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TheCentralNucleusoftheAmygdalaisaCriticalSubstrateforIndividualDifferencesinAnxiety
JonathanA.Oler1,2,AndrewS.Fox1,2,AlexanderJ.Shackman3andNedH.Kalin1,2
1. DepartmentofPsychiatryUniversityofWisconsinSchoolofMedicineandPublicHealth6001ResearchParkBoulevard,Madison,Wisconsin53719USA
2. HealthEmotionsResearchInstituteUniversityofWisconsin‐MadisonMadison,Wisconsin53719USA
3. DepartmentofPsychologyNeuroscienceandCognitiveScienceProgram,andtheMarylandNeuroimagingCenterUniversityofMaryland,CollegePark3123GBiology‐Psychology,CollegePark,Maryland20742USA
AcknowledgementsWethankthepersonneloftheHarlowCenterforBiologicalPsychology,HealthEmotions
ResearchInstitute,WaismanLaboratoryforBrainImagingandBehavior,andWisconsinNationalPrimateCenter.ThisworkwassupportedbytheNationalInstitutesofHealth(R01‐MH046729,R01‐MH081884,P50‐MH084051,R21‐MH09258),theHealthEmotionsResearchInstituteandtheUniversityofMaryland,CollegePark.
Please cite as Oler, J. A., Fox, A. S., Shackman, A. J. & Kalin, N. H. (in press). The central nucleus of the amygdala is a critical substrate for individual differences in anxiety. Living without an amygdala (D. G. Amaral, M. Bauman, & R. Adolphs, Eds.). Guilford Press.
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Researchintothefunctionoftheamygdalabeganwithexperimentsinrhesusmonkeys,
performedbyBrownandSchaefer(BrownandSchafer,1888)andlaterbyKlüverandBucy
(KlüverandBucy,1937;KlüverandBucy,1939).Thesestudiesledtofurthercritical
experimentsinnonhumanprimatesthatcontinuedtospecifytheamygdala’sroleinemotionand
socialbehavior(Weiskrantz,1956;Kling,1968;Kappetal.,1979;Pribrametal.,1979;Aggleton
andPassingham,1981;Rolls,1984;Zola‐Morganetal.,1991).Advancesinlesiontechniquesand
otherinvasiveandnon‐invasivemethodologieshavemotivatedmorenuancedhypotheses
regardingtheadaptiveroleoftheamygdalainfear,dangerdetection,socialbehavior,vigilance,
andtemperament(Kalin,1997;Whalen,1998;LeDoux,2000;Adolphs,2003;Amaral,2003).
Thereisnowgreatinterestinunderstandingalterationsinamygdalafunctioninrelationto
psychopathology,withaparticularemphasisonanxietyandaffectivedisorders.
Understandingtheroleoftheamygdalainanxietyandaffectivedisordersisessentialbecause
thesedisordersareamongthemostcommonpsychiatricillnessesinyouthandadults(33.7%
lifetimeincidenceofanyanxietydisorder;18.3%lifetimeincidenceofmajordepressive
disorder),andtheyarehighlycomorbidandoftenresistanttotreatment(Kessleretal.,2012).
Anxietydisordersfrequentlybeginduringthepreadolescentyearsandinmanycasesare
associatedwiththelateronsetofdepressionduringadolescenceandearlyadulthood.Research
demonstratesthatveryyoungchildrenwithextremeanxiety,asmanifestedbymarkedreactivity
tonoveltyand/orstrangers,areatincreasedrisktodevelopanxietyandaffectivedisorders.For
example,extremetemperamentalchildhoodanxietyisastrongpredictorofthelater
developmentofsocialanxietydisorder(Schwartzetal.,1999;Prioretal.,2000;Biedermanetal.,
2001;Hirshfeld‐Beckeretal.,2007;Chronis‐Tuscanoetal.,2009;Essexetal.,2010),and
depressivedisorders(Caspietal.,1996;GladstoneandParker,2006;Beesdoetal.,2007).A
recentmeta‐analysissupportsthecontentionthatextremechildhoodtemperamentalanxiety
mayrepresentthesinglebestpredictorofthelaterdevelopmentofsocialanxietydisorder
(ClaussandBlackford,2012).Appreciatingwhycertainindividualsarevulnerabletodeveloping
anxietydisordersrequiresanunderstandingoftheneuralmechanismsthatinfluencethe
developmentofadaptiveanxiety,aswellasextremetemperamentalanxiety(Yehudaand
LeDoux,2007;McEwenetal.,2012;Galatzer‐Levyetal.,2013;Goswamietal.,2013;Grupeand
Nitschke,2013;HolmesandSingewald,2013;Shackmanetal.,2013).
