Oxytocin and socioemotional aging--current knowledge and future trends

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Oxytocin and socioemotional aging--current knowledge and future trends
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Ebner NC, GM Maura, K MacDonald, L Westberg, and H Fischer. “Oxytocin and socioemotional aging--current knowledge and future trends” Frontiers in Human Neursocience 2013; 7: 487 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755210/
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Ebner, Natalie C
Maura, Gabriela M
MacDonald, Kai
Westberg, Lars
Fischer, Hakan
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The oxytocin (OT) system is involved in various aspects of social cognition and prosocial behavior. Specifically, OT has been examined in the context of social memory, emotion recognition, cooperation, trust, empathy, and bonding, and—though evidence is somewhat mixed-intranasal OT appears to benefit aspects of socioemotional functioning. However, most of the extant data on aging and OT is from animal research and human OT research has focused largely on young adults. As such, though we know that various socioemotional capacities change with age, we know little about whether age-related changes in the OT system may underlie age-related differences in socioemotional functioning. In this review, we take a genetic-neuro-behavioral approach and evaluate current evidence on age-related changes in the OT system as well as the putative effects of these alterations on age-related socioemotional functioning. Looking forward, we identify informational gaps and propose an Age-Related Genetic, Neurobiological, Sociobehavioral Model of Oxytocin (AGeNeS-OT model) which may structure and inform investigations into aging-related genetic, neural, and sociocognitive processes related to OT. As an exemplar of the use of the model, we report exploratory data suggesting differences in socioemotional processing associated with genetic variation in the oxytocin receptor gene (OXTR) in samples of young and older adults. Information gained from this arena has translational potential in depression, social stress, and anxiety-all of which have high relevance in aging—and may contribute to reducing social isolation and improving well-being of individuals across the lifespan. Keywords: oxytocin, aging, socioemotional functioning, amygdala, anterior cingulate
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ORIGINALRESEARCHARTICLEpublished:28August2013 doi:10.3389/fnhum.2013.00487 Oxytocinandsocioemotionalaging:Currentknowledge andfuturetrendsNatalieC.Ebner1* ,GabrielaM.Maura1,KaiMacDonald2,LarsWestberg3andHkanFischer4,51DepartmentofPsychology,UniversityofFlorida,Gainesville,FL,USA2DepartmentofPsychiatry,UniversityofCalifornia,SanDiego,LaJolla,CA,USA3DepartmentofPharmacology,UniversityofGothenburg,Gothenburg,Sweden4DepartmentofPsychology,StockholmUniversity,Stockholm,Sweden5AgingResearchCenter,KarolinskaInstitute,Stockholm,Sweden Editedby: SusanneLeiberg,Universityof Zurich,Switzerland Reviewedby: GregoryR.Samanez-Larkin, YaleUniversity,USA BrianW.Haas,Universityof Georgia,USA *Correspondence: NatalieC.Ebner,Departmentof Psychology,UniversityofFlorida, PsychologyBuilding,945Center Drive,POBox112250,Gainesville, FL32611,USA e-mail:natalie.ebner@u.eduTheoxytocin(OT)systemisinvolvedinvariousaspectsofsocialcognitionand prosocialbehavior.Specically,OThasbeenexaminedinthecontextofsocialmemory, emotionrecognition,cooperation,trust,empathy,andbonding,andthoughevidenceis somewhatmixed-intranasalOTappearstobenetaspectsofsocioemotionalfunctioning. However,mostoftheextantdataonagingandOTisfromanimalresearchandhuman OTresearchhasfocusedlargelyonyoungadults.Assuch,thoughweknowthatvarious socioemotionalcapacitieschangewithage,weknowlittleaboutwhetherage-related changesintheOTsystemmayunderlieage-relateddifferencesinsocioemotional functioning.Inthisreview,wetakeagenetic-neuro-behavioralapproachandevaluate currentevidenceonage-relatedchangesintheOTsystemaswellastheputativeeffectsof thesealterationsonage-relatedsocioemotionalfunctioning.Lookingforward,weidentify informationalgapsandproposean Age-RelatedGenetic,Neurobiological,Sociobehavioral ModelofOxytocin (AGeNeS-OTmodel )whichmaystructureandinforminvestigations intoaging-relatedgenetic,neural,andsociocognitiveprocessesrelatedtoOT.Asan exemplaroftheuseofthemodel,wereportexploratorydatasuggestingdifferences insocioemotionalprocessingassociatedwithgeneticvariationintheoxytocinreceptor gene( OXTR )insamplesofyoungandolderadults.Informationgainedfromthisarena hastranslationalpotentialindepression,socialstress,andanxiety-allofwhichhave highrelevanceinagingandmaycontributetoreducingsocialisolationandimproving well-beingofindividualsacrossthelifespan.Keywords:oxytocin,aging,socioemotionalfunctioning,amygdala,anteriorcingulateSocialandemotionalprocessesandtheirassociatedgenetic andneurobiologicalmechanismsinagingarestillincompletely understood(NielsenandMather,2011 ).Inthispaperweproposetocombineneuroendocrine,genetic,andsociobehavioral approachestoexaminetheroleoftheoxytocin(OT)systeminthecontextofsocioemotionalaging.Aspectsofthe OTsystemwarrantinginvestigationinclude:(1)changesin endogenousanddynamicOTlevels;(2)changesinsystems whichdirectlyimpactOTfunction(i.e.,gonadalhormones); (3)geneticvariationinaspectsoftheOTsystem,including thegeneforoxytocin( OXT ),itsreceptor( OXTR ),andthe relatedCD38system;(4)changesinOT-richneuralregions; (5)theeffectofexogenousOT.Thereisincreasingevidence thatOTplaysasignicantroleinmanyofthesocioemotional capacitiesthatundergoage-relatedchanges.However,todate, verylittleisknownabouttheroleofOTinhumanaging (Huffmeijeretal.,2012).Thus,itwillbecrucialforfuture researchtoclarifylinksbetweenage-relatedchangesinthe aforementionedaspectsoftheOTsystemandchangesinneuralprocessingandsubsequentalterationsinexperienceaswellas behaviorinsocioemotionaldomainsinoldercomparedtoyoung adults. Toforeshadow,thisfocusedreviewconceptuallyintegratestwo linesofresearch.First,wesummarizeevidenceforage-associated changesinsocioemotionalcapacities( Isaacowitzetal.,2007; Ruffmanetal.,2008;ScheibeandCarstensen,2010 ).Second,we reviewevidencefortheinvolvementofOTinsocioemotional functioning(Bartzetal.,2011;Meyer-Lindenbergetal.,2011; VanIJzendoornandBakermans-Kranenburg,2012 ).Synthesizing thesetwolinesofwork,wepresentan Age-RelatedGenetic, Neurobiological,SociobehavioralModelofOxytocin (AGeNeS-OT model )whichmaystimulatequestionsandorganizeinvestigationsintotheroleofOTinsocioemotionalaging.Asan exampleoftheuseoftheAGeNeSOT model,wereportpreliminarydatasuggestingneuralandbehavioraldifferencesin socioemotionalprocessingassociatedwithgeneticvariations in OXTR insamplesofyoungandolderadults.Weconcludebysuggestingfuturedirectionsforresearchimpliedby themodel.Ultimately,theseinvestigationswillincreaseour understandingoftheroleofOTinagingandwillhavethe FrontiersinHumanNeuroscience www.frontiersin.orgAugust2013|Volume7|Article487|1

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Ebneretal. Oxytocinandsocioemotionalaging potentialforgeneratingnewinterventionstoimprovehealth andwell-being.SOCIOEMOTIONALFUNCTIONINGANDAGINGFromlife'sbeginning,humansareconfrontedwithcritical, survival-enhancingsocioemotionalstimulirelatedtoselfand others.Tomaintainsuccessfulsocialinteractionsandavoidthe negativeconsequencesofsocialisolation( BaumeisterandLeary, 1995;Normanetal.,2011 ),welearntoquicklyandaccuratelyprocess,respondto,andremembersocialcues( BaronCohenetal.,2000;GradyandKeightley,2002;Adolphs,2003 ). Socioemotionalfunctioningmaybecomeparticularlyrelevantin oldagewhen-duetotheexperienceofincreasingphysicalailment,dependency,andage-relatedsociallosses-theexperienceof socialisolationoftenincreaseswithnegativeeffectsonphysical andmentalhealth( CornwellandWaite,2009 ). Theextantliteraturesuggestsamixedpictureofage-related changesinsocioemotionalcapabilities:Somecapacities(e.g., emotionregulation,emotionalproblemsolving)improvewith age,whereasotherskills(e.g.,recognitionofemotionsinothers) decline(cf. ScheibeandCarstensen,2010 ).Inparticular,across variousstudies,oldercomparedtoyoungadultsshowincreased emotionregulationcapacity( Carstensen,2006;Blanchard-Fields etal.,2007;Riedigeretal.,2009;ScheibeandBlanchard-Fields, 2009;Voelkleetal.,2013 )andgreatercondenceinthisability( Lawtonetal.,1992;GrossandLevenson,1997;Kesslerand Staudinger,2009 ).Themajorityofolderadultsarewell-adjusted emotionallyandreportrelativelyhighlevelsofaffectivewellbeingandemotionalstabilityasdocumentedincross-sectional ( Carstensenetal.,2000 )aswellaslongitudinal( Carstensenetal., 2011 )studies(seealso Charlesetal.,2001;Teachman,2006 ).In addition,oldercomparedtoyoungadultsareatleastequally(and oftenmore)effectiveintheirabilitytoregulatetheiremotional experiences,autonomicarousal,andoutwarddisplayofnegativeemotionsinlanguageandfaceswheninstructedtodoso ( Kunzmannetal.,2005;Magaietal.,2006;Phillipsetal.,2008 ), andshowimprovedsocioemotionalproblemsolvingcapacity ( Blanchard-Fieldsetal.,2007 ). Atthesametime,olderadultsoftenshowincreaseddifcultiesinaccuraterecognitionofsocialandemotionalcues(for reviewssee Isaacowitzetal.,2007;Ruffmanetal.,2008 ;see also EbnerandJohnson,2010 ;see Figure1A ).Recentfunctional magneticresonanceimaging(fMRI)datasuggeststhatthese difcultiesareassociatedwithgreateractivityindorsomedial prefrontalcortex(dmPFC)inoldercomparedtoyoungadults duringfacialemotionreading,particularlyforangryexpressions ( Williamsetal.,2006;Keightleyetal.,2007;Ebneretal.,2012 ; see Figure1C ).Thisassociationcomportswithpreviousevidence thatdmPFCisinvolvedincomplexprocessingandcognitiveand emotionalcontrol( AmodioandFrith,2006 ).Anotherage-related changeinsocioemotionalfunctioningisthatoldercomparedto youngadultsdemonstratemoreinterpersonaltrust( List,2004; Castleetal.,2012 ).Thischangemaybeduetothedifculty olderadultsoftenhavein"reading"theemotionsofothers, assuggestedbyrecentndingsthatoldercomparedtoyoung adultsarelessprocientatdetectinglies,mediatedbydecits inemotionrecognition( Ruffmanetal.,2012 ).Withrespectto changesinmemory,thereisevidencethatthemajorityofolder adultsexperiencedeclinesinrememberingcriticalsocioemotionalcues,includingnames( Crooketal.,1993;Verhaeghenand Salthouse,1997 )andfaces( Bartlettetal.,1989;Gradyetal., 1995;EbnerandJohnson,2009 ;see Figure1B ).Finally,interms ofsocialmotivation,thereisrobustevidencethatolderadults aremoreavoidance-orientedandlessapproach-orientedthan youngadults( Ebneretal.,2006;Freund,2006; Nikitinetal.in revision). Importantly,themechanismsunderlyingtheseage-related changesinsocioemotionalfunctioningarenotwell-understood yet.Onepotentialexplanationisdifferencesinvisualprocessing ( Isaacowitzetal.,2006;Ebneretal.,2011 ),perhapsasafunction ofage-relatedchangesinmotivation( MatherandCarstensen, 2005;Carstensen,2006;Samanez-LarkinandCarstensen,2011 ). Inparticular,thereisevidencethatoldercomparedtoyoung adultsspendmoretimelookingatpositivethannegativeinformation( Isaacowitzetal.,2006 )and,whenprocessingfaces,spend lesstimeviewingtheeyeregionandmoretimeviewingthemouth 0% 20% 40% 60% 80% 100% YAOA A Emotion Identification: % Correct * p < .05 C Dorsomedial prefrontal cortex: Brain Map, Parameter Estimates YA OA Activation (Parameter Estimates) B Face Memory: % Correct (Hits – False Alarms) 0% 20% 40% 60% 80% 100%YAOA * p < .05 FIGURE1|(A) Emotionidentication( Ebneretal.,2010 ); (B) Facememory( EbnerandJohnson,2009 ); (C) Emotionidentication:dorsomedialprefrontal cortex( Ebneretal.,2012 ).YA,Youngadults;OA,Olderadults. FrontiersinHumanNeurosciencewww.frontiersin.orgAugust2013|Volume7|Article487|2

