potential therapeutic targets for treating central respiratory disorders.