Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice
Yasuhiko Yamamoto, Mingkun Liang, Seiichi Munesue, Kisaburo Deguchi, Ai Harashima, Kazumi Furuhara, Teruko Yuhi, Jing Zhong, Shirin Akther, Hisanori Goto, Yuya Eguchi, Yasuko Kitao, Osamu Hori, Yoshitake Shiraishi, Noriyuki Ozaki, Yu Shimizu, Tomoya Kamide, Akifumi Yoshikawa, Yasuhiko Hayashi, Mitsutoshi Nakada, Olga Lopatina, Maria Gerasimenko, Yulia Komleva, Natalia Malinovskaya, Alla B Salmina, Masahide Asano, Katsuhiko Nishimori, Steven E Shoelson, Hiroshi Yamamoto, Haruhiro Higashida, Yasuhiko Yamamoto, Mingkun Liang, Seiichi Munesue, Kisaburo Deguchi, Ai Harashima, Kazumi Furuhara, Teruko Yuhi, Jing Zhong, Shirin Akther, Hisanori Goto, Yuya Eguchi, Yasuko Kitao, Osamu Hori, Yoshitake Shiraishi, Noriyuki Ozaki, Yu Shimizu, Tomoya Kamide, Akifumi Yoshikawa, Yasuhiko Hayashi, Mitsutoshi Nakada, Olga Lopatina, Maria Gerasimenko, Yulia Komleva, Natalia Malinovskaya, Alla B Salmina, Masahide Asano, Katsuhiko Nishimori, Steven E Shoelson, Hiroshi Yamamoto, Haruhiro Higashida
Abstract
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.
Conflict of interest statement
The authors declare no competing interests.
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References
- Brunton PJ, Russell JA. The expectant brain: adapting for motherhood. Nat. Rev. Neurosci. 2008;9:11–25. doi: 10.1038/nrn2280.
- Dulac C, O’Connell LA, Wu Z. Neural control of maternal and paternal behaviors. Science. 2014;345:765–770. doi: 10.1126/science.1253291.
- Carter, C. S. Oxytocin and human evolution. Curr. Top. Behav. Neurosci. 35, 291–319 (2018).
- Castel M, Gainer H, Dellmann HD. Neuronal secretory systems. Int. Rev. Cytol. 1984;88:303–459. doi: 10.1016/S0074-7696(08)62760-6.
- Jin D, et al. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature. 2007;446:41–45. doi: 10.1038/nature05526.
- Leng G, Pineda R, Sabatier N, Ludwig M. 60 Years of neuroendocrinology: the posterior pituitary, from Geoffrey Harris to our present understanding. J. Endocrinol. 2015;226:T173–T185. doi: 10.1530/JOE-15-0087.
- Insel TR. The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior. Neuron. 2010;65:768–779. doi: 10.1016/j.neuron.2010.03.005.
- Rilling JK, Young LJ. The biology of mammalian parenting and its effect on offspring social development. Science. 2014;345:771–776. doi: 10.1126/science.1252723.
- Higashida H, Yokoyama S, Kikuchi M, Munesue T. CD38 and its role in oxytocin secretion and social behavior. Horm. Behav. 2012;61:351–358. doi: 10.1016/j.yhbeh.2011.12.011.
- Insel TR. Translating oxytocin neuroscience to the clinic: A National Institute of Mental Health Perspective. Biol. Psychiatry. 2016;79:153–154. doi: 10.1016/j.biopsych.2015.02.002.
- Guastella AJ, et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol. Psychiatry. 2010;67:692–694. doi: 10.1016/j.biopsych.2009.09.020.
- Gordon I, et al. Intranasal oxytocin enhances connectivity in the neural circuitry supporting social motivation and social perception in children with autism. Sci. Rep. 2016;6:35054. doi: 10.1038/srep35054.
- Feifel D, Shilling PD, MacDonald K. A review of oxytocin’s effects on the positive, negative, and cognitive domains of schizophrenia. Biol. Psychiatry. 2016;79:222–233. doi: 10.1016/j.biopsych.2015.07.025.
- Zik JB, Roberts DL. The many faces of oxytocin: implications for psychiatry. Psychiatry Res. 2015;226:31–37. doi: 10.1016/j.psychres.2014.11.048.
- Bethlehem RA, Baron-Cohen S, van Honk J, Auyeung B, d Bos PA. The oxytocin paradox. Front. Behav. Neurosci. 2014;8:48. doi: 10.3389/fnbeh.2014.00048.
