Abstract
Research across species has shown that the neuropeptide oxytocin plays a key role in the regulation of social cognition and behavior. It is important for attachment, social exploration, and social recognition, as well as anxiety and stress-related behaviors. Based on oxytocin administration studies and measurements of peripheral oxytocin levels, it has been suggested that signaling of oxytocin is impaired in mental disorders associated with social deficits, including autism, borderline personality disorder, and social anxiety disorder. There are several factors influencing interindividual differences in social-cognitive abilities and differences in the susceptibility to psychiatric disorders, including variability in genes involved in oxytocin signaling. In addition to sequence variation, interindividual differences might in part be explained by variation in epigenetic processes influencing gene expression. Here, we provide an overview of the functional organization and epigenetic regulation of the murine and human oxytocin receptor gene.
Studies in mice have shown that the oxytocin receptor gene (Oxtr) is epigenetically regulated by DNA methylation with experience- and tissue-specific expression patterns. In humans, functional studies on epigenetic mechanisms have focused on oxytocin receptor gene (OXTR) DNA methylation and have provided evidence for the influence of OXTR promoter methylation on OXTR mRNA expression. A small number of studies have investigated the role of OXTR methylation in behavioral phenotypes and mental illness. There is first evidence that OXTR methylation is associated with different aspects of social cognition as well as with psychiatric disorders characterized by deficits in social cognition, including autism, high callous-unemotional traits in youth, social anxiety, and anorexia nervosa.
Given evidence that epigenetic states of genes can be modified by experiences, especially those occurring in sensitive periods early in development, we conclude with a discussion on the effects of traumatic experience on the developing oxytocin system. Epigenetic modification of genes involved in oxytocin signaling might play a part in the mechanisms mediating the long-term influence of early adverse experiences on socio-behavioral outcomes.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
Notes
- 1.
Certain areas of the genome contain regions of high CpG density. These regions, called “CpG islands,” are defined as a >200 bp region with GC content of more than 50 % and an observed/predicted CpG ratio of more than 0.6 (Gardiner-Garden and Frommer 1987). CpG islands often span the promoter region of genes and are associated with active gene expression (Saxonov et al. 2006). These stretches of DNA have a higher CpG density than the rest of the genome and tend to be unmethylated (Bird et al. 1985). However, when methylated, CpG islands in gene promoters contribute to transcriptional repression in most tissues (Razin 1998).
References
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297
Beitchman JH, Zai CC, Muir K, Berall L, Nowrouzi B, Choi E, Kennedy JL (2012) Childhood aggression, callous-unemotional traits and oxytocin genes. Eur Child Adolesc Psychiatry. doi:10.1007/s00787-012-0240-6
Bird A, Taggart M, Frommer M, Miller OJ, Macleod D (1985) A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40:91–99
Blakemore SJ, Boyer P, Pachot-Clouard M, Meltzoff A, Segebarth C, Decety J (2003) The detection of contingency and animacy from simple animations in the human brain. Cereb Cortex 13:837–844
Bonthuis PJ, Patteson JK, Rissman EF (2011) Acquisition of sexual receptivity: roles of chromatin acetylation, estrogen receptor-alpha, and ovarian hormones. Endocrinology 152:3172–3181. doi:10.1210/en.2010-1001
Cecil CA, Lysenko LJ, Jaffee SR et al (2014) Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study. Mol Psychiatry 19:1071–1077. doi:10.1038/mp.2014.95
