Oxytocin, stress and social behavior: neurogenetics of the human oxytocin system

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Oxytocin, stress and social behavior: neurogenetics of the human oxytocin system

Robert Kumsta

¹

and Markus Heinrichs

^1,2

Theneuropeptideoxytocinhashadkeyrolesthroughout mammalianevolutionintheregulationofcomplexsocial cognitionandbehaviors,suchasattachment,parentalcare, pair-bonding,aswellassocialexplorationandrecognition.

Recently,studieshavebeguntoprovideevidencethatthe functionofthisneuropeptideisimpairedinmentaldisorders associatedwithsocialdeficits.Inthisreview,wefocusonthe geneticmechanismsofinter-individualvariationinthesocial neuropeptidesignaling.Wediscussmoleculargeneticstudies whichidentifiedvariationsinspecificgenescontributingto individualdifferencesinsocialbehaviorandcognition,witha focusonthegenecodingfortheoxytocinreceptor(OXTR) emergingasaparticularlypromisingcandidate.Weconclude thatmolecularstudiesarewarrantedtoelucidatefunctional consequencesofvariantsthathaveshownstableassociations withsociobehavioralphenotypes.Withregardtothevariability inindividualresponsestooxytocinadministration,we advocatetheneedforpharmacogeneticapproachesinorder totesthowtheefficacyofoxytocinadministrationis modulatedbygeneticvariationofOXTRorothergenes involvedinoxytocinsignaling.

Addresses

1DepartmentofPsychology,LaboratoryforBiologicalandPersonality Psychology,UniversityofFreiburg,D-79104Freiburg,Germany

2FreiburgBrainImagingCenter,UniversityMedicalCenter,Universityof Freiburg,D-79106Freiburg,Germany

Correspondingauthors:Kumsta,Robert

(robert.kumsta@psychologie.uni-freiburg.de)andHeinrichs,Markus (heinrichs@psychologie.uni-freiburg.de)

CurrentOpinioninNeurobiology2012,23:xx–yy ThisreviewcomesfromathemedissueonNeurogenetics EditedbyRalphGreenspanandChristinePetit

0959-4388/$–seefrontmatter,#2012ElsevierLtd.Allrights reserved.

http://dx.doi.org/10.1016/j.conb.2012.09.004

Introduction

Researchinthesocialneuroscienceshasmadeconsider- able progress in identifying the neurobiological under- pinningsofcomplexsocialbehavior.Investigationsacross species have shown that the neuropeptide oxytocin, together with arginine vasopressin, plays a key role in encodinginformationrelevanttosocialinteractionsandis critically involved in the regulation of complex social cognition and behavior, including attachment, social

recognition, social exploration, as well as anxiety and fear-relatedbehaviors(forreview,see[1]).Twinstudies have provided evidence that social phenotypes show considerableheritability[2].Recentstudieshaveinves- tigated thegeneticmechanismsof inter-individualvari- ationin thesocialneuropeptide signaling. Inparticular, molecular genetic studies have identified variations in specific genes contributing to individual differences in socialbehaviorandcognition,andthegenecodingforthe oxytocin receptor (OXTR)hasemergedas aparticularly promisingcandidate.

Theaimofthisreviewistoprovideanoverviewofrecent association studies involving OXTR single nucleotide polymorphisms (SNP)(Figure 1) withafocus onsocio- behavioral phenotypes in healthy individuals. These include prosocialbehavior,parenting,empathy, positive affect,socialauditoryprocessing,andsensitivitytosocial supportorsupportseekingduringstress.Recentimaging genetics findings and genebyenvironment interactions will be discussed, followedby abrief account onother genesinvolvedinoxytocinergicsignaling.Studiesinves- tigating associationsbetweengeneticvariationof OXTR andautismspectrumdisorderorautistictraitswillnotbe coveredhere,andthereaderisreferredtoEbsteinetal.

[3]for acomprehensive accountof theroleof OXTRin autism.

