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A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans

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A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans
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  BiologicalPsychology 94 (2013) 74–81 ContentslistsavailableatSciVerseScienceDirect Biological   Psychology  journal   homepage:www.elsevier.com/locate/biopsycho A   risk   variant   foralcoholism   in   the   NMDA   receptor   affects   amygdalaactivity   during   fear   conditioning   in   humans Raffaele   Cacciaglia a ,Frauke   Nees a ,   Sebastian   T.   Pohlack a ,Michaela   Ruttorf  b ,Tobias   Winkelmann a ,Stephanie   H.   Witt c ,Vanessa   Nieratschker c ,Marcella   Rietschel c ,Herta   Flor a , ∗ a DepartmentofCognitiveandClinicalNeuroscience,CentralInstituteof    MentalHealth,MedicalFacultyMannheim,HeidelbergUniversity,Mannheim,Germany b ComputerAssistedClinicalMedicine,MedicalFacultyMannheim,HeidelbergUniversity,Mannheim,Germany c DepartmentofGeneticEpidemiologyinPsychiatry,CentralInstituteofMentalHealth,MedicalFacultyMannheim,HeidelbergUniversity,Mannheim,Germany a   r   ti   c   le   in   f   o  Articlehistory: Received18September2012Accepted10May2013 Available online xxx Keywords: SinglenucleotidepolymorphismNMDAreceptorAlcoholismFearconditioningAmygdala a   b   s   t   ra   ct Peopleat   high   riskfor   alcoholism   showdeficits   inaversive   learning,asindicated   by   impairedelectro-dermal   responses   during   fear   conditioning,   a   basicformof    associativelearningthatdepends   ontheamygdala.   Apositive   family   historyof    alcohol   dependence   has   also   been   related   todecreased   amygdalaresponses   during   emotional   processing.   In   the   presentstudy   we   reportreduced   amygdala   activity   duringthe   acquisition   ofconditioned   fear   inhealthy   carriers   of    arisk   variantfor   alcoholism   (rs2072450)   intheNR2A   subunit-containing   N-methyl- d -aspartate   (NMDA)-receptor.   Theseresultsindicate   thatrs2072450mightconfer   riskfor   alcoholdependence   through   deficientfear   acquisition   indexedby   adiminishedamygdala   responseduring   aversive   learning,   andprovide   a   neural   basisfor   a   weak   behavioral   inhibitionpreviouslydocumented   inindividuals   athigh   riskfor   alcohol   dependence.Carriers   of    the   riskvariantadditionally   exhibitdampened   insulaactivation,   afindingthatfurther   strengthens   ourdata,giventheimportance   of    this   brain   regioninfear   conditioning. © 2013 Elsevier B.V. All rights reserved. 1.Introduction Alcoholismisahighlydebilitatingdisordercurrentlyaffectingmorethanseventymillionpeopleworldwide(Parry,Patra,&Rehm,2011),withanestimatedheritabilityof    50–60%(Dick&Bierut,2006).Dysfunctionalglutamatergictransmissioniscrucialin   thepathophysiologyof    alcoholism,witha   criticalroleof    theNR2AsubunitoftheNMDAreceptor(Spanagel,2009). Inasystematicanalysisof    geneticvariationsinglutamater-gicneurotransmissiongenes,Schumannetal.(2008)discoveredseveralvariants,whichwereassociatedwithpositivefamilyhis-tory,earlyonsetofalcoholism,andriskydrinkingpatternsinadolescents.Oneofthesevariants(rs2072450),asinglenucleotidepolymorphismlocatedin   intron11of  GRIN2A ,   whichencodesNR2A,couldbereplicatedinanindependentsample.Homozygouscar-riersoftheCriskallelewerefoundtohavea   higherlifetime ∗ Correspondingauthorat:Departmentof    CognitiveandClinicalNeuroscienceCentralInstituteofMentalHealth,MedicalFacultyMannheim,HeidelbergUniver-sity,   SquareJ5,68159Mannheim,Germany.Tel.:+4962117036302;fax:+4962117036305. E-mailaddress: herta.flor@zi-mannheim.de(H.Flor). prevalenceofdrunkennessanda   higheramountofdrinkingocca-sions(Schumannetal.,2008).TheNR2Asubunitisabundantlyexpressedintheamygdala,whereitpromotesassociativelearningvialong-termpotentiat-ion(LTP)(Müller,Albrecht,&Gebhardt,2009).   