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Ebneretal. Oxytocinandsocioemotionalaging ( Firestoneetal.,2007 ).Thisage-differentialvisualprocessingpatternmaybeimportantgiventhattheeyevs.mouthregionsof afacecarrydifferentsocioemotionalinformation( Calderetal., 2000;Ebneretal.,2011 ). Acomplementary,mechanisticexplanationforage-related changesinsocioemotionalfunctionmaybechangesinbrain structureorfunctioninregionsassociatedwithsocioemotional processingsuchasamygdala,PFC,insula,orfusiformgyrus ( Keightleyetal.,2007;Grady,2008;Cacioppoetal.,2009; Ebneretal.,2012 ;see Ruffmanetal.,2008;Samanez-Larkin andCarstensen,2011;St.Jaquesetal.,2013 ,foroverviews).For instance,thereiswell-documented,age-relatedstructuraldecline inregionssuchasthelateralPFC(lPFC),insula,andstriatum ( Raz,2005;Razetal.,2005 ).Regardingfunctionalchanges,one commonndingisanage-relateddecreaseinamygdalaactivation duringtheperceptionofemotionalstimuli(especiallynegative stimuli)accompaniedbyanage-relatedincreaseinactivityina numberoflPFCandmPFCregions( Iidakaetal.,2002;GunningDixonetal.,2003;Fischeretal.,2005,2010;Tessitoreetal.,2005 ; butsee MatherandCarstensen,2005;Wrightetal.,2006;Ebner etal.,2013 ). Crucially,however,extantliteraturesuggeststhatage-related differencesinsocioemotionalprocessingcannotbeexplained solelybyage-relatedvisuoperceptualand/orneurocognitive changes( Samanez-LarkinandCarstensen,2011 ).Inaddition, itmaybethatchangesinsocioemotionalfunctionarealso linkedwithage-relatedalterationsinneuroendocrinefunction. Inparticular,theneuropeptideOTappearsasaparticularly promisingcandidate,givenincreasingevidenceofitsrolein socioemotionaldomains( InselandFernald,2004;Donaldson andYoung,2008;Bartzetal.,2011;Meyer-Lindenbergetal., 2011;Normanetal.,2011 ).However,todate,weknowvery littleaboutage-relatedchangesintheOTsystem,particularlyinthecontextofsocioemotionalaging( Huffmeijeretal., 2012 ).OXYTOCINANDSOCIOEMOTIONALFUNCTIONINGOTisanineaminoacidpeptide,withperipheralandcentralfunctions( GimplandFahrenholz,2001 ).Itissynthesized inmagnocellularneurosecretorycellsofparaventricularnuclei (PVN)andsupraopticnuclei(SON)ofthehypothalamusand releasedthroughtheposteriorpituitaryglandintotheperiphery ( Insel,2010 ).OTisalsoreleasedintothebrainbymagnocellulardendrites( LengandLudwig,2006 )andbyOT-releasing neuronsprojectingtospecicbrainregionssuchastheamygdala,hippocampus,andstriatum( Kimuraetal.,1992;Landgraf andNeumann,2004;Knoblochetal.,2012 ).HumanandanimalstudiescombinedsuggestthatthefunctionoftheOTsystem isreectedatavarietyofphysiologicalandanatomicallevels, including:(1)peripheralhormonelevels(i.e.,plasmaandsaliva); (2)centralhormonelevels[i.e.,incerebrospinaluid(CSF)]; (3)histologicallevels(i.e.,presenceandsizeofOTcells);(4) receptorlevels(inOTreceptorbindingindenedbrainregions); (5)geneticlevels,orthelevelof"neuropeptidergicindividuality"( MacDonald,2012 );i.e.,polymorphismsrelatedto OXT or OXTR ,orgenesrelatedtoOTrelease(i.e., CD38 ; Saueretal., 2012,2013 ). Inparticular,accumulatingevidencesuggeststhatOTmay serveasakeyeffectorinsocioemotionalfunctioningsuchas emotionrecognition,memoryforfaces,interpersonaltrust,and bondingasbrieysummarizednext(see Bartzetal.,2011; Meyer-Lindenbergetal.,2011;Normanetal.,2011;Zinkand Meyer-Lindenberg,2012 ,forcomprehensiveoverviews). Afterthediscoverythatcertainneuropeptidescouldbedeliveredintranasallytothehumanbrain( Bornetal.,2002 ),anumber ofexperimentalstudiesusingintranasalOTrevealedintriguing effectsondiverseaspectsofsocioemotionalfunctioning.For example,researchinhealthyadultssuggeststhatOTimpairsperformanceinverbalmemorytasks( Ferrieretal.,1980;Heinrichs etal.,2004 ;butsee Feifeletal.,2012 ),whileenhancingrecognitionofsocial(i.e.,faces)butnotnon-socialstimuli( Rimmele etal.,2009 ;seealso Heinrichsetal.,2004 ),especiallyforneutralandangrycomparedtohappyfaces( Savaskanetal.,2008 ). Furthermore,intranasaladministrationofOTincreasesoverall gazetimetowardfaces( Guastellaetal.,2008;Andarietal.,2010; Averbeck,2010;Gameretal.,2010 )andincreasesemotionrecognition,specicallyofhappyandfearfulfaces(andundercertain conditionsangryfaces;see Shahrestanietal.,2013 ,forarecent review). Inaddition,recentstudieshaveshownthatintranasal OTincreasesfacialtrustworthinessandattractivenessratings ( Theodoridouetal.,2009 )aswellasinterpersonaltrustandthe willingnesstotakesocialrisks( Kosfeldetal.,2005;Baumgartner etal.,2008;Phanetal.,2010 ).TheseeffectsofOTontrustseem tobeparticularlypronouncedinpositivesocialinteractions( Zak etal.,2005;Mikolajczaketal.,2010 )andwithrespecttoingroupvs.out-groupmembers( VanIJzendoornandBakermansKranenburg,2012 ).Moreover,theseeffectsseemmoderatedby interindividualdifferences( Rockliffetal.,2011 ;butsee Guastella etal.,2013 ),includinggeneticpolymorphismsassociatedwith OTfunction( RiedlandJavor,2011 ;seealso Rodriguesetal., 2009;MacDonald,2012 ,forreviews). Besidestheseeffectsonfacialprocessingandtrust,intranasal OThasbeenshowntoinuencesocialapproachbehavior,attachment,bonding,andsocialrejectionwithassociatedhealthbenets( Ditzenetal.,2009;Gouinetal.,2010;Scheeleetal.,2012; Schneidermanetal.,2012;Feketeetal.,2013 ).Forexample, intranasalOTincreasedpositiverelativetonegativebehaviors duringalaboratorycoupleconictandreducedpost-conict cortisollevels( Ditzenetal.,2009 ).ThispotentialstressreducingeffectofOThasbeenfurtherdocumentedbyevidencethat participantswithincreasedplasmaOThealedfasterandhada greaternumberofpositiveinteractionswithpartnersduringa 24-hhospitalstay( Gouinetal.,2010 ;seealso KŽriandKiss,2011; Kissetal.,2011 ;see Tayloretal.,2006,foradiscussionofOT'srole duringrelaxationvs.stress;seealso Feldmanetal.,2011 ). Anever-expandingbodyofneuroimagingdatasuggeststhat OT'seffectsonsocioemotionalfunctioningareduetoitsattenuationoftheneuralcircuitryforanxietyandaversionandits activationofsocialrewardneuralnetworks(cf. Yoshidaetal., 2009;ZinkandMeyer-Lindenberg,2012 ).Inparticular,anumberofstudieshaveprovidedevidencethattheamygdalamight beakeystructureforthemediationofthesocial-cognitiveeffects ofOT( Kirschetal.,2005;Domesetal.,2007a;Petrovicetal., FrontiersinHumanNeurosciencewww.frontiersin.orgAugust2013|Volume7|Article487|3

