RT Journal Article SR Electronic T1 Oxytocin facilitates allo-parental behavior under stress in laboratory mice JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0405-21.2022 DO 10.1523/ENEURO.0405-21.2022 A1 Yousuke Tsuneoka A1 Chihiro Yoshihara A1 Ryuko Ohnishi A1 Sachine Yoshida A1 Eri Miyazawa A1 Masanobu Yamada A1 Kazuhiko Horiguchi A1 W. Scott Young A1 Katsuhiko Nishimori A1 Tadafumi Kato A1 Kumi O. Kuroda YR 2022 UL http://www.eneuro.org/content/early/2022/01/10/ENEURO.0405-21.2022.abstract AB Oxytocin (Oxt) controls reproductive physiology and various kinds of social behaviors, but the exact contribution of Oxt to different components of parental care still needs to be determined. Here we illustrate the neuroanatomical relations of the parental nurturing-induced neuronal activation with magnocellular oxytocin neurons and fibers in the medial preoptic area (MPOA), the brain region critical for parental and alloparental behaviors. We utilized genetically-targeted mouse lines for Oxt, oxytocin receptor (Oxtr), vasopressin receptor 1a (Avpr1a), vasopressin receptor 1b (Avpr1b), and thyrotropin-releasing hormone (Trh) to systematically examine the role of Oxt-related signaling in pup-directed behaviors. The Oxtr-Avpr1a-Avpr1b triple knockout (TKO), and Oxt-Trh-Avpr1a-Avpr1b quadruple KO (QKO) mice were grossly healthy and fertile, except for their complete deficiency in milk ejection and modest deficiency in parturition secondary to maternal loss of the Oxt or Oxtr genes. In our minimal stress conditions, pup-directed behaviors in TKO and QKO mothers and fathers, virgin females and males were essentially indistinguishable from those of their littermates with other genotypes. However, Oxtr KO virgin females did show decreased pup retrieval in the pup-exposure assay performed right after restraint stress. This stress vulnerability in the Oxtr KO was abolished by the additional Avpr1b KO. The general stress sensitivity, as measured by plasma cortisol elevation after restraint stress or by the behavioral performance in the open field and elevated plus maze, were not altered in the Oxtr KO but were reduced in the Avpr1b KO females, indicating that the balance of neurohypophysial hormones affects the outcome of pup-directed behaviors.Significance StatementParental care without suckling induces the most significant transcriptional activation in the caregivers' anterior commissural nucleus, the third-largest population of oxytocin neurons in the medial preoptic area, but not in its non-oxytocinergic neurons. The pup-directed behaviors in postpartum mothers, fathers and virgin males and females of oxytocin receptor (Oxtr), vasopressin receptor (Avpr) 1a and 1b triple knockout mice were essentially normal in our standard experimental conditions with minimal stress. Under stressful conditions, however, Oxtr KO mice showed decreased parental nurturing behaviors, which was compensated for by combining with the Avpr1b KO.