Oxytocin Receptor Expression and Activation in Parasympathetic Brainstem Cardiac Vagal Neurons

Autonomic imbalance — particularly reduced activity from brainstem parasympathetic cardiac vagal neurons (CVNs)—is a major characteristic of many cardiorespiratory diseases. Therapeutic approaches to selectively enhance CVN activity have been limited by the lack of defined, translationally relevant targets. Previous studies have identified an important excitatory synaptic pathway from oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVN) to brainstem CVNs, suggesting that OXT could provide a key selective excitation of CVNs. In clinical studies, intranasal OXT has been shown to increases parasympathetic cardiac activity, improve autonomic balance, and reduce obstructive event durations and oxygen desaturations in obstructive sleep apnea patients. However, the mechanisms by which activation of hypothalamic OXT neurons, or intranasal OXT, enhance brainstem parasympathetic cardiac activity remain unclear. CVNs are located in two cholinergic brainstem nuclei: the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMNX). In this study, we characterize the co-localization of OXT receptors (OXTR) in both CVNs and non-CVN cholinergic neurons in the male and female mouse NA and DMNX nuclei. We found that OXT receptors are highly expressed in CVNs in the DMNX, but not in the NA. OXT increases the firing of DMNX CVN, with no effect on NA CVNs. Selective chemogenetic excitation of OXTR+ CVNs in the DMNX—achieved by a combination of Cre- and flp- dependent DREADDs expression— evoked a rapid and sustained bradycardia. These findings suggest that activation of DMNX CVNs expressing OXTR with oxytocin may represent a novel translational therapeutic target for restoring autonomic balance in cardiorespiratory disorders. Significance statement In this study we characterize the co-localization of OXT receptors in CVNs (OXTR), as well as non-CVN cholinergic neurons, located in the NA and DMNX nuclei. We found that OXT receptors are highly expressed in CVNs in the DMNX, but not in those within the NA. OXT increased the firing rate of CVNs in the DMNX, while having no effect on CVNs in the NA. Selective chemogenetic excitation of OXTR-positive CVNs in the DMNX—achieved through DREADD expression using a combination of Cre- and Flp-dependent viral vectors—evoked a rapid and sustained bradycardia. These findings suggest that activation of DMNX CVNs via oxytocin signaling could represent a novel translational therapeutic strategy to enhance autonomic balance in cardiorespiratory diseases.