The oxytocin-modulated brain circuit that synchronizes heart rate with breathing

Abstract The variation in heart rate in phase with breathing, called respiratory sinus arrhythmia (RSA), is cardio-protective 1,2 . RSA amplitude provides an index of health and physical fitness used both clinically, and by the broader population using “smart” watches. Relaxation and positive socio-emotional states can amplify RSA 3 , yet the underlying mechanism remains largely unknown. Here, we identify a hypothalamus-brainstem neuronal network through which the neuromodulator oxytocin (OT), known for its relaxing and prosocial effects 4 , amplifies RSA during calming behavior. OT neurons from the caudal paraventricular nucleus in the hypothalamus were found to regulate the activity of a subgroup of inhibitory neurons in the pre-Bötzinger complex, the brainstem neuronal group that generates the inspiratory rhythm. Specifically, OT amplifies the inspiratory glycinergic input from pre-Bötzinger complex neurons to cardiac-innervating parasympathetic neurons in the nucleus ambiguus. This leads to amplified respiratory modulation of parasympathetic activity to the heart, thereby amplifying RSA. Behaviorally, OT neurons participate in the restoration of RSA amplitude during recovery from stress. This work shows how a central action of OT induces a physiologically beneficial regulation of cardiac activity during a calming behavior, providing a foundation for therapeutic strategies for anxiety disorders and coping with stress. Furthermore, it identifies a phenotypic signature of a subpopulation of neurons controlling RSA, namely pre-Bötzinger complex neurons expressing the OT-receptor, enabling the specific modulation of RSA amplitude to resolve its physiological and psychological functions.