PharmacologicalinactivationofNR2AintheamygdaladisruptsPavlovianfearcondi-tioning(Walker&Davis,2008),abasicformofassociativeaversivelearning(Maren,2001). Heritabilityoffearconditioninghasbeenestimatedbetween35%and45%(Hettema,Annas,Neale,Kendler,&Fredrikson,2003)andseveralgeneshavepreviouslybeenshowntocontributetoindi-vidualdifferencesin   theacquisitionof    conditionedfear(Lonsdorf etal.,   2009,2010;Ridderetal.,   2012).Besidesthewell-establishedclinicalrelevanceoffearcondition-ingin   anxietyresearch(Lisseketal.,   2005;BarrettandArmony,2009;Indovinaetal.,2011),reducedfearconditioninghasalsobeenrelatedtotheemergenceofpsychopathy(Birbaumeretal.,2005), andalcoholdependence(Finnetal.,   1994,2001;Stephensetal.,2005).Previousstudiesshowedthat   individualsathighriskforalcoholdependencefailtoacquireassociationsbetweenthreateningandneutralstimuli,asindexedbyimpairedskinconductanceresponses(SCRs)(Finnetal.,1994;Stephensetal.,   2005).Suchfindingshave 0301-0511/$–seefrontmatter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.biopsycho.2013.05.006  76  R.Cacciagliaetal./    BiologicalPsychology 94 (2013) 74–81  Table   1 Demographic,behavioralandvolumetricdataofthesamples.Totalsample( N  =114)CC( N  =76)CA/AA( N  =   38)Inferentialstatistics M  ( SD )   M  ( SD ) M  ( SD )CC   vs.CA/AAAge(years)22.124.0622.094.2722.183.64 t  112  =   − 0.11, P  =0.91Sex:   N  female/male41/7325/5116/22   2 =   8.98, P  =0.003Handedness:right/left102/1269/733/5     2 =   0.42, P  =   0.58Education(years) 11.871.77 11.881.8311.861.66 t  112  =   − 0.05, P  =   0.95Trait   anxiety35.789.5136.3910.3234.587.67 t  112  =   0.99, P  =   0.34TBV   1202.14100.941210.9793.341184.49113.93 t  112  =   1.32, P  =0.18tAMGv   2.860.272.830.232.940.33 F  1,94  =   3.44, P  =   0.06 # rAMGv1.450.151.440.131.490.18 F  1,94  =   2.81, P  =   0.09 # lAMGv1.410.141.390.141.440.16 F  1,94  =   2.76, P  =   0.10 # TBV:totalbrainvolume;tAMGv:totalamygdalavolume;rAMGv:rightamygdalavolume;lAMGv:leftamygdalavolume. # Performedwithanalysisof    covariance,includinggenderascovariate.Neuroscience,London,UK)implementedonMATLABR2010a(TheMathWorksInc.,Natick,MA,USA).We   conductedstandardtemporalandspatialpreprocessing.Func-tionalvolumeswereslicetimecorrectedtoreferenceslice18   andrealignedto   thefirst   volumeusinga   rigidbodytransformationinordertocorrectforheadmove-ment.   Sixteensubjectswereremovedfromtheinitialgroupbecauseof    excessivemotionestimates(greaterthan3mmintranslationand2 ◦ inrotation),resultinginafinal   sampleof114participants.ImageswerenormalizedtotheMontrealNeurolog-ical   InstituteInternationalConsortiumforBrainMapping(MNI)space,usingtheEPItemplateprovidedbySPM8.Imagesweresmoothedwithan8mm ×   8   mm   ×   10mmfull-widthathalf-maximumGaussiankernel.Toremovelow-frequencynoise,ahigh-passfilter(cutoff1/128Hz)wasincludedandthetimeserieswerecorrectedforserialautocorrelationsusingfirst-orderautoregressivefunctionsAR(1).Foreachphase,afixedeffectsanalysiswasperformedby   settingupa   generallinearmodelincludingthefollowingexperimentalconditions:CS+ unpaired ,   CS −   andCS+ paired  forthe   acquisitionphasesandCS+andCS −   fortheextinction.Theseinputswerecon-volvedwitha   