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Ebneretal. Oxytocinandsocioemotionalaging 2008;Singeretal.,2008;Labuschagneetal.,2010;Riemetal., 2011;ZinkandMeyer-Lindenberg,2012 ;cf. Huffmeijeretal., 2012 ;butsee Domesetal.,2010 ).Forexample,OTattenuates amygdalaresponsetofear-inducingstimuli( Kirschetal.,2005 ). Baumgartneretal. ( 2008 ;seealso Kosfeldetal.,2005;Mikolajczak etal.,2010 )provideevidencethatOTreducedbetrayalaversiontobreachesoftrustviaareductioninbilateralamygdala activationandmidbrainregionsandgreaterventralstriatum andorbitofrontalcortex(OFC)activity.Furthermore,thereare suggestionsofspecicmodulatoryinuencesofOTonsubregionswithintheamygdaladuringprocessingofsocioemotional information( Gameretal.,2010 ;seealso Huberetal.,2005; Vivianietal.,2011;Knoblochetal.,2012 ).Thesecentraleffects, importantly,occurininteractionwithanetworkofotherneurochemicalsincludingestrogen,dopamine,andserotonin( Riedl andJavor,2011 ). ThustherearesuggestionsintheliteraturethatOTincreases approach-relatedbehaviors,whiledecreasingwithdrawal-related behaviors( KempandGuastella,2010 ).Atthesametime,however,thereisevidencesuggestingthatOTmayplayasomewhat morecomplexroleinsocialbehaviorthansimplydirecting approachvs.avoidancebehaviorand/orattentionalbiasesto positiveandnegativeinformation,respectively.Rather,OTmay increasesocialengagement,salienceofsocialagents,andsocial valueofprocessedinformation,largelyindependentofvalence ( Shamay-Tsooryetal.,2009;Tops,2009;Shamay-Tsoory,2010; Bartzetal.,2011 ).Inlinewiththissuggestion,brainregionssuch astheventraltegmentum,PFC,nucleusaccumbens,andinsula associatedwiththesocial-rewardneuralnetworkhaveshown sensitivetoOT( Balleineetal.,2007;Riemetal.,2011;WittfothSchardtetal.,2012;Groppeetal.,2013;Scheeleetal.,2013 ). ThecentraleffectsofOTaremediatedbyitsG-proteincoupledreceptor,locatedonavarietyoftissuesincludingthe brain,heart,kidney,anduterus( Loupetal.,1991;Gimpl andFahrenholz,2001 ).Polymorphismsofthegeneencoding theOTreceptor, OXTR ,havebeenshowntocontributeto individualdifferencesinvarioussocialphenotypes(cf. Gimpl andFahrenholz,2001;Meyer-Lindenbergetal.,2011;Ebstein etal.,2012;ZinkandMeyer-Lindenberg,2012;Kumstaetal., 2013;WestbergandWalum,2013 ).Forexample, OXTR singlenucleotidepolymorphisms(SNPs)havebeenassociatedwith lowerpositiveaffect( Luchtetal.,2009 ),lowerlevelsofresponsivenessofmotherstotheirtoddlers( Bakermans-Kranenburg andvanIJzendoorn,2008 ),lowerempathyscoresandincreased stressreactivity( Rodriguesetal.,2009 ),non-verbaldisplaysof prosociality( Koganetal.,2011 ),andpair-bonding( Walumetal., 2012 ). OXTR SNPshavealsobeenstudiedinrelationwithautism spectrumdisorder(ASD;see Ebsteinetal.,2012 ,forareview), withevidencethattheycontributetoriskforsomephenotypes observedinASD( Egawaetal.,2012 ;butsee Tanseyetal.,2010 ). Takentogether,thisreviewhighlightstheimportanceofsimultaneouslyconsideringbehavioral,neural,andgeneticperspectiveswhenexaminingOT'sroleinsocioemotionalfunctioning,as willbediscussedinmoredetailbelow(see Figure2 ).Inaddition, itraisesveimportantcaveatsandinformationalgaps. First,someoftheeffectsassociatedwithOTareinconsistentandcomefromsmall,homogeneoussamples,creatinga FIGURE2|Age-relatedGenetic,Neurobiological,Sociobehavioral ModelofOxytocin(AGeNeS-OTmodel). needforreplicationofkeyndingsinlarger,morerepresentative samples. Second,manyofOT'seffectsseemtovarybyindividualdifferencevariablessuchasthelevelofsocialprociency( Bartzetal., 2011 ;but Guastellaetal.,2013 ). Third,thereisincreasingevidencesuggestingthattheeffects ofOTaredependentoncontext( Domesetal.,2007b )and inuencedbyearlylifeexperiences(see MacDonald,2012 ,for areview).Forexample,women( Heimetal.,2008 )andmen ( MeinlschmidtandHeim,2007 )whowereabusedorneglected aschildrenshowedalteredOTsystemsensitivityasadults(e.g., decreasedCSFlevelofOT;seealso Winslowetal.,2003;Fries etal.,2005 ;butsee Anderson,2006 ;cf. MacDonald,2012 ,fora review). Fourth,duetoboththeoreticalsafetyconcernsusingOTin womenaswellasthecomplexityintroducedbyOT'ssex-specic effects,alargemajorityofstudiesconductedsofarrefertomen exclusively,eventhoughtherearegrowingindicationsthatsome ofOT'seffectsmaydifferbysex( Savaskanetal.,2008;Guastella etal.,2009;Domesetal.,2010;Marshetal.,2010 ;cf. MacDonald, 2012 ).Thissex-specicpatternraisesthepossibilitythatthe effectsofOTonsocialcognitionmaybedifferentiallyregulatedby gonadalsteroids(estrogenandtestosterone)orothersex-specic biologicalfactors( Cholerisetal.,2009;Gaboretal.,2012 ;seealso VanAndersetal.,2011 ;seealso WeismanandFeldman,2013 ). Afthshortcominginthecurrenthumanliteratureon oxytocincriticalinthepresentcontextisthatcurrentstudies havealmostexclusivelybeenconductedwithyoungadults.Given theaforementionedevidenceofage-groupdifferencesinsocioemotionalfunctioning( ScheibeandCarstensen,2010;SamanezLarkinandCarstensen,2011 ),acomprehensiveexaminationof aging-relatedaspectsoftheOTsystem(includinggenetic,neurobiological,andbehavioralaspects)iswarranted( Huffmeijeretal., 2012 ).OXYTOCINANDAGINGDespiteasignicantneedforresearchaddressingthegrowing oldersegmentofthepopulation,researchonOTandaging isscarceandinconclusive.Todate,thefewstudiesthathave FrontiersinHumanNeurosciencewww.frontiersin.orgAugust2013|Volume7|Article487|4