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Ourultimategoalistoprovideinsightintothedevelopmentalissuesrelatedtotheonset
ofmoodandanxietydisorders.Therefore,wehavefocusedoureffortsonunderstandingthe
developmentalpathophysiologyoftheseillnessesbystudyingtheroleoftheamygdalaearlyin
thelifeofprimatesasitrelatestotheinitialmanifestationsofextremeanxiety.Ourstudiesin
youngrhesusmonkeyssuggestthatthecentralnucleusoftheamygdala(Ce)andthebednucleus
ofthestriaterminalis(BST;partoftheextendedamygdala),arekeysubstratesfortrait‐like
differencesinanxiety.TheCeisoftenconceptualizedasthemajoroutputstructureofthe
amygdalaforprojectionstothebrainstemandhypothalamus,andtheCeisthoughtto
coordinateandgatethephysiologicalandbehavioraleffectsoffear(Davis,2000;Pareetal.,
2004;Ciocchietal.,2010;Haubensaketal.,2010).AdditionalhypothesesofCefunctionhave
beenpostulatedtoaccountforitsroleinappetitivelearningandattention(Kappetal.,1992;
GallagherandHolland,1994;Gallagher,2000;Everittetal.,2003;Gabrieletal.,2003).TheCeis
alsoconceptualizedasthetemporallobecomponentofthe‘centralextendedamygdala’,a
hypothesizedmacrostructualanatomicentitythatextendsintothebasalforebrain(Alheidand
Heimer,1988;deOlmosandHeimer,1999;HeimerandVanHoesen,2006).Thebasalforebrain
isacomplexregionthathasonlyrecentlybecomeaccessibletostudyinthelivingprimate.
Becauseofitsstrategiclocationandputativefunctions,dysfunctionofthebasalforebrainhas
beenimplicatedinvariousneuropsychiatricdisorders(Heimer,2003).Themajorcomponentsof
thebasalforebrain,includingthecholinergicnucleusbasalisofMynert,theventralstriatopallidal
systemandtheextendedamygdala,arehighlyinterdigitatedmakingitchallengingtoelucidate
selectivefunctionsofthesebasalforebraincomponents(Zaborszkyetal.,2008).Thecentral
extendedamygdalaconceptproposedbyHeimerandcolleaguestodescribethecontinuumof
GABA‐ergicneuronsthatrunfromCe,throughthesubstantiainnominata,toBSTandtheshellof
thenucleusaccumbenscomplementstheothermodelsofCefunctionmentionedabove.In
additiontobeinghighlyinterconnected,theCeandBSTsharemanyofthesameefferenttargets,
reinforcingtheideathatCeandBSTtogetherformacoherentfunctionalunit(deOlmosand
Heimer,1999).Consistentwiththeseanatomicalandneurochemicalfindings,functionalMRI
(fMRI)datafromourlaboratorydemonstratethatinmonkeysandhumanstheCeandBST
displayhighlysignificantfunctionalconnectivityatrestorunderanesthesia,supportingthe
hypothesisthatthesestructuresformadiscretecircuit(Oleretal.,2012).Analternativeview,
however,considerstheCe,sublenticularsubstantiainnominataandBSTcontinuumas
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differentiatedcomponentsofastriatopallidalprojectionsystem(Dongetal.,2001;Swanson,
2003).
RodentstudiessuggestanimportantdissociationbetweensubdivisionsoftheCeandtheBST
withrespecttodefensivebehaviors,suchthatthemedialdivisionoftheCe(CeM)isinvolvedin
rapid,phasicfear‐relatedresponding,whereastheBSTviainputsfromthelateraldivisionofthe
Ce(CeL)isthoughttomediateslower,sustainedanxiety‐likeresponsestodiffuseorambiguous
threats(WalkerandDavis,2008).Additionally,recenthumanimagingstudieshaveassociated
theBSTregionwithvigilance,threatmonitoringandanticipatoryanxiety(Straubeetal.,2007;
Alvarezetal.,2010;Mobbsetal.,2010;Somervilleetal.,2010;Choietal.,2013;Grupeetal.,
2013;Averyetal.,2014),andsomeevidenceforaCeandBSTfunctionaldissociation,similarto
thatinrodents,hasbeenreportedinhumans(Davisetal.,2010).