General social phenotypes

Severalmoleculargeneticstudiesinnonclinicalsubjects have shown associations between OXTR and general sociobehavioralphenotypes.Concerningprosocialbeha- vior,Koganetal.[4]showedthatasingleintronicOXTR SNP,rs53576,previouslyassociatedwithautism[5]plays animportantroleintheregulationofprosocialbehavior, with G homozygotes displaying higher prosociality in nonverbaldisplays,asjudgedbyoutsideobservers’rat- ingsofsilentbehavior.Inalaboratory-basedexperiment whichincludedatwo-personinvestmentgamemeasur- ing trust, trustworthiness behavior, and risk behavior, Kruegeretal.[6]showedthatthers53576GGgenotype wasassociatedwithhighertrustbutwasnotrelatedtoa general increase in trustworthy or riskbehaviors. In a study on real world prosocial behavior (i.e. volunteer work, charitable activities and commitment to civic duty), no main effect of OXTRrs53576 wasobserved.

However,genotypeinteractedwithperceivedthreatto predictcharitableactivities,suchthattheGGgenotype buffered the negative association between threat and prosocialbehaviors[7].AneffectofanotherOXTRSNP

www.sciencedirect.com CurrentOpinioninNeurobiology2012,23:1–6

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(rs1042778) on prosocial behavior in an economic exchange game [8] could not be replicated in a sub- sequentstudy[9].

TwostudiesfoundassociationsbetweenOXTRSNPsand sensitiveparenting.Inparticular,motherswhocarriedat leastoneOXTRrs53576Aalleleshowedlowerlevelsof sensitiveresponsivenessto theirtoddlers [10].Interest- ingly,Aallelecarriersalsoshowedreducedphysiological reactivity to repeated infant cry sounds [11]. Feldman etal.[12]showedthattheTTgenotypeofanotherOXTR SNP(rs1042778)wasassociatedwithlessparentaltouch (and also with lower plasma oxytocin levels). Further associationstudiesonOXTRrs53576reportthatAallele carriers exhibited lower empathy [13], lower positive affect scores [14], and more self-reported difficulty in hearing and understanding people under background noise[15].

Tosummarize,thesestudiessuggestthatpolymorphisms intheOXTRgene(Figure 1),particularlyrs53576 (but alsors2254298 andrs1042778), contributeto themodu- lationofsocialbehaviorinhealthy subjects.

Socialstress and social support

Inadditiontoitsroleinsocialbehaviorandsocialcogni- tion, oxytocin has been found to dampen the stress response in humans (for review, see [16]). Intranasal administration ofoxytocin hasbeen shownto attenuate neuroendocrinestressreactivity[17]andhasbeenassoci- ated with decreasedamygdala activationin responseto

threateningstimuli[18,19].Rodriguesetal.[13]showeda linkbetweenOXTRrs53576anddispositionalaswellas physiological stress reactivity. A allele carriers reported higher levels of reactivity across a range of stressful contexts,and greater cardiovascular reactivity indicated byheartrateduringastartleanticipationtask(butseealso Normanet al.[20],who found thatindividualswiththe GGgenotypeshowedhigherlevelsofsympatheticreac- tivitytopsychologicalstress).Onthebasisofthefindings that oxytocin administration, in particular when combined with social support, reduces the neuroendocrine andsubjectivestressresponse,astudyfromourlaboratory investigatedwhetherOXTRrs53576might interactwith stress-protective effects of social support [21]. It was shown that socialsupport by thepartnerbefore astan- dardizedlaboratorystressorwasassociatedwithreduced cortisolandsubjectivestressresponsesin maleGallele carriers. Conversely, individuals with the rs53576 AA genotype did not benefit from social support. Interest- ingly,Kimetal.[22]showedthatinAmericans(butnot Koreans), AA genotype carriers are less likely to seek socialsupportcomparedtoGallelecarriersduringtimes of distress.Theseresultsshow thatgeneticvariation of OXTR influences sensitivity to social context, thereby modulatingtheeffectivenessofpositivesocialinteraction asaprotectivebufferagainstastressfulexperience.