- Striepens N, et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci. Rep. 2013;3:3440. doi: 10.1038/srep03440.
- Neumann ID, Maloumby R, Beiderbeck DI, Lukas M, Landgraf R. Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology. 2013;38:1985–1993. doi: 10.1016/j.psyneuen.2013.03.003.
- Rault JL. Effects of positive and negative human contacts and intranasal oxytocin on cerebrospinal fluid oxytocin. Psychoneuroendocrinology. 2016;69:60–66. doi: 10.1016/j.psyneuen.2016.03.015.
- Lefevre A. A comparison of methods to measure central and peripheral oxytocin concentrations in human and non-human primates. Sci. Rep. 2017;7:17222. doi: 10.1038/s41598-017-17674-7.
- Ermisch A, et al. On the blood-brain barrier to peptides: accumulation of labelled vasopressin, DesGlyNH2-vasopressin and oxytocin by brain regions. Endocrinol. Exp. 1985;19:29–37.
- Pardridge WM. Drug transport across the blood-brain barrier. J. Cereb. Blood Flow Metab. 2012;32:1959–1972. doi: 10.1038/jcbfm.2012.126.
- Senatus LM, Schmidt AM. The AGE-RAGE axis: implications for age-associated arterial diseases. Front. Genet. 2017;8:187. doi: 10.3389/fgene.2017.00187.
- Kamide T, et al. RAGE mediates vascular injury and inflammation after global cerebral ischemia. Neurochem. Int. 2012;60:220–228. doi: 10.1016/j.neuint.2011.12.008.
- Manigrasso MB, Juranek J, Ramasamy R, Schmidt AM. Unlocking the biology of RAGE in diabetic microvascular complications. Trends Endocrinol. Metab. 2014;25:15–22. doi: 10.1016/j.tem.2013.08.002.
- Takuma K, et al. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc. Natl Acad. Sci. USA. 2009;106:20021–20026. doi: 10.1073/pnas.0905686106.
- Yamamoto Y, et al. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J. Clin. Invest. 2001;108:261–268. doi: 10.1172/JCI11771.
- Yamamoto Y, et al. Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J. Immunol. 2011;186:3248–3257. doi: 10.4049/jimmunol.1002253.
- Yamamoto Y, Yamamoto H. RAGE-mediated inflammation, type 2 diabetes, and diabetic vascular complication. Front. Endocrinol. 2013;4:105. doi: 10.3389/fendo.2013.00105.
- Yonekura H, et al. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem. J. 2003;370:1097–1109. doi: 10.1042/bj20021371.
- Motoyoshi S, et al. cAMP ameliorates inflammation by modulation of macrophage receptor for advanced glycation end-products. Biochem. J. 2014;463:75–82. doi: 10.1042/BJ20140084.
- Mackic JB, et al. Human blood-brain barrier receptors for Alzheimer’s amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J. Clin. Invest. 1998;102:734–743. doi: 10.1172/JCI2029.
- Yamamoto Y, et al. Short-chain aldehyde-derived ligands for RAGE and their actions on endothelial cells. Diabetes Res. Clin. Pract. 2007;77:S30–S40. doi: 10.1016/j.diabres.2007.01.030.
- Matsumoto K, et al. Immunohistochemical analysis of transporters related to clearance of amyloid-β peptides through blood-cerebrospinal fluid barrier in human brain. Histochem. Cell. Biol. 2015;144:597–611. doi: 10.1007/s00418-015-1366-7.
- Deane R, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat. Med. 2003;9:907–913. doi: 10.1038/nm890.
- Deane R, et al. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J. Clin. Invest. 2012;122:1377–1392. doi: 10.1172/JCI58642.
- Saito R, Araki S, Yamamoto Y, Kusuhara K. Elevated endogenous secretory receptor for advanced glycation end products (esRAGE) levels are associated with circulating soluble RAGE levels in diabetic children. J. Pediatr. Endocrinol. Metab. 2017;30:63–69. doi: 10.1515/jpem-2016-0262.
- Gasparotto J, et al. Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment. J. Biol. Chem. 2018;293:226–244. doi: 10.1074/jbc.M117.786756.
- Takayanagi Y, et al. Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc. Natl Acad. Sci. USA. 2005;102:16096–16101. doi: 10.1073/pnas.0505312102.