Herewereviewstudiesfromrhesusmonkeysaimedatunderstandingtheroleofthe
amygdalaintemperamentalanxiety,andprovideevidencedemonstratingthatthecentral
extendedamygdalaplaysacriticalroleinearly‐lifeanxiety.Wefirstrecountthedevelopment
andvalidationofthenon‐humanprimatemodelofchildhoodanxiety.Next,wediscuss
neuroimagingandgeneticevidencefromtherhesusmonkeyshowingthattheanxious
phenotype,oranxioustemperament,isheritableandstronglyrelatedtoindividualdifferencesin
Cefunction.Wethendescribeevidencefrommechanisticstudiesdemonstratingthatbehavioral
expressionofprimateanxietycriticallydependsupontheintegrityoftheCe.Weconcludeby
outliningtheimplicationsofthesefindingsforunderstandingtheriskforanxiety‐related
psychopathology,forpotentiallydevelopingmoreeffectiveearly‐lifeinterventions,andfor
understandingnormalvariationinchildhoodtemperament.
DevelopingtheHumanIntruderParadigmandtheConceptofAnxiousTemperament
Fromournonhumanprimatestudies,wedevelopedthetermanxioustemperament(AT)to
describeanindividual’sunderlyingpredispositiontodisplayextremeanxiety‐relatedbehavioral
andphysiologicalresponsesearlyinlife.Thereisconsiderableevidencethattheamygdalaplays
acriticalroleinnormalfearandemotionalprocessing(Aggleton,1992;Aggleton,2000;
Shinnick‐Gallagheretal.,2003),alteredamygdalafunctionhasbeenreportedinadultswith
anxietydisorders(EtkinandWager,2007)andadministrationofclinicallyeffectiveanxiolytics
reducesamygdalaactivationinadose‐dependentmanner(Paulusetal.,2005).Inaddition,
adultswithahistoryofchildhoodATdisplayincreasedamygdalareactivitytonovelor
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potentiallyfearfulstimuli(Schwartzetal.,2003;BlackfordandPine,2012).However,the
amygdala’scontributiontoearlylifepresentationoftrait‐likeindividualdifferencesinchildhood
anxietyremainsunclear.Specifyingtheprocesseswithintheamygdalathatunderliethe
developmentofnormalandabnormalanxietywillbeessentialfordevelopingnovel
neuroscientifically‐groundedinterventionsfortreatingandpreventinganxiety‐related
psychopathology.
ThebehavioralassayformonkeysdevelopedbyKalinandSheltontermed‘thehuman
intruderparadigm’wasconceptualized,inpart,tomapontostudiescharacterizingbehavioral
inhibitioninhumanchildren.Thehumanintruderparadigmconsistsofthreedifferent
consecutivelypresentedconditions(Alone,No‐Eye‐Contact,andStare)thatelicitdifferent,
contextuallyappropriate,anxiety‐relateddefensiveresponses(KalinandShelton,1989);see
Figure1).Inthe‘Alone’condition,animalsareseparatedfromtheircage‐matesandplacedby
themselvesinanoveltestcage.Duringthe‘No‐Eye‐Contact’(NEC)condition,whichfollowsthe
Alonecondition,ahumanintruderenterstheroomandat2.5metersfromthecagepresents
his/herprofiletothemonkey.Thecriticalcomponentofthisconditionisthelackofeyecontact
betweenthehumanintruderandthetestmonkey.Whileeyecontactsignalsadirectthreat,the
avoidanceofeyecontactprovidesadifferentpotentiallythreateningcontext.Theintruderthen
leavestheroomforabriefperiod.Uponreentering,the‘Stare’conditionensues,duringwhich
theintrudercontinuouslystaresatthemonkeywithaneutralfacialexpression(Kalin,1997).
