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 OXT/OXTR 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.

Gaze into my eyes: Humans bond emotionally as we gaze into each other's eyes—a process mediated by the hormone oxytocin. Nagasawa et al. show that such gaze-mediated bonding also exists between us and our closest animal companions, dogs (see the Perspective by MacLean and Hare). They found that mutual gazing increased oxytocin levels, and sniffing oxytocin increased gazing in dogs, an effect that transferred to their owners. Wolves, who rarely engage in eye contact with their human handlers, seem resistant to this effect. Science , this issue p. 333 ; see also p. 280

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/2Creceptor 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.

The oxytocin receptor has been suggested to be involved in energy metabolism, such as food intake and energy consumption. Here, we demonstrate that oxytocin receptor-deficient (Oxtr^−/−) male mice exhibited late-onset obesity with increases in abdominal fat pads and fasting plasma triglycerides. Daily food intake and spontaneous motor activity of Oxtr^−/− mice were not significantly different as compared with wild-type mice. In contrast, brown adipose tissue in Oxtr^−/− mice contained large lipid droplets and cold-induced thermogenesis was impaired. This study demonstrates that oxytocin receptor plays essential roles in the regulation of energy homeostasis.