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      RAGE regulates oxytocin transport into the brain

      1 , , 2

      Communications Biology

      Nature Publishing Group UK

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          Abstract

          Oxytocin, a nonapeptide hormone, has a key role in female reproductive functions as well as in social memory in the brain. In our recent Communications Biology article, we reported that oxytocin is transported from the peripheral blood into the brain by the receptor for advanced glycation end-products (RAGE) in endothelial cells at the blood−brain barrier. Additionally, we found that oral oxytocin is absorbed by RAGE on intestinal epithelial cells at the blood−intestinal barrier. From a physiological perspective, we herein outline the continuing research regarding oxytocin and social behaviour.

          Abstract

          Yamamoto and Higashido discuss the possible routes of the hormone oxytocin in the body, and highlight their recent study in Communications Biology where they showed that the RAGE receptor is a transporter for oxytocin across the blood−brain barrier.

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          Most cited references 19

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          CD38 is critical for social behaviour by regulating oxytocin secretion.

          CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders.
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            Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans

            There has been an unprecedented interest in the modulatory effects of intranasal oxytocin on human social cognition and behaviour, however as yet no study has actually demonstrated that this modality of administration increases concentrations of the peptide in the brain as well as blood in humans. Here using combined blood and cerebrospinal fluid (CSF) sampling in subjects receiving either 24 IU of oxytocin (n = 11) or placebo (n = 4) we have shown that oxytocin levels significantly increased in both plasma and CSF. However, whereas oxytocin plasma concentrations peaked at 15 min after intranasal administration and decreased after 75 min, CSF concentrations took up to 75 min to reach a significant level. Moreover, there was no correlation (r = <0.10) between oxytocin plasma and CSF concentrations. Together, these data provide crucial insights into the plasma and CSF kinetics of intranasally administered oxytocin.
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              Neural control of maternal and paternal behaviors.

              Parental care, including feeding and protection of young, is essential for the survival as well as mental and physical well-being of the offspring. A large variety of parental behaviors has been described across species and sexes, raising fascinating questions about how animals identify the young and how brain circuits drive and modulate parental displays in males and females. Recent studies have begun to uncover a striking antagonistic interplay between brain systems underlying parental care and infant-directed aggression in both males and females, as well as a large range of intrinsic and environmentally driven neural modulation and plasticity. Improved understanding of the neural control of parental interactions in animals should provide novel insights into the complex issue of human parental care in both health and disease.
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                Author and article information

                Contributors
                haruhiro@med.kanazawa-u.ac.jp
                Journal
                Commun Biol
                Commun Biol
                Communications Biology
                Nature Publishing Group UK (London )
                2399-3642
                13 February 2020
                13 February 2020
                2020
                : 3
                Affiliations
                [1 ]ISNI 0000 0001 2308 3329, GRID grid.9707.9, Departments of Biochemistry and Molecular Vascular Biology, , Kanazawa University Graduate School of Medical Sciences, ; Kanazawa, 920-8640 Japan
                [2 ]ISNI 0000 0001 2308 3329, GRID grid.9707.9, Department of Basic Research on Social Recognition and Memory, Research Centre for Child Mental Development, , Kanazawa University, ; Kanazawa, 920-8640 Japan
                Article
                799
                10.1038/s42003-020-0799-2
                7018824
                32054984
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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