Pharmacological manipulation of oxytocin receptor signaling during mouse embryonic development results in sex-specific behavioral effects in adulthood.

The oxytocin (Oxt) system is a known neuromodulator of social behaviors, but also appears to contribute to the development of sex-specific neural circuitry. In this latter role, the Oxt system helps to lay the foundation for sex-specific behaviors across the life span. In mice, the Oxt system emerges in early development, with sex differences in the expression of Oxt and a temporal offset in the expression of the Oxt receptor (Oxtr) relative to Oxt. In females, Oxt mRNA is detectable by embryonic day (E) 16.5, but in males, Oxt mRNA is not measurable until after birth. However, in both sexes, Oxtr mRNA is detectable by E12.5 and binding by E16.5. While the postnatal Oxt system has been studied, little is known about the embryonic Oxt system. Therefore, we hypothesize that it directly contributes to the developmental trajectory of the brain, ultimately affecting adult sex-specific behaviors. To test this hypothesis, Oxtr signaling was transiently disrupted at E16.5 using an Oxtr antagonist (OxtrA) and the effects on adult behavior evaluated. OxtrA-treated adult males displayed increased agonistic behavior, social investigation, and depressive-like behavior compared to vehicle-injected controls, while OxtrA-treated adult females had impaired social recognition memory compared to vehicle-injected controls. These data are the first to identify a functional link between the organizational activity of the embryonic Oxt system and adult behavior. Further, this work suggests that the Oxt system does more than serve as a neuromodulator in adulthood, but rather, may help shape the development of the neural circuitry regulating sex-specific behaviors.