Champagne FA (2008) Epigenetic mechanisms and the transgenerational effects of maternal care. Front Neuroendocrinol 29:386–397. doi:10.1016/j.yfrne.2008.03.003
Champagne F, Diorio J, Sharma S, Meaney MJ (2001) Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors. Proc Natl Acad Sci U S A 98:12736–12741. doi:10.1073/pnas.221224598
Champagne FA, Weaver IC, Diorio J, Dymov S, Szyf M, Meaney MJ (2006) Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology 147:2909–2915. doi:10.1210/en.2005-1119
Chen FS, Kumsta R, von Dawans B, Monakhov M, Ebstein RP, Heinrichs M (2011) Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce stress in humans. Proc Natl Acad Sci U S A 108:19937–19942. doi:10.1073/pnas.1113079108
Choi J-W, Kang S-M, Lee Y, Hong S-H, Sanek NA, Young WS, Lee H-J (2013a) MicroRNA profiling in the mouse hypothalamus reveals oxytocin-regulating microRNA. J Neurochem 126:331–337. doi:10.1111/jnc.12308
Choi SW, Claycombe KJ, Martinez JA, Friso S, Schalinske KL (2013b) Nutritional epigenomics: a portal to disease prevention. Adv Nutr 4:530–532. doi:10.3945/an.113.004168
Cook JR, MacIntyre DA, Samara E et al (2015) Exogenous oxytocin modulates human myometrial microRNAs. Am J Obstet Gynecol 1–9. doi:10.1016/j.ajog.2015.03.015
Dadds MR, Moul C, Cauchi A, Dobson-Stone C, Hawes DJ, Brennan J, Ebstein RE (2014) Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy. Dev Psychopathol 26:33–40. doi:10.1017/S0954579413000497
Ditzen B, Nater UM, Schaer M, La Marca R, Bodenmann G, Ehlert U, Heinrichs M (2013) Sex-specific effects of intranasal oxytocin on autonomic nervous system and emotional responses to couple conflict. Soc Cogn Affect Neurosci 8:897–902. doi:10.1093/scan/nss083
Domes G, Heinrichs M, Glascher J, Buchel C, Braus D, Herpertz S (2007a) Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 62:1187–1190. doi:10.1016/j.biopsych.2007.03.025
Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC (2007b) Oxytocin improves “mind-reading” in humans. Biol Psychiatry 61:731–733
Domes G, Lischke A, Berger C, Grossmann A, Hauenstein K, Heinrichs M, Herpertz SC (2010) Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 35:83–93, doi:S0306-4530(09)00207-8 [pii], 10.1016/j.psyneuen.2009.06.016
Domes G, Sibold M, Schulze L, Lischke A, Herpertz SC, Heinrichs M (2012) Intranasal oxytocin increases covert attention to positive social cues. Psychol Med 1–7, doi:S0033291712002565 [pii], 10.1017/S0033291712002565
Ebstein RP, Knafo A, Mankuta D, Chew SH, Lai PS (2012) The contributions of oxytocin and vasopressin pathway genes to human behavior. Horm Behav 61:359–379. doi:10.1016/j.yhbeh.2011.12.014
Fleming JG, Spencer TE, Safe SH, Bazer FW (2006) Estrogen regulates transcription of the ovine oxytocin receptor gene through GC-rich SP1 promoter elements. Endocrinology 147:899–911. doi:10.1210/en.2005-1120
Frick PJ, White SF (2008) Research review: the importance of callous-unemotional traits for developmental models of aggressive and antisocial behavior. J Child Psychol Psychiatry 49:359–375. doi:10.1111/j.1469-7610.2007.01862.x
Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol 196:261–282
Gertz J, Varley KE, Reddy TE et al (2011) Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation. PLoS Genet 7:e1002228. doi:10.1371/journal.pgen.1002228.s007
Gilbert R, Widom CS, Browne K, Fergusson D, Webb E, Janson S (2009) Burden and consequences of child maltreatment in high-income countries. Lancet 373:68–81. doi:10.1016/S0140-6736(08)61706-7
Gould BR, Zingg HH (2003) Mapping oxytocin receptor gene expression in the mouse brain and mammary gland using an oxytocin receptor-LacZ reporter mouse. Neuroscience 122:155–167
Graff J, Tsai LH (2013) Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 14:97–111. doi:10.1038/nrn3427
Graff J, Joseph NF, Horn ME et al (2014) Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell 156:261–276. doi:10.1016/j.cell.2013.12.020
