Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice

• Published in: Communications biology Vol. 2; no. 1; p. 76
• Main Authors: Yamamoto, Yasuhiko, Liang, Mingkun, Munesue, Seiichi, Deguchi, Kisaburo, Harashima, Ai, Furuhara, Kazumi, Yuhi, Teruko, Zhong, Jing, Akther, Shirin, Goto, Hisanori, Eguchi, Yuya, Kitao, Yasuko, Hori, Osamu, Shiraishi, Yoshitake, Ozaki, Noriyuki, Shimizu, Yu, Kamide, Tomoya, Yoshikawa, Akifumi, Hayashi, Yasuhiko, Nakada, Mitsutoshi, Lopatina, Olga, Gerasimenko, Maria, Komleva, Yulia, Malinovskaya, Natalia, Salmina, Alla B., Asano, Masahide, Nishimori, Katsuhiko, Shoelson, Steven E., Yamamoto, Hiroshi, Higashida, Haruhiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.02.2019; Nature Publishing Group
• Subjects: 13/51; 14/19; 14/28; 631/378/1341; 631/443/376; 64/60; 82/103; 82/16; Advanced glycosylation end products; Animals; Behavior; Biology; Biomedical and Life Sciences; Blood-brain barrier; Brain - metabolism; CD38 antigen; Endothelial cells; Endothelial Cells - metabolism; Female; Glycosylation; Humans; Hyperactivity; Lactation; Life Sciences; Male; Maternal behavior; Maternal Behavior - physiology; Maternal Behavior - psychology; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Object Attachment; Oxytocin; Oxytocin - metabolism; Receptor for Advanced Glycation End Products - blood; Receptor for Advanced Glycation End Products - genetics; Receptor for Advanced Glycation End Products - metabolism; Receptors, Oxytocin - genetics; Receptors, Oxytocin - metabolism; Uterus
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-019-0325-6

Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bonding behaviours. Mice lacking secreted oxcytocin ( Oxt −/− , Cd38 −/− ) or its receptor ( Oxtr −/− ) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt −/− and Cd38 −/− , but not Oxtr −/− mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager −/− male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager −/− mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding. Yasuhiko Yamamoto et al. show that oxytocin is transported into the brain by the receptor for advanced glycation end-products (RAGE) on the blood-brain barrier. This study explains how circulating oxytocin crosses the blood-brain barrier, which is important to manifest oxytocin’s maternal bonding effects.