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Ebneretal. Oxytocinandsocioemotionalaging addressedage-relateddifferencesintheOTsystemalmostexclusivelyrefertonon-humanspecieswithlimitedapplicabilityto humans( Quinn,2005 ).Also,studiesconductedtodatearecharacterizedbylargemethodologicaldifferencesintermsofspecies examined,OTparametersmeasured,brainregionstargeted,etc., whichmakesadirectcomparisondifcultandameta-analytic approachnotfeasible.Mostimportantly,atheoreticalframework forgeneratinghypothesesregardingage-relateddifferencesinthe OTsystem(includingchangesinendogenousOTphysiology, function,anddifferentialresponsetoexogenousOT)isentirely lacking(cf. Huffmeijeretal.,2012 ). Table1 providesasummaryofthecurrentstudiesonOT andaging.Whereassomestudiessuggestnonoticeableeffectsof agingontheOTsystem( Fliersetal.,1985;Zbuzeketal.,1988; Wierdaetal.,1991;Arlettietal.,1995 ),otherstudiesreportagerelatedchange( FliersandSwaab,1983;Melisetal.,1992,1995; Arsenijevicetal.,1995;Parkeretal.,2010 ).Notably,someofthe studiesreportingcomparabilityoftheOTsystemacrossolderand Table1|LiteratureReviewonOxytocinandAging. AuthorsSpeciesAgegroupMeasurementDifferenceMainndings EVIDENCEOFSTABILITYINTHEOTSYSTEMINAGING Arlettietal.(1995) Rats(M)OIntraperitonealOT injection O = YComparableimprovedsocialmemory andanti-depressanteffectofOT injection Fliersetal.(1985) Rats(M)Y/OOTberdensityO = YComparableOTberdensityinthe brain Wierdaetal.(1991) Human(M,F)Y/ONumberofOT cellsinPVN (post-mortem) O = YComparablenumbersof OT-expressingcellsinPVN(normal agingandAlzheimer'sDisease) Yuetal.(2006) Rats(M)Y/OOTcellsizeand numbersinSON O = YComparablecellnumbers,cellsize,or reactivedensityofNOS-expressing neurons EVIDENCEOFCHANGEINTHEOTSYSTEMWITHAGE Arsenijevicetal.(1995) Rats(M)Y/OOTreceptor binding O < YAge-relateddecreaseinbindingtoOT receptorsincaudateputamen, olfactorytubercle,andventromedial hypothalamicnucleus FliersandSwaab(1983) Rats(M)Y/MA/OPlasmaOTlevelsO > Y (neurosecretory activity) O = Y(plasma levels) Age-relatedincreaseinOTsecretion inPVN(butnotSON);Comparable plasmaOTlevels Kecketal.(2000) Rats(M)OIntracerebraland peripheralOT releasepatterns O > Y (peripheral) O < Y (intracerebral) Age-relatedincreaseinbasal peripheralOTsecretionanddecrease instress-inducedintra-PVNOT secretion Melisetal.(1992) Rats(M)Y/MA/OOTlevelsO < Y(CNS) O = Y(HNSand plasma) Age-relateddecreaseinOTlevelsin septumandhippocampus; comparableOTlevelsin hypothalamusandhypophysis,andno changeforplasmaOTlevels Melisetal.(1995) Rats(M)Y/MA/OOT-like immunoreactive peptidesinthymic extract O > YAge-relatedincreaseincontentof OT-likeimmunoreactivepeptidesin thymicextract Parkeretal.(2010) Rhesusmonkeys(F)Y/OCSFOTlevelsO > YCSFOTlevelspositivelycorrelated withadultfemaleage(butnegatively correlatedwithinfantage) Zbuzeketal.(1988) Rats(M)OPlasmaand hypothalamicOT concentration O = Y(plasma, hypothalamic concentration) O > Y(secretory release) ComparableOTconcentrationin plasmaandhypothalamus;age-related increaseinsecretoryreleaseofOT Y,Youngsubjects;MA,Middle-agedsubjects;O,Oldersubjects;M,Male;F,Female;OT,Oxytocin;PVN,Paraventricularnucleiofhypothalamus;SON, Supraoptic nuclei(SON)ofhypothalamus;AVP,Argininevasopressin;NOS,Nitricoxidesynthase;CSF,Cerebrospinaluid. FrontiersinHumanNeurosciencewww.frontiersin.orgAugust2013|Volume7|Article487|5

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Ebneretal. Oxytocinandsocioemotionalaging youngsubjectsrefertoperipheralOTlevels( FliersandSwaab, 1983;Zbuzeketal.,1988;Melisetal.,1992 ),whereasseveralofthe studiesdocumentingage-relatedchangerelatetocentralOTlevels ( FliersandSwaab,1983;Melisetal.,1992;Arsenijevicetal.,1995; Parkeretal.,2010 ).Thus,itispossiblethatagingmaychange OTtransmissionintheCNSbutnotintheneurohypophyseal (peripheral)system( Melisetal.,1999 ).Asummaryoftheevidencereportedin Table1 wouldbethatcurrentevidencedoes notallowyetarmconclusionoftheexistenceordirectionof age-relatedchangesintheOTsystem,leavingthequestionopen toempiricalexamination. Toourknowledge,onlyoneveryrecentstudyexplicitly examinedtheeffectsofintranasalOTinagroupofolder men(meanageof80years)focusingonOT'seffectsonsocial engagementandphysicalhealth( Barrazaetal.,2013 ).Results fromthisdouble-blind,placebo-controlled10-dayclinicaltrial suggestedimprovementindispositionalgratitudeinolderadults intheOTcomparedtotheplacebogroup.Inaddition,theOT grouphadaslowerdeclineinphysicalfunctioninganddecreased self-reportedfatiguethantheplacebogroup.Nochangesin mood,cardiovascularstates,orsocialactivityandengagement patternswereobservedacrossthestudyinterval.Importantly, thisstudydidnotincludeacomparisongroupofyoungadults anddidnotextensivelyexploreOT'seffectsonotheraspectsof socioemotionalfunctioning.Thus,itiscriticaltofollowupon theserstpromisingndingsregardingOTandagingandto conductsystematicexaminationsofagedifferencesinbaseline levelsofOT.Inaddition,acomprehensiveevaluationofboth single-doseaswellaslonger-termadministrationofintranasal OTanditseffectonsocioemotionalfunctioninginyoungand oldermenandwomeniswarranted.Finally,thesestudiesshould takeintoaccountgeneticvariationsrelatedtoOT.OXYTOCINANDSOCIOEMOTIONALAGING:AGE-RELATED GENETIC,NEUROBIOLOGICAL,SOCIOBEHAVIORALMODEL OFOXYTOCINBasedonthefollowingrationale,weproposean OTXAge interaction(see Figure3C )astheguidingworkinghypothesisforfuture researchontheroleofOTinsocioemotionalaging:Asmentionedabove,thereisearlyevidencethatthebenecialeffects ofOTinsocioemotionaldomains(see Figure3A )varybyindividualfactors( Bartzetal.,2011 ).Notably,"preexistingsocial impairment"seemstoplayarole,inthatmoresociallyimpaired individualsbenetmorefromOTthanlesssociallyimpaired individuals( Bartzetal.,2010;Guastellaetal.,2010 ;butsee Bakermans-KranenburgandvanIJzendoorn,2013 ).Alsothere maybea"ceilingeffect,"apointbeyondwhichOTcannotfurtherimprovesocialabilities( Bartzetal.,2011 ).Aslaidoutabove, olderadultsexperiencedecitsinvarioussocioemotionalcapacities( ScheibeandCarstensen,2010 ;see Figure3B ),rendering themmoresociallyimpairedthanyoungadultsinsomeregards. Therefore,itmaywellbethatOTisparticularlybenecialinolder comparedtoyoungadults(see Figure3C ). However,analternativehypothesisexists:Asreportedabove, eventhoughsomeaspectsofsocioemotionalfunctioning(i.e., emotionrecognitionandmemoryforemotionalinformation) declinewithage,otheraspectsincreaseorremainstable.Thatis, Interaction: OT X Age OT OT P P Main Effect: Age *+ Function/Behavior+ Function/ Behavior Main Effect: OT OT P+ Function/ BehaviorA B C FIGURE3|(A) MaineffectforAge; (B) MaineffectforOxytocin; (C) OxytocinXAgeinteractioneffect.Schematicrepresentationofguiding workinghypotheses.YA,Youngadults,OA,Olderadults;OT,Oxytocin,P, Placebo. givenbroadevidenceforapositivityeffectandforhealthysocioemotionalfunctioninginoldage( Carstensen,2006;Carstensen etal.,2011 ),aswellassomeevidenceforincreasedtrustworthinessinoldage( Castleetal.,2012 ),onaverage,olderadultscan bedescribedashighlypositive,trustworthy,andprosocial.These characteristicsmaybeadaptiveinsomecontexts(e.g.,socialinteractionswithincloserelationships)butmaladaptiveinothers(e.g., puttingagingadultsatgreatersusceptibilitytofraud).Thisreasoning,combinedwiththecurrentlackofproofthatagingis associatedwithdeclinesintheOTsystemandmixedevidence regardingOT'seffectoncognitiveperformance( Heinrichsetal., 2004;Feifeletal.,2012 ),suggestthepossibilitythatundercertaincircumstancesOTmayhaveharmfuleffectsinolderadults. GiventhatOTiscurrentlybeinginvestigatedinclinicalpopulationssuchasschizophrenia(cf. MacDonaldandFeifel,2012, 2013 ),comprisingsamplesofpeoplewhoarelatemiddle-aged, athoroughinvestigationofage-relatedaspectsoftheOTsystemincludingbenecialordetrimentaleffectsonoutcomemeasures insocioemotionalaswellascognitivedomains-willbecrucial. Assummarizedabove,theOTsystemisrepresentedatgenetic, neural,andbehaviorallevels( Meyer-Lindenbergetal.,2011 ). Furthermore,eachoftheselevelsandtheirfunctionalinteractionsareinuencedbytheagingprocess.Wethereforepropose forfutureresearchinthedomainofOTandsocioemotionalaging toadoptan Age-RelatedGenetic,Neurobiological,Sociobehavioral ModelofOxytocin ( AGeNeS-OTmodel ; Figure2 ).Inparticular, FrontiersinHumanNeurosciencewww.frontiersin.orgAugust2013|Volume7|Article487|6

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Ebneretal. Oxytocinandsocioemotionalaging thismodelsuggeststhatacomprehensiveexaminationofthecentralOTsystemshouldconsiderinteractionsbetweenOT-related genes( OXT,OXTR,CD38; Meyer-Lindenbergetal.,2011;Sauer etal.,2013 ),thebrain(e.g.,amygdala,frontalcortex,brainstem,ventraltegmentalarea; Pedersenetal.,1994;Kirschetal., 2005;Balleineetal.,2007;Baumgartneretal.,2008;Gameretal., 2010 ),andbehavior(e.g.,socialmemory,emotionidentication, approach/avoidancebiases; Rimmeleetal.,2009;Domesetal., 2010;Lischkeetal.,2011 ),bycombininggenetics,functional andstructuralbrainimaging,andsociobehavioralmeasures. Crucially,themodelproposesthatinteractionsbetweenneuroendocrineandsociobehavioralfactorsneedtobeconsideredfrom adevelopmentalperspective,takingagevariationsintoaccount. Alongtheselines,themodeloffersatheoreticalframeworkto addressvitalresearchquestions:(1)AreOT-relatedgenotypes associatedwithcompositionandqualityofsocialnetworksinthe elderly?Howdobrainstructuresinvolvedinsocialprocessing suchasmPFCandOFC,temporoparietaljunction,oramygdalamediatetheserelationships?(2)Isolderadults'increased socialavoidancecomparedtoapproachmotivationrepresented inneuralprocessingdifferencesinbrainnetworksinvolvingPFC andamygdala?Towhatextentdotheseassociationsinteract withOT-relatedgenotypes?(3)Aredetrimentaleffectsthatearly abusehasonmorbidityandmortalityintheelderlymoderated byOT-relatedgenotypesorOTlevels?Howisthisrelationship structurallyandfunctionallyrepresentedinthebrain?(4)Are effectsofsocialrelationshipsoncognitivefunctioninginthe elderlymediatedbytheOTsystem(eitherOT-levelsorOT-related genotypes)?Dostructuralchangesinbrainregionssuchasthe hippocampusunderliethisrelationship? Intheattempttoprovideaconcreteempiricalapplicationofthe AGeNeS-OTModel ,weherepresentapreliminary reportofanexperimentinwhichweexaminedassociations between OXTR polymorphisms,brainactivityandbehavioral responseduringreadingoffacialemotionsinyoungandolder adults.Thisexploratory,secondarydataanalysiswasbased onourgroup'spreviousndingofincreasedactivationin ventromedialPFC(vmPFC)duringemotionidenticationof happycomparedtoangryfacesandincreaseddorsomedialPFC (dmPFC)activitytoangrycomparedtohappyfaces( Ebner etal.,2012 ;seealso Keightleyetal.,2007 )inbothyoung andolderadults.Inthepresentsetofanalyses,weexaminedtheextenttowhichtheseprocessingdifferencesinmPFC wouldbefurtherqualiedwhenconsidering OXTR polymorphismsinbothoftheagegroups.Inparticular,weexamined (1)theextenttowhich OXTR polymorphismswereassociatedwithdifferencesinyoungandolderadults'brainactivityinbilateralmPFC( Haxbyetal.,2000,2002;Pessoaand Adolphs,2010;Ebneretal.,2012 )duringafacialemotionreadingtask;and(2)theextenttowhich OXTR polymorphismswere associatedwithyoungandolderadults'abilitytoreadfacial emotions. Young[ n = 25,12females, M = 25 1years( SD = 3 6, range = 2031)]andolder[ n = 29,17females, M = 68 3years ( SD = 2 8,range = 6574)]healthyparticipantsunderwentfMRI ona3TSiemensMagnetomTrioTimscanner,whileidentifyinghappy,neutral,andangryfacialemotions(see Ebneretal., 2012 ,fordetailsonparticipants,studydesign,andimageacquisition).ParticipantsweresubsequentlygenotypedbyKBioscience (http://www kbioscience co uk)usingKASParmethodologyfor 14 OXTR singlenucleotidepolymorphisms(SNPsinorderfrom the3tothe5end:rs7632287,rs6770632,rs1042778,rs237887, rs2268493,rs2254298,rs53576,rs237897,rs4686302,rs4564970, rs2301261,rs2268498,rs2270465,rs75775),previouslyshownto beassociatedwithsocialbehavior( Apicellaetal.,2010;MeyerLindenbergetal.,2011;Ebsteinetal.,2012;Walumetal.,2012; WestbergandWalum,2013 ). Datafromthisevent-relatedfMRIstudywasanalyzedusing StatisticalParametricMapping(SPM5;WellcomeDepartment ofImagingNeuroscience)andpre-processinganddataanalysis wasconductedasreportedin Ebneretal.