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 increase CVN activity have been limited by lack of identified selective translational targets. Recent work has shown that there is an important excitatory synaptic pathway from oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVN) to brainstem CVNs, and that OXT could provide a key selective excitation of CVNs. In clinical studies, intranasal OXT increases parasympathetic cardiac activity, autonomic balance, and reduces obstructive event durations and oxygen desaturations in obstructive sleep apnea patients. However, the mechanisms by which activation of hypothalamic OXT neurons, or intranasal OXT, increases brainstem parasympathetic cardiac activity is poorly understood. 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 in CVNs (OXTR), as well as non-CVN cholinergic neurons, located in the NA and DMNX nuclei. Selective chemogenetic excitation of OXTR+ CVNs was performed by expressing DREADDs with a combination of Cre and flp dependent viruses. We found that OXT receptors are highly expressed in CVNs in the DMNX and OXT increases DMNX CVN activity, but the receptors and responses are absent in CVNs in the NA. Selective chemogenetic activation of OXTR+ CVNs in the DMNX evoked a rapid and sustained bradycardia.