- Ferguson JN, et al. Social amnesia in mice lacking the oxytocin gene. Nat. Genet. 2000;25:284–288. doi: 10.1038/77040.
- Modi ME, Young LJ. The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies. Horm. Behav. 2012;61:340–350. doi: 10.1016/j.yhbeh.2011.12.010.
- Myint KM, et al. RAGE control of diabetic nephropathy in a mouse model: effects of RAGE gene disruption and administration of low-molecular weight heparin. Diabetes. 2006;55:2510–2522. doi: 10.2337/db06-0221.
- Takeuchi A, et al. Low molecular weight heparin suppresses receptor for advanced glycation end products-mediated expression of malignant phenotype in human fibrosarcoma cells. Cancer Sci. 2013;104:740–749. doi: 10.1111/cas.12133.
- Xue J, et al. Change in the molecular dimension of a RAGE-ligand complex triggers RAGE signaling. Structure. 2016;24:1509–1522. doi: 10.1016/j.str.2016.06.021.
- Pollak TA, et al. The blood-brain barrier in psychosis. Lancet Psychiatry. 2018;5:79–92. doi: 10.1016/S2215-0366(17)30293-6.
- Lundquist S, et al. Prediction of drug transport through the blood-brain barrier in vivo: a comparison between two in vitro cell models. Pharm. Res. 2002;19:976–981. doi: 10.1023/A:1016462205267.
- Nakagawa S, et al. Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cell. Mol. Neurobiol. 2007;27:687–694. doi: 10.1007/s10571-007-9195-4.
- Yoshida M, et al. Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J. Neurosci. 2009;29:2259–2271. doi: 10.1523/JNEUROSCI.5593-08.2009.
- Rilling JK, et al. Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology. 2014;39:237–248. doi: 10.1016/j.psyneuen.2013.09.022.
- Scheele D, et al. Opposing effects of oxytocin on moral judgment in males and females. Hum. Brain Mapp. 2014;35:6067–6076. doi: 10.1002/hbm.22605.
- Steinman MQ, et al. Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin. Biol. Psychiatry. 2016;80:406–414. doi: 10.1016/j.biopsych.2015.10.007.
- Numan M, Numan MJ. Projection sites of medial preoptic area and ventral bed nucleus of the stria terminalis neurons that express Fos during maternal behavior in female rats. J. Neuroendocrinol. 1997;9:369–384. doi: 10.1046/j.1365-2826.1997.t01-1-00597.x.
- Martinez LA, Levy MJ, Petrulis A. Endogenous oxytocin is necessary for preferential Fos expression to male odors in the bed nucleus of the stria terminalis in female Syrian hamsters. Horm. Behav. 2013;64:653–664. doi: 10.1016/j.yhbeh.2013.08.016.
- Zhong J, et al. c-Fos expression in the paternal mouse brain induced by communicative interaction with maternal mates. Mol. Brain. 2014;7:66. doi: 10.1186/s13041-014-0066-x.
- Feldman R, et al. Sensitive parenting is associated with plasma oxytocin and polymorphisms in the OXTR and CD38 genes. Biol. Psychiatry. 2012;72:175–181. doi: 10.1016/j.biopsych.2011.12.025.
- Politte LC, Henry CA, McDougle CJ. Psychopharmacological interventions in autism spectrum disorder. Harv. Rev. Psychiatry. 2014;22:76–92. doi: 10.1097/HRP.0000000000000030.
- Cai Q, Feng L, Yap KZ. Systematic review and meta-analysis of reported adverse events of long-term intranasal oxytocin treatment for autism spectrum disorder. Psychiatry Clin. Neurosci. 2018;72:140–151. doi: 10.1111/pcn.12627.
- Munesue T, et al. Oxytocin for male subjects with autism spectrum disorder and comorbid intellectual disabilities: a randomized pilot study. Front. Psychiatry. 2016;7:2. doi: 10.3389/fpsyt.2016.00002.
- Sakatani S, et al. Deletion of RAGE causes hyperactivity and increased sensitivity to auditory stimuli in mice. PLoS One. 2009;4:e8309. doi: 10.1371/journal.pone.0008309.
- Zhang G, Cai D. Circadian intervention of obesity development via resting-stage feeding manipulation or oxytocin treatment. Am. J. Physiol. Endocrinol. Metab. 2011;301:E1004–E1012. doi: 10.1152/ajpendo.00196.2011.
- Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol. Rev. 2001;81:629–683. doi: 10.1152/physrev.2001.81.2.629.
- Kagerbauer SM, et al. Plasma oxytocin and vasopressin do not predict neuropeptide concentrations in human cerebrospinal fluid. J. Neuroendocrinol. 2013;25:668–673. doi: 10.1111/jne.12038.
- Martin J, et al. Vasopressin and oxytocin in CSF and plasma of patients with aneurysmal subarachnoid haemorrhage. Neuropeptides. 2014;48:91–96. doi: 10.1016/j.npep.2013.12.004.
- Brandtzaeg OK, et al. Proteomics tools reveal startlingly high amounts of oxytocin in plasma and serum. Sci. Rep. 2016;6:31693. doi: 10.1038/srep31693.
- Hileman SM, Pierroz DD, Flier JS. Leptin, nutrition, and reproduction: timing is everything. J. Clin. Endocrinol. Metab. 2000;85:804–847. doi: 10.1210/jcem.85.2.6490.
- Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol. Dis. 2010;37:13–25. doi: 10.1016/j.nbd.2009.07.030.
- Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci. 2012;35:649–659. doi: 10.1016/j.tins.2012.08.004.
- Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol. Psychiatry. 2016;79:243–250. doi: 10.1016/j.biopsych.2015.05.003.
- Dal Monte O, Noble PL, Turchi J, Cummins A, Averbeck BB. CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PLoS One. 2014;29:e103677. doi: 10.1371/journal.pone.0103677.
- Temesi A, Thuróczy J, Balogh L, Miklósi Aacute. Increased serum and urinary oxytocin concentrations after nasal administration in beagle dogs. Front. Vet. Sci. 2017;4:147. doi: 10.3389/fvets.2017.00147.
- Quintana DS, et al. Saliva oxytocin measures do not reflect peripheral plasma concentrations after intranasal oxytocin administration in men. Horm. Behav. 2018;102:85–92. doi: 10.1016/j.yhbeh.2018.05.004.
- Mens WB, Laczi F, Tonnaer JA, de Kloet ER, van Wimersma Greidanus TB. Vasopressin and oxytocin content in cerebrospinal fluid and in various brain areas after administration of histamine and pentylenetetrazol. Pharmacol. Biochem. Behav. 1983;19:587–591. doi: 10.1016/0091-3057(83)90332-5.
- Tanaka A, et al. Delivery of oxytocin to the brain for the treatment of autism spectrum disorder by nasal application. Mol. Pharm. 2018;15:1105–1111. doi: 10.1021/acs.molpharmaceut.7b00991.
- Higashida H, et al. Intestinal transepithelial permeability of oxytocin into the blood is dependent on the receptor for advanced glycation end products in mice. Sci. Rep. 2017;7:7883. doi: 10.1038/s41598-017-07949-4.
- Bridges RS. Neuroendocrine regulation of maternal behavior. Front. Neuroendocrinol. 2015;36:178–196. doi: 10.1016/j.yfrne.2014.11.007.
- Liu C, et al. Pet-1 is required across different stages of life to regulate serotonergic function. Nat. Neurosci. 2010;13:1190–1198. doi: 10.1038/nn.2623.
- Landgraf R, Ermisch A, Hess J. Indications for a brain uptake of labelled vasopressin and ocytocin and the problem of the blood-brain barrier. Endokrinologie. 1979;73:77–81.
- Lopatina O, et al. H. Communication impairment in ultrasonic vocal repertoire during the suckling period of Cd157 knockout mice: transient improvement by oxytocin. Front. Neurosci. 2017;11:266. doi: 10.3389/fnins.2017.00266.
- Liu L, Duff K. A technique for serial collection of cerebrospinal fluid from the cisterna magna in mouse. J. Vis. Exp. 2008;21:pii: 960.
- Paxinos, G. & Franklin, K. B. J. The Mouse Brain in Stereotaxic Coordinates. 2. (Academic Press, San Diego, 2001).
- Zhong. J, et al. Cyclic ADP-ribose and heat regulate oxytocin release via CD38 and TRPM2 in the hypothalamus during social or psychological stress in mice. Front. Neurosci. 2016;10:304. doi: 10.3389/fnins.2016.00304.
- Cherepanov SM, et al. Effects of three lipidated oxytocin analogs on behavioral deficits in CD38 knockout mice. Brain Sci. 2017;7:10. doi: 10.3390/brainsci7100132.
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