(2012) .Thefollowing T -contrastswerespeciedacrossyoungandolderadults,based onourpreviousndings( Ebneretal.,2012 ):(1) HappyFaces > AngryFaces ,(2) AngryFaces > HappyFaces .Wefocusedonselect regionsofinterest(ROIs:bilateralmedialfrontalgyrusandanteriorcingulategyrus)inwhichwehadpreviouslyseenprocessing differencesforhappyvs.angryfaces,atathresholdof p < 0 05, FDRcorrected.Foreachregionofactivationidentiedbythese twocontrasts,peakvoxelbetavalueswereextractedforeachparticipanttoproduceasinglevalueforeachconditionofinterest. Thesevaluesaredepictedinthebargraphsof Figure4 .Inthe fashionoffollow-up F -and t -tests( p < 0 05),foreachofthe 14 OXTR SNPsthatweregenotyped,weexamineddifferencesin brainactivationbetweenpolymorphismsacrossthetotalsample aswellasseparatelyforyoungandolderadults.Themostconsistentassociationsfoundintheseanalyseswereinrelationto OXTR rs237887(cf. Lereretal.,2008;Israeletal.,2009;Liuetal.,2010; Lorietal.,2012 ;butsee Apicellaetal.,2010 ). OXTR rs237887AAcarriers( n = 10youngparticipants; n = 10olderparticipants)andGA/GGcarriers( n = 15young participants; n = 19olderparticipants)werecomparableinterms ofchronologicalage,levelofeducation,cognitivestatus(e.g., MiniMentalStateExamination; Folsteinetal.,1975 ;2-Back DigitsTask; Kirchner,1958 ;VerbalFluencyTask; Lezak,1995 ), andaffectivevariables(GeriatricDepressionScale; Brinketal., 1982;Gottfries,1997 ;State-TraitAnxietyInventory; Spielberger etal.,1970 ). Forthecontrast HappyFaces > AngryFaces ,wefoundgreater BOLDresponsetohappycomparedtoangryfacesinbilateralanteriorcingulatecortex(ACC;MNI: x = 3, y = 45, z = 0 and x =Š 3,y = 51, z = 0)andbilateralmPFC(MNI: x = 3, y = 60, z =Š 3and x =Š 3, y = 57, z =Š 3). Figure4A shows brainactivityinleftACC(MNI: x =Š 3, y = 51, z = 0)forthis contrast.Tothenexamineassociationsbetween OXTR rs237887 polymorphismsandbrainactivityduringfacialemotionidenticationofhappyvs.angryfacesinyoungandolderadults, weconductedfollow-upunivariateANOVAcollapsedacross youngandolderparticipantsonextractedbetavaluesatthe peakvoxelofactivation.LeftACCactivitywasgreaterforAA carriersthanGA/GGcarriers[ F( 1 51 )= 6 51, p = 0 014, 2 p= 0 11;see Figure4B ].Moreinterestingly,however,thiseffectwas morepronouncedinolderthanyoungadults,astestedinunivariateANOVAsconductedseparatelywithinyoungandolder participants[Youngparticipants: F( 1 23 )= 2 38, p = 0 136, 2 p= FrontiersinHumanNeurosciencewww.frontiersin.orgAugust2013|Volume7|Article487|7

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Ebneretal. Oxytocinandsocioemotionalaging 0 09;Olderparticipants: F( 1 26 )= 3 09, p = 0 035, 2 p= 0 16; see Figure4C ].Acomparablepatternofresultswasfoundfor rightACC[ F( 1 51 )= 6 34, p = 0 015, 2 p= 0 11].Inaddition, theresultsforleft[ F( 1 51 )= 3 24, p = 0 078, 2 p= 0 06]and FIGURE4|AreaofAnteriorCingulateCortex(ACC)showingHappy Faces > AngryFaces(T-contrast).(A) LeftACC(BA32,10;MNI: x =Š 3, y = 51, z = 0;clustersize:26voxels;maximum T -valueforcluster:4.19). TheregionofactivationrepresentstheT-mapofthecontrast;itisdisplayed onthestandardreferencebraininSPM.Thecrosshairindicatesthepeak voxel(localmaximum)withintheregionofactivation. (B) Bargraphsshow themeanleftACCparameterestimates(betavalues)separatelyfor OXTR rs237887AAandGA/GGcarriers. (C) BargraphsshowthemeanleftACC parameterestimates(betavalues)separatelyfor OXTR rs237887AAand GA/GGcarriersandyoungandolderparticipants,respectively;betas depictedwereextractedforeachindividualfroma5-mmspherearoundthe localmaximumwithintheregionofactivationandaveragedtoproducea singlevalueforeachconditionofinterest,respectively.Note.p < 0 05. Errorbarsrepresentstandarderrorsofthebetween-groupdifferences. right[ F( 1 51 )= 1 29, p = 0 261, 2 p= 0 03]mPFCpointedinthe samedirectionbutwerenotsignicant. ACCisabrainregionassociatedwithaffectiveprocessing ( Bushetal.,2000;AmodioandFrith,2006;Ebneretal.,2012 ), suggestingthatAAcomparedtoGA/GGcarriersmayprocess happycomparedtoangryfacesmoreaffectively.ThisinterpretationwasfurthersupportedbythendingthatAA-genotype carriersof OXTR rs237887( M = 1111ms, SD = 171ms)were fasteratlabelinghappyexpressionsthanindividualscarryinga G-allele[ M = 1212ms, SD = 173ms; F( 1 50 )= 4 26, p = 0 044, 2 p= 0 08],withcomparableeffectsinyoungandolderparticipants.Nocomparableeffectwasfoundforaccuracyinemotion expressionidentication.However,interestingly,greaterrecruitmentofrightACCinindividualscarryingaG-allelewaspositivelycorrelated( r = 0 35; p = 0 049)withaccuracyinreading happyfacesbutuncorrelatedinAA-genotypecarriers( r = 0 05; p = 0 838).ThissuggeststhatGA/GGcarriers,asthegroup whoneededmoretimeonthetask,benettedfromrecruiting ACCduringthefacialemotionreadingtask.ThispositivebrainbehaviorcorrelationinGA/GGcarrierswascomparableinyoung andolderparticipants(Fisher's z =Š 0 42; p = 0 337). Forthecontrast AngryFaces > HappyFaces, wefound greaterBOLDresponsetoangrycomparedtohappyfacesin leftmPFC(MNI: x =Š 6, y = 15, z = 51).Inafollow-upunivariateANOVAcollapsedacrossyoungandolderparticipants onextractedbetavaluesatthepeakvoxelofactivation,activityinleftmPFCdidnotvaryby OXTR rs237887polymorphism ( p > 0 05). Toourknowledgethisistherststudythatconsidersyoung andolderparticipantsinagenetic-neuro-behavioralexaminationoffacialemotionprocessing,assuggestedinthe AGeNeSOTmodel .Thoughthissecondarydataanalysiswaslargely exploratoryandreplicationinalargerindependentsampleof youngandolderadultsiswarranted,ourstudyprovidessome rstindicationofaroleof OXTR rs237887inreadingpositivecomparedtonegativefacialexpressions,withsomevariation asafunctionoftheageoftheparticipant.Intriguingly, OXTR rs237887haspreviouslybeenassociatedwithsusceptibilityforBox1|Questionsforfutureresearch. 