Sexually Dimorphic Oxytocin Receptor-Expressing Neurons In The Anteroventral Periventricular Nucleus Regulates Maternal Behavior

Abstract

The neurohypophysial hormone oxytocin is involved in the regulation of social behaviors, including social recognition, pair bonding, and sex-specific parental behaviors in a variety of species. Oxytocin triggers these social behaviors by binding to oxytocin receptors (OXTR) in various parts of the brain. Oxytocin-induced sex-typical behavior, therefore, suggests a sexual dimorphic distribution of OXTR in the brain. In recent years, the oxytocin system in the brain received tremendous attention as a potential pharmacological target for treatment of many psychiatric disorders, such as anxiety, autism spectrum disorders, and even sex-specific psychiatric disorder like postpartum depression (PPD). An important problem and a critical barrier to progress in the field is that despite the importance, the cellular characterization and distribution of the OXTR expressing neurons in the brain are still largely unknown. The overall long-term objective of this project is to elucidate the physiological and behavioral significance of the estrogen-dependent, sexually dimorphic OXTR in the AVPV. This study was conducted to map OXTR expressing neurons in the hypothalamic medial preoptic area (MPOA), a region known as sexually dimorphic and hormone-sensitive area. We revealed using OXTR-reporter mice in which a part of the OXTR gene was replaced with fluorescent protein, Venus, that OXTR neurons are predominantly present in the anteroventral periventricular nucleus (AVPV) in the MPOA of females, but not of males. Moreover, the expression of OXTR in neurons of the AVPV in females depends upon estrogen. Ovariectomy (OVX) resulted in total loss of OXTR-Venus neurons in the AVPV. Because the onset of proper maternal behavior at parturition requires activation of OXTR in the MPOA, the female specific expression of OXTR in neurons of the AVPV implies that these neurons are involved in the induction of maternal behavior. The dopaminergic neurons in the AVPV are known to play a role in the regulation of maternal behavior. Our study showed that a fraction of the OXTR neurons are immunoreactive to tyrosine hydroxylase, an enzyme essential for dopamine synthesis, implying that some of the OXTR neurons are dopaminergic as well. Using immunocytochemistry and fluorescence microscopy, the exact distribution of OXTR-expressing dopaminergic neurons was shown and the changes in their expression during pregnancy and postpartum states were quantified. Using a chemogenetic approach to specifically inactivate OXTR neurons, this study shows that OXTR neurons in the AVPV are critical to regulate maternal behavior. Understanding sex differences in the oxytocin system in the brain could ultimately lead to sex-specific