[insertFigure1here]
Anumberofstandardizedbehavioralparadigmsexisttomeasurechildhoodbehavioral
inhibition(Foxetal.,2005).Theseparadigmsincludetheintroductionofastrangertotheroom
withayoungchild(Bussetal.,2004),andexposureofachildtonovelobjectsandsocial
situations(Kaganetal.,1988).Individualdifferencesinphysiologicalresponsestostresshave
alsobeenexaminedinrelationtobehavioralinhibition.Manyofthesestudieshavefocusedon
pituitary‐adrenalactivityandreportmixedresults.Initialstudiesdemonstratedassociations
betweencortisolandbehavioralinhibitioninchildren,orbetweencortisolandATinmonkeys
(Kalinetal.,1998;Essexetal.,2002),howeverlaterstudiesdidnotconsistentlyreplicatethese
findings(Shackmanetal.,2013).Whilenotasextensivelystudied,evidencepointstoan
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associationbetweenheartrateandrightfrontalEEGasymmetrywithextremechildhoodBIand
monkeyAT(Davidsonetal.,1992;Davidsonetal.,1993;Kalinetal.,1998;Foxetal.,2005).
OurdefinitionofATparallelstheconstructofbehavioralinhibitionusedbyKaganand
colleaguesintheirdescriptionofextremelyshytoddlersthatwereobservedtobecomeimmobile
andhesitanttovocalizeinthefaceofpotentialthreat(Kaganetal.,1988).Freezingbehaviorin
responsetotheNECconditionofthehumanintruderparadigm,becauseofitsobvioussimilarity
tohumanbehavioralinhibition,wastheinitialmetricusedtoassessthreat‐relatedanxietyin
youngmonkeys(KalinandShelton,1989;KalinandShelton,2000;KalinandShelton,2003;
Kalinetal.,2005).Asavalidationofitsrelevancetoanxiety,wedemonstratedthatNEC‐induced
freezinginmonkeyscanbereducedbyadministrationofthebenzodiazepine,diazepam,a
commonpharmacologicaltreatmentforclinicallysignificantanxiety(KalinandShelton,1989;
Davidsonetal.,1993;Kalin,2003),andincreasedwithadministrationofß‐carboline,an
anxiogenicbenzodiazepineinverseagonist(Kalinetal.,1992).Welaterexpandedthe
assessmentofmonkeyanxietytomovebeyondjustasinglebehavioralmeasure(i.e.,freezing)to
acompositemeasure,byincludingdecreasesinspontaneouscoo‐calls(Foxetal.,2005)aswell
asindividualdifferencesinthreat‐inducedcortisollevels(Jahnetal.,2010).Thiswas,inpart,
basedontheobservationthatanimalswithelevatedfreezinginresponsetotheNECcondition
concomitantlyemittedfewervocalizations(KalinandShelton,1989).Threat‐inducedcortisol
wasaddedtogaugeindividualdifferencesinpituitary‐adrenalreactivity(KalinandShelton,
1989;Kalinetal.,1998).Itisimportanttonote,thatwhenexaminingtherelationsamongthe
threecomponentsofAT(freezing,reducedcooingandcortisollevels)inalargesample,
individualdifferencesincortisollevelsdonotsignificantlycorrelatewitheitherbehavioral
metric,whereasfreezingandcooingaremoderatelyinverselycorrelated(Shackmanetal.,
2013).TheinclusionofcortisolinthecompositemeasureofATisintendedtocapturethe
heterogeneityinindividualdifferencesinthephysiologicalresponsetofearandanxietyeliciting
stimuli.Interestingly,theATcompositebetterpredictsindividualdifferencesinamygdala
metabolismthananyoneofitsthreecomponents(Foxetal.,2008;Shackmanetal.,2013).
Tobeclear,wespecificallyusethetermATtooperationalizethetheoreticalconstruct
representinganindividual’sdispositiontobehavewithreticenceandrespondtopotentialthreat
withextremebehavioralandphysiologicalreactivity.OurdefinitionofATincludesbehavioral
inhibition(i.e.,freezinganddecreasedspontaneousvocalization),butalsotakesintoaccountthe
degreeofpituitary‐adrenalstress‐responsivenessoftheindividual(seeFigure2a).
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Table1demonstratesthetranslationalutilityofATasamodelforchildhoodbehavioral
inhibitionortheearlychildhoodriskfordevelopingsocialanxiety.Asmentionedabove,itiswell
documentedthathighlyanxiouschildrenareatsubstantialriskforsocialanxietydisorder(SAD).