Psychologicalresourcessuchasoptimism,mastery,and self-esteemare alsodiscussedasstress buffersand are predictorsoflong-termhealthoutcomes.Saphire-Bern- stein et al.[23] reported that rs53576 Aallele carriers

Figure1

Chr 3p25.3

ATG TGA

rs237897 rs53576

Untranslated region Coding region Intron rs1042778 rs13316193

rs237889 rs2254298

rs2268494

5′ 3′

Oxytocin receptor

Current Opinion in Neurobiology

Geneticvariantsintheoxytocinreceptorgene(OXTR).The(OXTR)geneislocatedonchromosome3p25-3p26.2,spans17kb,andcontainsthree intronsandfourexons.The389aminoacidpolypeptidewithseventransmembranedomainsbelongstotheclassIGprotein-coupledreceptor.Two singlenucleotidepolymorphisms(SNPs)inthethirdintronofOXTRhaveemergedasparticularlypromisingcandidatesinthestudyofsociobehavioral phenotypes(indicatedinbold):rs53576(G/A)andrs2254298(G/A).ThemainSNPswiththeirlocationandrsnumberareshownabove.Exonsare indicatedbythedarkershadedboxes,andtheuntranslatedregionsareshownbythelighterboxes.Variantsinthegeneareshownbyarrows.Chr, chromosome.

Figuremodified,withpermission,from[1].

CurrentOpinioninNeurobiology2012,23:1–6 www.sciencedirect.com

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hadlowerlevelsofoptimism,mastery,andself-esteem.

The observed association with depressive symptoms seemstobelargelymediatedbytheinfluenceofOXTR variation on psychological resources. However, the association between rs53576 and optimism could not be replicated in a large sample of Caucasian women [24].

Neurogenetics: structuraland functional neuroimaging

The imaging genetics approach, which relates genetic variantstobrainstructureandfunction,canbeemployed to come to a better understanding of the neurobiology underlying the observed associations between OXTR variants and social behavior and cognition phenotypes.

Ithasbeensuggestedthatso-calledendophenotypes(or intermediate phenotypes)canprovideabridgebetween genotypeandbehavioralphenotype.Severalstudieshave shown associations between OXTR SNPs and morpho- metricalterationsaswellasdifferencesinactivityofkey limbic structures involvedin social behaviorand in the pathophysiologyofpsychiatricdisorderscharacterizedby impaired social functioning. For instance, an increased functionalcouplingbetweenhypothalamusandamygdala

during processing ofemotionally salientsocialcueswas observedinrs53576Aallelecarriers.Moreover,thisallele was associated with morphometric alterations of the hypothalamusandamygdala,andwasrelatedtoreduced rewarddependencescoresoftheTridimensionalPerson- ality Questionnaire in males [25]. Three other studies found thatthers2254298 SNPisassociated with amyg- dalavolume.InalargeJapanesesample,Inoueetal.[26]

reportedlargerbilateralamygdalavolumeinrs2254298A allele carriers, which was also found in a sample of adolescent girlsof mixed ethnicity[27].Tostet al. [28]

extended these findings by investigating structure and function of emotion regulatory circuits including the hypothalamus,amygdala, and thedorsal anterior cingu- lategyrus(dACG)inalargeCaucasiansample.Whileno effectsofrs2254298onamygdalavolumewereobserved, a significant decrease in hypothalamus gray matter volume was observed in rs2254298 A carriers, an effect drivenmainlybymales.Similartofindingsonrs53576,an increase in thestructuralcouplingofhypothalamusand dACGwasobservedinrs2254298Acarriers.Finally,the rs2254298Aallelewasassociatedwithdeficientdeactiva- tion of dACG during emotional face processing (see Figure 2).