1.IsagingaccompaniedbyincreasesordecreasesincentralandperipheralreleaseofOT? 2.DoesthedynamicactivityoftheOTsystemchangewithageand,ifso,howandwhy? 3.Doage-relateddifferencesinOTsystemdynamicsunderlieage-relateddifferencesinsocioemotionalfunctioning?Ifso,howdo thesechangesframeourunderstandingoftheage-associatedchangesinimportantsocialskills(i.e.,readingfacialemotions,facememory, approach,andavoidancebehavior)? 4.HowdoOT-relatedindividualgenetic(andepigenetic)differencesinteractwithneuralandbehaviorage-relatedchangesin socioemotionaldomains? 5.DoestheOTsystemmediatesomeoftheeffectsofadverseearlyexperienceonhealthandwell-being?Howdoesthisplayoutin oldage? 6.DoestheOTsystemmediatesomeofthesalutarypsychologicalandhealtheffectsofongoingsocialrelationships(bothintimate andlargersocialnetworks)?Towhatextentdoage-relatedchangesinsocialrelationshipsinuencetheseeffects? 7.HowdosexdifferencesinOTsystemdynamicsplayoutinthecontextofaging?Forexample,whatistheroleofage-relatedchanges inestrogenandtestosterone? 8.DoestheOTsystemhavearoleinage-relatedchangesincognitionandmemory? 9.MightOTbeaneffectivetreatmentforconditionslikesocialanxietyordepressionintheelderly?Wouldsuchtreatmentimprove qualityoflife? 10.MightolderadultsbeatincreasedriskofOT-relatedsideeffects(i.e.,hyponatremia)withchronicdosing? FrontiersinHumanNeurosciencewww.frontiersin.orgAugust2013|Volume7|Article487|8

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Ebneretal. Oxytocinandsocioemotionalaging ASD( Liuetal.,2010 ),prosocialbehavior( Israeletal.,2009 butsee Apicellaetal.,2010 ),andfacerecognition( Lorietal., 2012 ).Wefoundimprovedprocessingofhappycompared toangryfacesforAAcarrierscomparedtoGA/GGcarriers,asreectedintheirfasterresponsetimeinreadinghappy facesandtheirincreasedrecruitmentofACCduringemotionreadingofhappycomparedtoangryfaces.Examining youngandolderparticipantsseparately,thisincreasedactivationofACCinAAcomparedtoGA/GGcarrierswasmore pronouncedinolderthanyoungparticipants.Thisisveryinterestinggivenbroadevidenceofpreferentialprocessingofpositiveovernegativeinformationinoldercomparedtoyoung adults( MatherandCarstensen,2005 ).Inaddition,ourndingssuggestthatGA/GGcarriers'abilitytocorrectlyidentifyhappyfacesimprovedwhenrecruitingACCduringthe task.FUTURETRENDSINRESEARCHONOXYTOCINAND SOCIOEMOTIONALAGINGTakentogether,thisresearchreviewindicatesthatatargeted investigationofage-relatedchangesintheOTsystemespecially onethatconsidersgenetic,neural,andbehavioralprocesses hasthepotentialtosubstantivelyincreaseourunderstandingof socioemotionalchangeinaging.Webelievethatour AGeNeSOTmodel willbeafruitfulconceptualbasisinthatitraises asetofvitalresearchquestionsnecessarytoreneourunderstandingofOT-relateddynamicsinaginginsocioemotional contexts(see Box1 ).Inaddition,futureresearchalongthose lineshasgreatpotentialtoinformbothpharmacologicaland psychosocialinterventionstargetingsocialandemotionaldysfunctionintheelderly.Inparticular,thereisanincreasingbody ofresearchsuggestingasignicantroleofOTinthecontextof variousdisorderscharacterizedbysocioemotionaldysfunction suchassocial-bondingdecitsorrelatedtosocialanxietyand stress( Zetzscheetal.,1996;Heinrichsetal.,2003;Tayloretal., 2006 ;see MacDonaldandFeifel,2012 ,foranoverview),decits withgreatrelevanceinanagingcontext.Thus,futureresearch towardimplementationofpharmacologicalneuropeptidetreatmentswiththepotentialtodecreaseemotionalandsocialstress, anxiety,anddepression( ArlettiandBertolini,1987;Carterand Altemus,1997 )willbeimportant.Theseinterventionsmayconsequentlypromotepositivesocialinteractionandwillingnessto engageinmorefrequentlyrewardingsocialrisks( Heinrichsetal., 2003;Kosfeldetal.,2005 ),improvinghealthandlifequalityup untillateinlife.ACKNOWLEDGMENTSThisresearchwassupportedinpartbytheNIH/NCATSClinical andTranslationalScienceAwardtotheUniversityofFloridaUL1 TR000064(pilotawardtoNatalieC.Ebner)andtheSwedish ResearchCouncil(2008-2356)andtheKonungGustafV:soch DrottningVictoriasFrimurarstiftelse(HŒkanFischer).Some ofKaiMacDonald'sworkwassupportedbytheGoodenough NeuroscienceResearchFund.TheauthorswishtothankDrs. DavidFeifelandRonaldCohenforconstructivediscussions regardingvariousaspectsofthismanuscript.REFERENCESAdolphs,R.(2003).Cognitiveneuroscienceofhumansocialbehaviour. Nat.Rev.Neurosci. 4,165178.doi: 10.1038/nrn1056 Amodio,D.M.,andFrith,C.D. (2006).Meetingoftheminds: themedialfrontalcortexand socialcognition. Nat.Rev. Neurosci. 7,268277.doi:10.1038/ nrn1884 Andari,E.,Duhamel,J.,Zalla,T., Herbrecht,E.,Leboyer,M.,and Sirigu,A.(2010).Promoting socialbehaviorwithoxytocinin high-functioningautismspectrumdisorders. Proc.Natl.Acad. Sci.U.S.A. 107,43894394.doi: 10.1073/pnas.0910249107 Anderson,G.M.(2006).Report ofalteredurinaryoxytocinand AVPexcretioninneglected orphansshouldbereconsidered. J.AutismDev.Disord. 36, 829830.doi:10.1007/s10803-0060153-7 Apicella,C.L.,Cesarini,D., Johannesson,M.,Dawes,C.T., Lichtenstein,P.,andWallace,B. 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