Distinct projections of PVN oxytocin neurons regulate the divergent defensive behaviors in response to social threat

The central oxytocin (OXT) system is involved in various aspects of social behavior and emotional regulation. However, the neuronal basis of the functional diversity of paraventricular nucleus (PVN) OXT neurons that modulate the defensive behaviors in response to social threat remains unclear. This study found that acute social defeat stress (ASDS) activates PVN OXT neurons in mice, promoting defensive behaviors during and after ASDS. When the mice were attacked, the nucleus accumbens (NAc)–projecting PVN OXT (OXT PVN-NAc ) neurons were inhibited, while the central amygdala (CeA)–projecting PVN OXT (OXT PVN-CeA ) neurons were activated. Studies using rabies virus tracing and circuit-specific Oxt knockout revealed that the lateral hypothalamic area (LHA) innervates both OXT PVN-NAc and OXT PVN-CeA neurons, whereas the lateral habenula (LHb) exclusively innervated OXT PVN-CeA neurons. LHA-innervated PVN OXT neurons respond to both social interaction and social defeat (SD). They promote the fight-back behavior during SD and decrease social avoidance after ASDS. In contrast, the LHb-PVN OXT -CeA circuit responded exclusively to SD promoting escape behavior during defeat and increasing the social avoidance after ASDS. Knocking down the OXT receptor ( Oxtr ) in the NAc decreases fight-back behavior, while knocking down Oxtr in the CeA decreases the escape behavior during defeat and immobility after defeat. These findings clarify that PVN OXT neurons embedded in different circuits promote distinct defensive behaviors in response to social threats and provide insights into the various effects of systematic OXT-based therapies for emotional and social disorders.