canonicalhemodynamicresponsefunction(firstorderexpansion)tocreatethedesignmatrix.Thesix   parametersdescribingtherigidbodytransforma-tionwereimplementedasconfoundvariablesinthestatisticalanalysistocovaryout   signalthatwas   correlatedwithheadmotion.At   grouplevel,a   randomeffectsanalysiswas   usedtoanalyzethedata,usingvoxel-wisetwo-sample t  -testswiththecontrastofinterest(CS+>CS − ).Regionsof    interest(ROIs)werebilaterallydefinedaccordingtoourapriorihypothesesusingtheMNI   templateAutomatedAnatomicalLabeling(Tzourio-Mazoyeret   al.,2002),   implementedin   theWakeForestPickAtlas(Maldjianetal.,2003).Besidesourmainhypothesisfortheamygdala,weinves- tigatedgroupdifferencesinadditionalregionsinvolvedinfear   conditioning,suchas   theinsulaandtheanteriorcingulatecortex(BüchelandDolan,2000).Todeter- minegroupdifferenceswithintheseROIs,we   adoptedasmallvolumecorrectionaccordingtoSPM8.Resultswereconsideredsignificantat   P  FWE  <0.05,   correctedformultiplecomparisonsusingafamily-wiseerror(FWE)rateapproach.Contrastesti-mateswereobtainedbyextractingtheweightedmeanwithintheselectedROIs.Here,theBOLDvaluesof    eachvoxelwithintheROIweretakenasweightswhencomputingtheaverageacrossall   theselectedvoxels.Tothispurpose,weusedtheREX   toolboxforSPM8(http://web.mit.edu/swg/software.htm).  2.6.2.Volumetricassessmentof    theamygdala Duetopoorimagequality,19studyparticipantshadto   beexcludedfromthevol-umetricanalysis.Allimageswerethree-dimensionallyassembledandresampledtoa   1mm 3 voxelsize,applyingatri-linearinterpolationalgorithm.Thecoronalplanewas   setparalleltotheline   passingthroughtheanteriorandposteriorcommissureinordertoachievethebestorientationformanualvolumetryof    theamygdala(Brierleyet   al.,2002).   Thebordersofthe   amygdalaeweremanuallyoutlinedusingthesoft-wareBRAINS2(Magnottaetal.,2002).Tracingwas   performedinnativespacebya   trainedoperator(R.C.)who   wasblindto   theexperimentalconditions.Thepro-cedurewascarriedout   inthecoronalplane,constantlycheckingthesagittalandtheaxialviews.FordetailsaboutthesegmentationprotocolpleaserefertotheSupplementaryInformation.  2.6.3.Totalbrainvolumemeasurement  Tofurtherguaranteecomparabilitybetweengroupswe   additionallyassessedtotalbrainvolume(sumof    grayandwhitematter).Thetotalbrainvolumeofeachparticipantwas   computedby   amultistepalgorithm,using   theBrainExtractionTool(BET)(Smith,2002)   andtheautomatedsegmentationtool(FAST)(Zhangetal.,2001)fromtheFunctionalMagneticResonanceImagingof    theBrain(FMRIB)soft-warelibrary(http://www.fmrib.ox.ac.uk/fsl/).Forthestatisticalanalysis,individualamygdalarawvolumeswerecorrectedfortotalbrainvolume.  2.6.4.   Statisticalanalysis Tocontrolforgendereffectsonbrainactivation,analysisof    variancewasper-formedontheextractedBOLDvalues(weightedmean)fromtheregionsof    interest,selectinggroupandgenderasfixedbetween-subjectfactors.StructuralMRIdata,SCRs   andself-reportdatawereanalyzedwiththePredictiveAnalyticsSoftwarerelease18.0.1(PASW,SPSSInc.,Chicago,IL).Noneof    thedependentvariablesvio-latedtheassumptionof    normalityof    distributions,whichwasassessedusingtheKolmogorov–Smirnovtest.Inorderto   detectsignificantdifferencesinamygdalavolumesaswellasintotalbrainvolume,we   conducteda   univariateanalysisof covariance(ANCOVA),includinggroupasfixedfactorandgenderascovariate.Theassumptionofhomogeneityof    varianceswasexaminedusingthe   Levene’sstatistics.ToassessSCRbaselinedifferences, t  -testswereconductedforthehabituation.Toinvestigateconditioning,arepeatedmeasuresanalysisof    variance(rmANOVA)wasused,includingCS-type(2levels:CS+;CS − )andphase(3levels:acq1,acq2,ext)aswithin-subjectsfactors,andgroup(2levels:CC-group,CA/AAgroup)asbetween-subjectsfactor.Incaseof    Mauchly’stestviolation,aGreenhouse–Geissercorrectionwas   applied.ForsignificantinteractionsinvolvingCS-type,Bonferronicorrected t  -teststestswereconductedforeachgroup.Pearson’scorrelationcoefficient(2-tailed)wasusedtoinvestigaterelationshipsbetweentheextractedBOLDvalues(weightedmean)intheamygdalaanddifferentialSCRduringacquisitionphases.Subjectiveratingswereanalyzedlikethe   SCRs,byrunningarmANOVAwithCS-type   andlearningphaseaswithin-subject,andgroupandgenderasbetween-subjectfactors.Foreachof    theanalysesthealphalevelwassetat0.05. 3.Results  3.1.SCRs DescriptivestatisticsforthesubgroupwithavailableSCRdata( N    =   54)arereportedin   SupplementaryTable2.Duringhabituation,neithergenotypegroupshowedsignifi-cantlydifferentSCRstotheCS+andCS − .   Additionally,noeffectof genotypecouldbefoundforthisphase.TheSCRsduringacquisitionandextinctionrevealedsignificanteffectsof    CS   type( F  1,52 =17.47, Fig.1. Schematicrepresentationof    thecuedconditioningparadigm.Duringhabituation,thetwo   conditionedstimuli(CS+;CS − )   werepresentedwithoutanytemporalcontingencywiththeunconditionedstimulus(US).Duringbothearlyandlateacquisitionphases,theCS+was   coupledwiththeUSin50%of    thecasesinadelayfashion,whilethe   CS −   wasneverfollowedbyshock.Duringextinction,onlyconditionedstimuliwerepresented,whiletheUS   was   omitted.CS:conditionedstimulus;US:unconditionedstimulus.  R.Cacciagliaetal./BiologicalPsychology 94 (2013) 74–81 77 Fig.2. Skinconductanceresponses(SCRs)duringthefearconditioningparadigm.Analysisofskinconductanceresponsesindicatesthatbothgenotypegroups(CCandCA/AA)successfullyshowconditioning,asrevealedbysignificantCS+/CS − differentiationduringbothearly(Acq1)andlateacquisitionphases(Acq2).Errorbarsrepresentstandarderror   of    themean.** P    <   0.01.* P  <   0.05. P  <0.001)andCS-type ×   phase( F  2,104 =   7.51, P  =0.002),indicatingadifferentiationbetweenCS+andCS − ,   whichwassignificantlyrelatedtothelearningphase,butnotto   thegenotypegroup.Inthefollow-up t  -testsbothgenotypegroupsshowedsignificantlyhigherSCRstotheCS+versusCS − duringearly(CC: t  68 =3.07, P  =   0.004;CA/AA: t  36 =2.17, P  =0.037)andlateacquisition(CC: t  68 =2.11, P  =0.040;CA/AA: t  36 =2.05, P  =   0.048).Duringextinctionneithergroupdisplayeda   significantCS+/CS −   differenceintheSCRs(Fig.2).Inclusionofgenderasadditionalbetween-subjectfactordidnotresultinsignificantdifferencesbetweenmaleandfemalepartici-pants.  3.2.Self-reportdata Theanalysisof    theself-reportdatayieldedcomparableresultsastheSCRs.Forallratingcategories,significanteffectsof    CS-type(arousal: F  1,110 =73.19, P  <   0.001;emotionalvalence: F  1,110 =112.01, P  <0.001;CS–UScontingency: F  1,110 =   495.98, P  <   0.001)andCS-type × phase(arousal: F  2,220 =   16.98, P  <0.001;emotionalvalence: F  2,220 =54.88, P  <   0.001;CS–UScontingency: F  2,220 =167.38, P  <0.001)werefound.Follow-up t  -testsrevealedthatbothgroupsshowedsignificantCS+/CS −   differentiationduringearlyacquisitionforarousal(CC: t  112 =6.57, P  <   0.001;CA/AA: t  74 =3.89, P  <   0.001),emotionalvalence(CC: t  112 =7.53, P  <0.001;CA/AA: t  74 =9.04, P  <0.001)andCS–UScontingency(CC: t  112 =14.21, P  <   0.001;CA/AA: t  74 =13.28, P  <   0.001).Similarresultswereobtainedforthelateacquisitionphaseforarousal(CC: t  112 =7.26, P  <   0.001;CA/AA: t  74 =5.05, P  <   0.001),emotionalvalence(CC: t  112 =7.96, P  <0.001;CA/AA: t  74 =9.81, P  <   0.001)andCS–UScontingency(CC: t  112 =26.28, P  <   0.001;CA/AA: t  74 =12.45, P  <   0.001).Nosignificantdifferentiationwas   foundduringhabituationor   extinction.Further,nosignificanteffectsof    genotype,orgenotype ×   gender,couldbefoundin   anyratingcategoryforanyphase.Additionalanalyseswereconductedforthesubsampleswith( N  =   54)andwithout( N    =   60)availableSCRdata.Repeatedmeas-uresanalysisofvarianceandfollow-up t  -testsyieldedcomparableresultsasintheentiresample( N  =   114),withbothgenotypegroupsshowingsignificantdifferentiationinallratingscategoriesduringtheacquisitionphases,andsuccessfulextinction,butnosignificanteffectof    genotype,orgenotype ×   gender.  3.3.fMRI  Whole-brainanalysesconductedontheentiresample( N    =   114)forearlyandlateacquisition,andtheextinctionphase,revealedsignificantactivationsin   severalbrainregionsrelevantforfearconditioning,suchastheinsula,thalamus,cerebellumandsupra-marginalgyrus(Sehlmeyeretal.,   2009)(seeSupplementaryTable1).Withingenotypegroups,wefoundamygdalaactivationonlyintheCA/AA-group.However,thisdidnotsurvivecorrectionfor Fig.3. Reducedamygdalaactivationduringacquisitionof    conditionedfear   inrs2072450homozygousC-allelecarriers(CC-group, N    =   76),comparedtoA-allelecarriers(CA/AA-group, N  =   38).(A)CS+   >   CS − contrastisfamilywiseerror-correctedfortheregionof    interest(ROI)(rightamygdala:[  x =   31,  y =   4,    z  =   − 18]).Colorsinthebarindicate t  -scores.(B)Weighted-meanscoresintheregionof    interestfortherightandleftamygdala.Barsindicatestandarderrorof    themean.  78  R.Cacciagliaetal./    BiologicalPsychology 94 (2013) 74–81 Fig.4. Reducedinsulaactivationduringacquisitionofconditionedfearinrs2072450homozygousC-allelecarriers(CC-group, N  =76)comparedtoA-allelecarriers(CA/AA-group, N    =38).(A)CS+>   CS −   contrastis   familywiseerror-correctedfortheregionof    interest(ROI)(leftinsula:[  x =   − 41,  y   =17,  z    =   − 6].Colorsinthebarindicate t  -scores.(B)Weighted-meanscoresintheregionofinterestforthe   leftandrightinsuladuringlateacquisitionof    conditionedfear(CS+>CS −   contrast).Barsindicatestandarderrorof the   mean. multipletesting(earlyacquisition: t  37 =2.25, P  uncorrected =0.015, P  FWE =   0.24;lateacquisition: t  37 =2.01, P  uncorrected =0.025, P  FWE =0.34).FortheROIanalyses,theCC-groupcomparedtotheCA/AA-groupshowedreducedamygdalaactivationduringearlyacqui-sition,which,however,didnotsurvivecorrectionformultipletesting( t  =2.33, P  FWE =0.204, P  uncorrected =   0.011, k   =9[  x = − 24,  y =   4,  z  = − 18]).Duringlateacquisition,theCC-groupcomparedtotheCA/AA-groupshowedsignificantlyreducedactivationintherightamygdala,whichsurvivedstatisticalcorrection( t  =   3.12, P  FWE =   0.032, k =   22)(Fig.3).Thisresultremainedsignificantaftercontrollingfortotal( t  =3.13, P  FWE =0.015, k =   23)andrightamyg-dalavolume( t  =3.06, P  FWE =0.018, k =23).Inaddition,theCC-groupdisplayedasignificantlyreducedactivationintheleftinsula,alsoduringlateacquisition( t  =3.62, P  FWE =   0.034, k   =146)(Fig.4).Nosignificantgroup ×   genderinteractionwasobservedforthedif-ferentialamygdala( F  1,113 =   0.209, P  =0.648)orinsulaactivation( F  1,113 =0.050, P  =   0.824).We   additionallycomparedthetwogroupsusingawhole-brainanalysis,which,however,didnotyieldanysignificantresults.Duringearlyacquisition,wedid   notfindsignificantcorrelationsbetweendifferentialSCRsandamygdalaactivationin   eithertheCC-group(rightamygdala: r  33 =0.29, P  =   0.1;leftamygdala: r  33 =0.21, P  =0.2)ortheCA/AA-group(rightamygdala: r  17 =0.02, P  =   0.95;leftamygdala: r  17 =0.08, P  =   0.75).However,duringlateacquisition,theCA/AA-groupdisplayeda   significantpositivecorrelationbetweenthedifferentialSCRsandtherightamygdalaactivation(rightamyg-dala: r  17 =0.56, P  =   0.01;leftamygdala: r  17 =0.44, P  =   0.06),whilenosignificantcorrelationswerefoundin   theCC-group(rightamyg-dala: r  33 =0.2, P  =0.25;leftamygdala: r  33 =0.21, P    =0.22).Nosignificantbetween-groupdifferencescouldbeobservedfortheanteriorcingulatecortex,duringeitheracquisitionorextinction.Duringextinction,nosignificantgenotypeeffectswereobserved.We   conductedadditionalanalysesonthesubsamplewith( N  =54)andwithout( N  =   60)availableSCRdata,usingthesameROImasksemployedin   theentiresample( N    =   114).For   thesubsamplewithavailableSCRdata,reducedamygdalaandinsulaactivationwerepresentduringlateacquisitionin   theCC-comparedto   theCA/AA-group,which,however,didnotsurvivecorrectionformul-tipletesting(rightamygdala: t    =2.65, P  FWE =   0.06, k   =   19;leftinsula: t  =2.47, P  FWE =0.41, k   =   37).Similarresultswerepresentinthesub-groupwithoutSCRs,wheretheCC-groupshowednon-significantreducedactivationsintherightamygdala( t  =2.31, P  FWE =0.11, k =9)andtheleftinsula( t  =   3.32, P  FWE =0.09, k   =   52).Further,tosecurethatthebetween-genotypegroupresultsyieldedintheentiresamplewerenotsignificantlydrivenbyeithersubsample,wecomparedbrainactivitybetweenthetwo   subgroups,irrespec-tive   of    genotype.As   expected,wefoundnosignificantdifferencesintherightamygdala( t  112 = − 0.33, P  =   0.74)ortheleftinsulaacti-vation( t  112 = − 0.21, P  =0.84)duringlateacquisitionbetweenthesubsamples.  3.4.Volumeoftheamygdala Nosignificantgroupdifferenceswerefoundin   eithertotal,rightorleftamygdalavolume,althoughtherewasatrend   towardsmallervolumesintheCC   comparedto   theCA/AAgroup(Table1).Genderwasnot   significantlyrelatedto   totalamygdalavolume( F  1,94 =   0.26, P  =0.37).Thetwogroupsdid   not   significantlydifferintotalbrainvolume.Anadditionalcomparisonin   thereducedsamplewithavailableSCRsdata( N    =   54)yieldednon-significantbetween-groupdifferencesin   amygdalavolume(SupplementaryTable2),how-ever,whentestingdifferencesin   thesubgroupwithoutSCRdata( N  =   60),theCC-groupdisplayedreducedvolumesona   trend-level,consistentwiththeanalysisconductedontheentiresample(Sup-plementaryTable3). 4.Discussion In   thisstudywe   employedanimaginggeneticsapproachtodeterminebrainactivityaswellaselectrodermalresponsesandself-reportedarousal,valenceandcontingencyratingsduringcuedfearconditioningincarriersofa   riskvariantforalcoholdepend-ence(CC-group)in   the GRIN2A geneencodingNR2A,comparedtocarriersofthenon-riskvariant(CA/AA-group).BasedonstudiesdescribingNR2Aascriticalinfearacquisition(Mülleretal.,   2009;WalkerandDavis,2008)   andonpreviousreports,whichfoundareducedconditionabilitytothreateningstimuliin   peopleatriskforalcoholism(Finnetal.,1994,2001;Stephensetal.,   2005),   wehypothesizedtofindlessCS+/CS − discriminationincarriersoftheriskvariant.Giventhatlowerthreat-relatedamygdalaresponsivityin   individualsatriskforalcoholdependencehasbeendocumented(TessnerandHill,2010;Heitzegetal.,2008;Glahnetal.,   2007;NikolovaandHariri,2012),wealsoexpectedtofindreducedactiva-tionin   thisbrainregionin   therisk-allelegroup,duringacquisitionofconditionedfear.Further,asreducedamydgalasizehasbeenpreviouslydocumentedin   alcohol-dependentindividuals(Wraseetal.,2008)andinchildrenof    alcoholics(Hill   etal.,   2001;Benegaletal.,   2007),we   alsoquantifiedamygdalavolume.
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