TheDiagnosticandStatisticalManualofMentalDisorders(DSM‐V)liststhefollowingascriteria
forSADdiagnosis,manyfeaturesofwhicharesharedbybothchildhoodbehavioralinhibition
andmonkeyAT(italicsadded):SADCriterionA:Markedfearoranxietyaboutoneormoresocial
situationsinwhichtheindividualisexposedtopossiblescrutinybyothers.Examplesinclude
socialinteractions(e.g.,meetingunfamiliarpeople),beingobserved,andperforminginfrontof
others.CriterionB:Theindividualfearsthatheorshewillactinawayorshowanxiety
symptomsthatwillbenegativelyevaluated.CriterionC:Thesocialsituationsalmostalways
provokefearoranxiety.Note:Inchildren,thefearoranxietymaybeexpressedbycrying,
tantrums,freezing,clinging,shrinking,orfailingtospeakinsocialsituations.CriterionD:The
socialsituationsareavoidedorenduredwithintensefearoranxiety.CriterionE:Thefearor
anxietyisoutofproportiontotheactualthreatposedbythesocialsituationandtothe
socioculturalcontext.CriterionF:Thefear,anxiety,oravoidanceispersistent,typicallylasting
for6monthsormore.CriterionG:Thefear,anxiety,oravoidancecausesclinicallysignificant
distressorimpairmentinsocial,occupational,orotherimportantareasoffunctioning.Criterion
H:Thefear,anxiety,oravoidanceisnotattributabletothephysiologicaleffectsofasubstanceor
anothermedicalcondition.CriterionI:Thefear,anxiety,oravoidanceisnotbetterexplainedby
thesymptomsofanothermentaldisorder.CriterionJ:Ifanothermedicalconditionispresent,the
fear,anxiety,oravoidanceisclearlyunrelatedorisexcessive(AmericanPsychiatricAssociation,
2013).AsshowninTable1,theATphenotypeinyoungmonkeysandthebehaviorallyinhibited
phenotypeinyoungchildrenshareanumberofcommonfeatures.Manyofthesecommon
featuresareantecedentsofSAD.WebelievethatextremeATinchildren,whenstableandtrait‐
like,hasthehallmarksofsub‐thresholdSADbutisnotsevereenoughtosatisfythefunctional
impairmentcriterion.
[inserttable1here]
NeuroimagingstudieslinkindividualdifferencesinCefunctiontoanxiety
Ourinitial18F‐fluorodeoxyglucose(FDG)‐positronemissiontomography(PET)imagingstudies
demonstratedthatmonkeyATwascorrelatedwithmetabolismintheamygdalaandthe
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extendedamygdala(i.e.,BST),aswellasanteriorhippocampus,anteriortemporallobe,and
periaqueductalgrey(PAG)(Foxetal.,2005;Kalinetal.,2005).FDGisaradiolabeledglucose
analogwithahalf‐lifeof~110minutesthatdoesnotgetmetabolizedandremainstrappedin
metabolicallyactivecells(Sokoloffetal.,1977).BecausethetimecourseofFDGuptakereflects
brainactivityoveranapproximate30‐minuteperiod,andremainsstablydetectableinthebrain,
itisanidealradiotracertosimultaneouslystudybehaviorandbrainactivityelicitedbyexposure
toethologically‐relevantsituations(seeFigure2b).FDG‐PETisthereforeparticularlyusefulin
understandingthesustainedbrainresponsesassociatedwithtemperament,whichbydefinition
isapersistentandrelativelycontext‐independentemotionaldisposition.
[insertFigure2here]
WeperformedFDG‐PETscansonanimalsexposedto4differentconditions,2ofwhichwere
stressful(NECandAlone‐separationfromcage‐mateintoatest‐cage)and2ofwhichwere
nonstressful(inhome‐cagewithoutcage‐mate,andinhome‐cagewithcage‐mate).Ourfindings
revealedconsistentpositivecorrelationsbetweenindividualdifferencesinNEC‐elicitedATwith
metabolismintheamygdala,hippocampus,anteriortemporalpole,andPAGregardlessofthe
stressfulornonstressfulconditioninwhichbrainmetabolicactivitywasassessed(Foxetal.,
2008).Remarkably,theATbrainmetabolismphenotypewasdiscernibleintheabsenceof
provocation,whenmonkeyswereathomewiththeircage‐mate,somethingthatisvirtually
impossibletomeasureinhumans.TheseresultssuggestthattheneuralcorrelatesofATare
stableacrosscontextsandnotascontext‐dependentastheobservablebehavioralandpituitary‐
adrenalresponsesassociatedwithAT.Similarly,weexaminedthestabilityofAT’sneural
substratesacrosstimebyassessingFDG‐PETandATinresponsetoNECin24animals3‐times
overthecourseof6‐18months(Foxetal.,2012).Resultsdemonstratedthatbrainmetabolism
withinAT‐relatedregionswasstableovertime,andmeanbrainmetabolism(acrossthe3
assessments)predictedmeanAT(Foxetal.,2012).Collectively,thesedataindicatethatthetrait‐
likenatureofATisreflectedbycontext‐independentandtemporallystableneuralsubstrates
thatareinstantiatedintheinherentactivityofanindividual’sbrain.