Figure2

Hypothalamus ^0.25 rs53576

rs2254298

0.2

0.15 0.1

0.05

0.00

-0.25

-0.50

-0.75

G/G A/G A/A

T = 0.0 T = 2.8 ACC

PFC

vmPFC

Amygdala

Brainstem

Amygdala [–27, –3, –24]Anterior Cingulate [3, 42, 15]

G/G A camer

y = –3

x = 1 t = 0.0 t = 3.1

(a) (b)

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Current Opinion in Neurobiology

Neuropeptidesandsocial-emotionalinformationprocessinginhumans.OxytocinreceptorSNPshavebeenassociatedwithstructuralandfunctional changesinbrainregionsinvolvedinaregulatorycircuitofsocial–emotionalinformationprocessing.(a)Top-downcontroloftheamygdala(shownby blackarrows)arisesfromtheanteriorcingulatecortex(ACC)andventralmedialprefrontalcortex(vmPFC).Bottom-upmodulationoftheamygdala (shownbytheredarrow)arisesfromneuronsinthehypothalamusthatexpresstheneuropeptidesOXTandAVP,whichtargetdistinctneuronal populationsinthecentralamygdala.Projectionsfromtheamygdalatothebrainstem,viathehypothalamus,regulatetheexpressionofautonomic reactionstosocialsignals(shownbydottedarrows).(b)Anincreaseinthefunctionalcorrelationofthehypothalamusandamygdalahasbeen observedinrs53576Aallelecarriers.Theblueregionillustratesthehypothalamusseedregionoftheanalysis[25].(c)rs2254298hasbeenassociated withamygdalavolumeintwostudies[26,27].Furthermore,decreasedhypothalamusgraymattervolumeandanincreaseinfunctionalcouplingof hypothalamus,dACGandamygdalawasobservedinrs2254298Acarriers[28],showninpanel(c).Part(a)modified,withpermission,from[1],part(b) modified,withpermission,from[25],part(c)modified,withpermission,from[28].

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Taken together, these imaging studies suggest that geneticvariationof OXTRaffectsalimbiccircuitinvol- vingtheamygdala,thehypothalamus,andthecingulate gyrus.The findings provide support for thenotionthat OXTRSNPsmediatetheireffectsonsocialcognitionand behaviorbymodulating neuralcircuitsforprocessing of socialinformationandnegativeaffect[29].

Gene–environment interaction

Itiswelldocumentedthatearlyenvironmentalfactorscan have long-lasting influences on health outcomes. For instance,thereisastronglinkbetweenadversechildhood experience (such as sexual/physical abuse, emotional neglect,orbeingrearedininstitutions)andmentalhealth problemsinadulthood[30].Neurobiologicalmechanisms underlying this relationship involve alterations of stress responsesystems,andalsodeficitsinemotionprocessing and emotional regulation [31], an effect that might be mediatedthroughoxytocinfunctioning[32].Indeed,the developingcentralnervous oxytocinsystem representsa targetfortheeffectsofearlyadversity.Forinstance,ina sampleofadultwomenwithahistoryofearlyabuse,Heim et al. [33] found decreased oxytocin concentrations in cerebrospinalfluid (CSF)in women reportingmoderate tosevereexposuretovariousformsofchildhoodabuseor neglectascomparedtowomenwithnoneor mildforms.

Bradleyetal.[34]providedevidenceforagene-environ- mentinteractioninvolvingOXTR.Theyshowedthatthe relationship between childhood maltreatment and both emotionaldysregulationandattachmentstylewasmoder- ated by OXTR SNP rs53576. A sample of low-income, AfricanAmericanmaleandfemaleGallelecarrierswere atincreasedriskforemotionaldysregulationwhenexposed tomultiplecategoriesofchildhood abuse,andexhibited enhanceddisorganized adultattachment comparedto A allelecarriers.ItisofnotethatitwastheGallelecarriers whoshowedbothincreasedvulnerabilitytowardsemotion and attachment problems following childhoodmaltreat- ment,andbenefitedfromstressbufferingeffectsofsocial support. This might be explained by the differential susceptibility theory recently proposed by Belsky et al.

