The oxytocin receptor (OXTR) and its ligand, oxytocin (OXT), regulate reproductive physiology (i.e., parturition and lactation) and sociosexual behaviors. To define the essential functions of OXTR, we generated mice with a null mutation in the Oxtr gene (Oxtr ؊/؊ ) and compared them with OXT-deficient (Oxt ؊/؊ ) mice. Oxtr ؊/؊ mice were viable and had no obvious deficits in fertility or reproductive behavior. Oxtr ؊/؊ dams exhibited normal parturition but demonstrated defects in lactation and maternal nurturing. Infant Oxtr ؊/؊ males emitted fewer ultrasonic vocalizations than wild-type littermates in response to social isolation. Adult Oxtr ؊/؊ males also showed deficits in social discrimination and elevated aggressive behavior. Ligand Oxt ؊/؊ males from Oxt ؊/؊ dams, but not from Oxt ؉/؊ dams, showed similar high levels of aggression. These data suggest a developmental role for the OXT͞OXTR system in shaping adult aggressive behavior. Our studies demonstrate that OXTR plays a critical role in regulating several aspects of social behavior and may have important implications for developmental psychiatric disorders characterized by deficits in social behavior.lactation ͉ maternal behavior ͉ ultrasonic vocalization ͉ social discrimination ͉ aggressive behavior

The oxytocin receptor has been implicated in the regulation of reproductive physiology as well as social and emotional behaviors. The neurochemical mechanisms by which oxytocin receptor modulates social and emotional behavior remains elusive, in part because of a lack of sensitive and selective antibodies for cellular localization. To more precisely characterize oxytocin receptor-expressing neurons within the brain, we generated an oxytocin receptor-reporter mouse in which part of the oxytocin receptor gene was replaced with Venus cDNA (a variant of yellow fluorescent protein). Examination of the Venus expression revealed that, in the raphe nuclei, about one-half of tryptophan hydroxylase-immunoreactive neurons were positive for Venus, suggesting a potential role for oxytocin in the modulation of serotonin release. Oxytocin infusion facilitated serotonin release within the median raphe nucleus and reduced anxiety-related behavior. Infusion of a 5-HT 2A/2C receptor antagonist blocked the anxiolytic effect of oxytocin, suggesting that oxytocin receptor activation in serotonergic neurons mediates the anxiolytic effects of oxytocin. This is the first demonstration that oxytocin may regulate serotonin release and exert anxiolytic effects via direct activation of oxytocin receptor expressed in serotonergic neurons of the raphe nuclei. These results also have important implications for psychiatric disorders such as autism and depression in which both the oxytocin and serotonin systems have been implicated.

Human-like modes of communication, including mutual gaze, in dogs may have been acquired during domestication with humans. We show that gazing behavior from dogs, but not wolves, increased urinary oxytocin concentrations in owners, which consequently facilitated owners' affiliation and increased oxytocin concentration in dogs. Further, nasally administered oxytocin increased gazing behavior in dogs, which in turn increased urinary oxytocin concentrations in owners. These findings support the existence of an interspecies oxytocin-mediated positive loop facilitated and modulated by gazing, which may have supported the coevolution of human-dog bonding by engaging common modes of communicating social attachment.

The hypothalamic paraventricular nucleus (PVN) functions as a center to integrate various neuronal activities for regulating feeding behavior. Nesfatin-1, a recently discovered anorectic molecule, is localized in the PVN. However, the anorectic neural pathway of nesfatin-1 remains unknown. Here we show that central injection of nesfatin-1 activates the PVN and brain stem nucleus tractus solitarius (NTS). In the PVN, nesfatin-1 targets both magnocellular and parvocellular oxytocin neurons and nesfatin-1 neurons themselves and stimulates oxytocin release. Immunoelectron micrographs reveal nesfatin-1 specifically in the secretory vesicles of PVN neurons, and immunoneutralization against endogenous nesfatin-1 suppresses oxytocin release in the PVN, suggesting paracrine/autocrine actions of nesfatin-1. Nesfatin-1-induced anorexia is abolished by an oxytocin receptor antagonist. Moreover, oxytocin terminals are closely associated with and oxytocin activates pro-opiomelanocortin neurons in the NTS. Oxytocin induces melanocortin-dependent anorexia in leptin-resistant Zucker-fatty rats. The present results reveal the nesfatin-1-operative oxytocinergic signaling in the PVN that triggers leptin-independent melanocortin-mediated anorexia.