Hypothalamic Oxytocin Neuronal Activation Induces Bipolar-Like Mood Changes in Mice in a Sex- and Dosage-Dependent Manner

Clinical studies have suggested that increased plasma oxytocin (OT) levels are a promising biomarker for bipolar disorder (BD), and our earlier post-mortem study found increased OT activity in the hypothalamic paraventricular nucleus (OT PVN ) in BD. However, the potential contribution of the supraoptic nucleus (SON, OT SON ), a major part of the central OT system, to BD remains unknown. We therefore systematically performed independent acute or chronic chemogenetic activation of OT PVN , OT SON , or OT PVN+SON experiments in OT-cre mice. We found that acute activation of OT PVN+SON neurons led to slight mania-like (anti-depression-like) behaviors both in male and female mice, while chronic activation of OT PVN or OT PVN+SON led to sex-dependent behavioural changes from depression/anxiety-like to mania-like, accompanied by stress-related molecular changes in a sex- dependent manner in the medial prefrontal cortex. Our findings imply that OT may be involved in bipolar-like mood changes in a sex- and dosage-dependent manner.