[35], in which those most susceptible to adversity are simultaneouslythemostlikelytobenefitfromsupportive experiences,andsupportsthenotionthatgeneticvariation ofOXTRinfluencessensitivitytosocialcontext.

Furtherevidenceforgene-environmentinteractionswas found in a sample of adolescent girls with respect to symptomsofdepressionandanxiety.Girlswhohadboth highearlyadversityandwereheterozygousfortheOXTR rs2254298 polymorphism reported the highest levels of symptomsofphysical andsocialanxietyanddepression [36]. These findings strengthen the notion that the relationship between childhood adversity and risk for mentalhealthproblemsinvolvesoxytocinneurobiology, andthatpartof theoutcomeheterogeneityisexplained bygeneticvariationatOXTR.

Otheroxytocin pathwaygenes

Whereasalargenumberofinvestigationshavefocused on the receptor for oxytocin and its relation to social phenotypes, little attention has been paid to other playersinvolvedintheoxytocinpathway.Theseinclude the gene for oxytocin (OXT; coding for the precursor proteinoxytocin-neurophysin-I),thegeneencodingthe enzymethatmetabolizesoxytocin,oxytocinase(human leucyl/cystinylaminopeptidase; LNPEP), as well as CD38,akeymediatorofoxytocinbrainrelease.Forall thesegenes,associationswithautismhavebeenreported (forreview,see[3]).RegardingLNPEP,noassociations with behavioral phenotypes have been reported, and onlyonestudyinvolvingOXTSNPshasbeenpublished in a healthy subject sample. Love et al. [37], using [¹¹C]raclopride positron emission tomography, found thatOXTSNPrs4813625(locatedupstreamofthegene) was associated with dopamine responses to a standar- dized stressor (moderate levels ofsustained pain) ina sex-specific manner. In a recent study, rs3796863 of CD38 was associated with neural processing of social stimuli. Homozygotes for the C allele showed slower reactiontimesandhigheractivationoftheleftfusiform gyrusduringfacematchingandgazeprocessing,aneffect thatwasmodulatedbyintranasaloxytocinadministration [38].

Conclusions

TheseinvestigationsshowthatOXTRSNPsareimport- antinexplainingvariabilityofhumansocialbehaviorand socialcognition,andthattheseeffectsmightbemediated bymodulationofneuralcircuitsunderlyingprocessingof socialinformation.Ithastobekeptinmindthatmostof the investigated OXTR SNPs are located in introns or intergene regions, with unclear functionality. To our knowledgeonly one presumablyfunctional SNPin the promoter region (rs2268498) has been associated with behavioral phenotypes,that is negative affect [39] and moraljudgments[40].

Molecular studiesare warranted to elucidate functional consequencesofvariants thathaveshownstableassoci- ations with sociobehavioral phenotypes.With regard to clinical utility, it has been proposed that patients with mentaldisordersassociatedwithseveredeficitsinsocial interactionsmightprofitfromtherapyapproacheswhere oxytocin administration is combined with interaction- basedpsychotherapy[1,16,32].Considerablevariability inindividualresponsestooxytocinhasbeendocumented, suggestingthat intranasaloxytocinadministration inter- actswithgeneticallyinfluenceddifferencesintheoxyto- cinsystem,for instance in thenumber, organization, or functioningofOXTRs.Futurestudiesusingapharmaco- geneticapproachwillshedlightonwhethertheefficacy of exogenous oxytocin administration is influenced by genetic variation of OXTR or other genes involved in oxytocinsignaling.

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Acknowledgement

TheauthorsgratefullyacknowledgegrantsupportfromtheDeutsche Forschungsgemeinschaft(DFG,HE5310/1-1,KU2479/3-1).

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