TofurtherexploretheneuralsubstrateunderlyingATandtoelucidatetheheritablebasisof
AT,weperformedanexperimentexaminingFDG‐PETandATinresponsetotheNECcontextina
largesample(n=238)ofyoungrhesusmonkeys(Oleretal.,2010).Becauseofthestatistical
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poweraffordedbythelargesamplesize,weusedextremelystringentstatisticalthresholds
(Šidákcorrected),whichincreasesconfidenceinthefindings.Consistentwithearlierfindings,
theimagingdatademonstratedthatmetabolisminanteriortemporallobestructuresincluding
theCeregion,anteriorhippocampusandanteriortemporalcortexpredictedindividual
differencesinAT(Figure3).
[insertFigure3here]
AttheŠidákthreshold(p=0.00000005875),largebilateralanteriortemporallobeclusters
thatcorrelatedpositivelywithATwereobserved(Oleretal.,2010).Theanteriortemporallobe
clusterscontainedmultiplespatialpeaks,eachofwhichcorrelatedwithAT.Therefore,we
furtherresolvedthelocationofthepeakcorrelationswithintheanteriortemporallobeclusters
bycalculatingthespatialconfidenceintervalsrepresentingvolumesthatwith95%certainty
containedthepeakcorrelationsbetweenmetabolicactivityandAT(seeOleretal.,2010for
details).Tofurtherdemarcateanddefinethelocationofthesepeaks,weusedinvivo
chemoarchitectonictechniquestodemonstratethatthisfunctionally‐definedregioncorresponds
totheCe,adegreeofprecisionthatisdifficulttoachieveusingconventionalimagingtechniques
inhumans.Thevolumescontainedwithinthe95%confidenceintervalsweresuperimposedona
voxelwisemapofserotonintransporter(5‐HTT)bindingcreatedfromanindependentsampleof
rhesusmonkeysassessedwith11C‐DASBPET(Christianetal.,2009;Oleretal.,2009).This5‐
HTTmap(seeFigure4)canbeusedtolocalizetheCeanddifferentiateitfromtheanterior
hippocampus,sincecomparedtosurroundingregionsthelateraldivisionoftheCe(CeL)hasthe
highestdensityof5‐HTTbinding(O'RourkeandFudge,2006).
[insertFigure4here]
DemonstratingheritabilityofATandinitialstudiesofthegeneticbasisofAT
ToascertainwhetherindividualdifferencesinATareheritable,wetookadvantageofthefact
thattheyoungrhesusmonkeysinthestudyallbelongtoasinglemultigenerationalpedigreeof
morethan1,800individuals.Thepoweroftheextendedpedigreeapproachtoquantitative
geneticanalysisstemsfromthemanycloselyrelated,distantlyrelatedandunrelatedpairsof
individualsthatallcontributeinformationabouttheeffectsofsharedgenesonphenotypic
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similarity.Specifically,amongthemonkeyswithphenotypedataandconfirmedlineage,there
werethreefull‐siblingpairs,189half‐siblingpairs,128third‐degreerelativepairs,372fourth‐
degreerelativepairs,andmuchlargernumbersofmoredistantlyrelatedandunrelatedpairs.
Usingageneralvariancecomponentsmethod(AlmasyandBlangero,1998),weestimatedthe
heritabilityofATwhileincludingcovariatessuchassex,age,andtheirinteractionsinthemean
effectsmodeltocontrolforextraneoussourcesofvariance(formethodologicaldetailssee
supplementalmaterialsfromOleretal.,2010).Consistentwithpreviousreportsinrhesus
monkeys(Williamsonetal.,2003;Rogersetal.,2008),andthegeneticepidemiologyofhuman
anxietydisorders(Hettemaetal.,2001),approximately36%ofthevariabilityinATwas
accountedforbythepair‐wiserelationshipsamongtheanimals.