Gregory SG, Connelly JJ, Towers AJ et al (2009) Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 7:62. doi:10.1186/1741-7015-7-62
Guastella AJ, Mitchell PB, Dadds MR (2008) Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry 63:3–5, doi:S0006-3223(07)00617-8 [pii], 10.1016/j.biopsych.2007.06.026
Guastella AJ, Howard AL, Dadds MR, Mitchell P, Carson DS (2009) A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder. Psychoneuroendocrinology 34:917–923, doi:S0306-4530(09)00023-7 [pii], 10.1016/j.psyneuen.2009.01.005
Harony-Nicolas H, Mamrut S, Brodsky L, Shahar-Gold H, Barki-Harrington L, Wagner S (2014) Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation. Psychoneuroendocrinology 39:121–131. doi:10.1016/j.psyneuen.2013.10.004
Hawk JD, Florian C, Abel T (2011) Post-training intrahippocampal inhibition of class I histone deacetylases enhances long-term object-location memory. Learn Mem 18:367–370. doi:10.1101/lm.2097411
Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB (2008a) The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 33:693–710. doi:10.1016/j.psyneuen.2008.03.008
Heim C, Young LJ, Newport DJ, Mletzko T, Miller AH, Nemeroff CB (2008b) Lower CSF oxytocin concentrations in women with a history of childhood abuse. Mol Psychiatry, doi:mp2008112 [pii], 10.1038/mp.2008.112
Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U (2003) Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 54:1389–1398, doi:S0006322303004657 [pii]
Heinrichs M, von Dawans B, Domes G (2009) Oxytocin, vasopressin, and human social behavior. Front Neuroendocrinol 30:548–557, doi:S0091-3022(09)00029-6 [pii], 10.1016/j.yfrne.2009.05.005
Hoge EA, Pollack MH, Kaufman RE, Zak PJ, Simon NM (2008) Oxytocin levels in social anxiety disorder. CNS Neurosci Ther 14:165–170. doi:10.1111/j.1755-5949.2008.00051.x
Ivell R, Walther N (1999) The role of sex steroids in the oxytocin hormone system. Mol Cell Endocrinol 151:95–101
Jack A, Connelly JJ, Morris JP (2012) DNA methylation of the oxytocin receptor gene predicts neural response to ambiguous social stimuli. Front Hum Neurosci 6:280. doi:10.3389/fnhum.2012.00280
Keebaugh AC, Young LJ (2011) Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults. Horm Behav 60:498–504. doi:10.1016/j.yhbeh.2011.07.018
Kim YR, Kim JH, Kim MJ, Treasure J (2014) Differential methylation of the oxytocin receptor gene in patients with anorexia nervosa: a pilot study. PLoS One 9:e88673. doi:10.1371/journal.pone.0088673
Kirsch P, Esslinger C, Chen Q et al (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25:11489–11493, doi:25/49/11489 [pii], 10.1523/JNEUROSCI.3984-05.2005
Kubota Y, Kimura T, Hashimoto K et al (1996) Structure and expression of the mouse oxytocin receptor gene. Mol Cell Endocrinol 124:25–32
Kusui C, Kimura T, Ogita K et al (2001) DNA methylation of the human oxytocin receptor gene promoter regulates tissue-specific gene suppression. Biochem Biophys Res Commun 289:681–686. doi:10.1006/bbrc.2001.6024, S0006-291X(01)96024-3 [pii]
Lawson EA, Holsen LM, Santin M et al (2012) Oxytocin secretion is associated with severity of disordered eating psychopathology and insular cortex hypoactivation in anorexia nervosa. J Clin Endocrinol Metab 97:E1898–E1908. doi:10.1210/jc.2012-1702
Maguire S, O’Dell A, Touyz L, Russell J (2013) Oxytocin and anorexia nervosa: a review of the emerging literature. Eur Eat Disord Rev 21:475–478. doi:10.1002/erv.2252
Mamrut S, Harony H, Sood R et al (2013) DNA methylation of specific CpG sites in the promoter region regulates the transcription of the mouse oxytocin receptor. PLoS One 8:e56869. doi:10.1371/journal.pone.0056869
Mill J, Heijmans BT (2013) From promises to practical strategies in epigenetic epidemiology. Nat Rev Genet 14:585–594. doi:10.1038/nrg3405
Moser D, Ekawardhani S, Kumsta R et al (2008) Functional analysis of a potassium-chloride Co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA methylation site. Neuropsychopharmacology 34:458–467. doi:10.1038/npp.2008.77
Moul C, Killcross S, Dadds MR (2012) A model of differential amygdala activation in psychopathy. Psychol Rev 119:789–806. doi:10.1037/a0029342
Neumann ID (2002) Involvement of the brain oxytocin system in stress coping: interactions with the hypothalamo-pituitary-adrenal axis. Prog Brain Res 139:147–162
Peña CJ, Neugut YD, Champagne FA (2013) Developmental timing of the effects of maternal care on gene expression and epigenetic regulation of hormone receptor levels in female rats. Endocrinology 154:4340–4351. doi:10.1210/en.2013-1595
Prestridge DS (1995) Predicting Pol II promoter sequences using transcription factor binding sites. J Mol Biol 249:923–932. doi:10.1006/jmbi.1995.0349
Puglia MH, Lillard TS, Morris JP, Connelly JJ (2015) Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain. Proc Natl Acad Sci U S A 112:3308–3313. doi:10.1073/pnas.1422096112
Razin A (1998) CpG methylation, chromatin structure and gene silencing-a three-way connection. EMBO J 17:4905–4908. doi:10.1093/emboj/17.17.4905
Richlin VA, Arevalo JM, Zack JA, Cole SW (2004) Stress-induced enhancement of NF-kappaB DNA-binding in the peripheral blood leukocyte pool: effects of lymphocyte redistribution. Brain Behav Immun 18:231–237. doi:10.1016/j.bbi.2003.08.001
Ross HE, Freeman SM, Spiegel LL, Ren X, Terwilliger EF, Young LJ (2009) Variation in oxytocin receptor density in the nucleus accumbens has differential effects on affiliative behaviors in monogamous and polygamous voles. J Neurosci 29:1312–1318. doi:10.1523/JNEUROSCI.5039-08.2009
Sakai JT, Crowley TJ, Stallings MC et al (2012) Test of association between 10 single nucleotide polymorphisms in the oxytocin receptor gene and conduct disorder. Psychiatr Genet 22:99–102. doi:10.1097/YPG.0b013e32834c0cb2
Saxonov S, Berg P, Brutlag DL (2006) A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci U S A 103:1412–1417. doi:10.1073/pnas.0510310103
Stefanko DP, Barrett RM, Ly AR, Reolon GK, Wood MA (2009) Modulation of long-term memory for object recognition via HDAC inhibition. Proc Natl Acad Sci U S A 106:9447–9452. doi:10.1073/pnas.0903964106
Unternährer E, Luers P, Mill J et al (2012) Dynamic changes in DNA methylation of stress-associated genes (OXTR, BDNF) after acute psychosocial stress. Transl Psychiatry 2:e150. doi:10.1038/tp.2012.77
Wang H, Duclot F, Liu Y, Wang Z, Kabbaj M (2013) Histone deacetylase inhibitors facilitate partner preference formation in female prairie voles. Nat Neurosci 16:919–924. doi:10.1038/nn.3420
Wismer Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD (2005) Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci U S A 102:17237–17240. doi:10.1073/pnas.0504767102
Yi P, Melnyk S, Pogribna M, Pogribny IP, Hine RJ, James SJ (2000) Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem 275:29318–29323. doi:10.1074/jbc.M002725200
Zhang TY, Meaney MJ (2010) Epigenetics and the environmental regulation of the genome and its function. Annu Rev Psychol 61(439–466):C431–C433. doi:10.1146/annurev.psych.60.110707.163625
Zhang H, Wang F, Kranzler HR et al (2014) Identification of methylation quantitative trait loci (mQTLs) influencing promoter DNA methylation of alcohol dependence risk genes. Hum Genet 133:1093–1104. doi:10.1007/s00439-014-1452-2
Ziegler C, Dannlowski U, Brauer D et al (2015) Oxytocin receptor gene methylation: converging multilevel evidence for a role in social anxiety. Neuropsychopharmacology. doi:10.1038/npp.2015.2
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Kumsta, R., Zang, J.C.S., Moser, D. (2016). Oxytocin Receptors and Neurobehavior. In: Spengler, D., Binder, E. (eds) Epigenetics and Neuroendocrinology . Epigenetics and Human Health. Springer, Cham. https://doi.org/10.1007/978-3-319-29901-3_10
Download citation
DOI: https://doi.org/10.1007/978-3-319-29901-3_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-29900-6
Online ISBN: 978-3-319-29901-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)