Weusedthissamequantitativegeneticapproachtoestimatetheheritabilityofmetabolic
activityateachvoxelwhereFDGmetabolismsignificantlypredicteddifferencesintheanxious
phenotype(seeFigure5).Remarkably,althoughglucosemetabolismintheCeandanterior
hippocampalpeakregionsweresimilarlypredicativeofAT,theseregionsweredifferentially
heritable.UnlikeCemetabolism,anteriorhippocampalmetabolismwassignificantlyheritable
andthislevelofheritabilitywassignificantlygreaterthantheheritabilityestimatefortheCe
(Oleretal.,2010).Weinterpretedthesefindingscautiouslyaseventhislargesamplesizeis
relativelymodestfortestsofadditivegeneticeffects,buttheresultssuggestthattheCemaybe
particularlyinfluencedbytheenvironmentandexperience,andsetthestageforfurther
experimentsaimedatunderstandingtheneurodevelopmentaloriginsorAT.Theseresultsalso
highlighttheimportantobservationthatitispossibletodissociateheritablefromnon‐heritable
neuralsubstrates‐somethingthat,toourknowledge,hasneverbeenshowninpriorwork.
[insertFigure5here]
Atamorespecificlevel,weexaminedDNAvariationincandidategenesastheyrelatetoAT
anditsunderlyingamygdalarandhippocampalmetabolism.Weselectedtheserotonin
transporter‐linkedpolymorphicregion(5‐HTTLPR)becausevariationinthisgenewasshownby
numerousgroupstopredictfear‐relatedbehaviorsandtheriskforaffectivedisorders(Hariri
andHolmes,2006).Theeffectsofthe5‐HTTLPRgenotypeontherisktodevelopanxietyarenot
straightforward,andmayonlyberevealedwhenexaminingbrainreactivity,forexamplewhen
comparingstressfulandnon‐stressfulconditionsor,asisrequiredintheanalysisoffMRIdata,a
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changefrombaseline.Weobservednoeffectofthe5‐HTTLPRpromoterrepeatlength
polymorphismonATorAT‐relatedglucosemetabolism(Oleretal.,2010).Thiswasnot
surprisingconsideringthat1)alargeimagingstudyusingarterialspinlabelingfoundnoeffectof
5‐HTTLPRgenotypeonbaselineamygdalabloodflow(Vivianietal.,2010),and2)aprevious
studyinasmallersampleofmonkeysfailedtoobserve5‐HTTLPRgenotype‐relateddifferences
inNEC‐inducedFDG(Kalinetal.,2008).Kalinetal.,(2008)did,however,find5‐HTTLPR
genotype‐relatedalterationswhencomparingthedifferenceinmetabolismbetweentheNEC
conditionanda“safe”condition,wheretheanimalswereadministeredFDGintheirhomecages.
IncontrasttotheATfindings,thesedatademonstrateanassociationbetweencontext‐
dependentmetabolicchangesandthe5‐HTTLPRgenotype.Interestingly,inthesamesampleof
monkeysthe5‐HTTLPRgenotypewasnotsignificantlyassociatedwith11C‐DASBbinding,a
measureof5‐HTtransporteravailability(Christianetal.,2009).Collectively,thesefindings
highlightthecomplexityoftheinfluencethatthe5‐HTTLPR,andotherfunctional
polymorphisms,haveonbehaviorandtheriskforpsychopathology,andsupporttheideathat
neurogeneticsresearchshouldfocusongene environmentinteractions(Caspietal.,2010;
Hydeetal.,2011;Bogdanetal.,2013).
Incontrasttotheshortandlongallelicvariationinthe5‐HTTLPR,singlenucleotide
polymorphisms(SNPs)inthecorticotropinreleasinghormonereceptor1(CRHR1)gene,which
hasbeenassociatedwithriskforthedevelopmentofanxiety‐relateddisorders(Bradleyetal.,
2008),weresignificantlyassociatedwithbothATandAT‐relatedglucosemetabolism.
Specifically,SNPsinexon6oftherhesusCRHR1geneappeartoconferanincreasedlikelihoodof
elevatedATandgreaterNEC‐relatedmetabolismintheCeandanteriorhippocampus(Rogerset
al.,2013).Thisfindingisparticularlyinterestingbecauseexon6isfoundprimarilyinanthropoid
primates.MuchofthehumanCRHR1geneticdatareportgene environmentinteractions,
especiallyinteractionswithearlychildhoodtrauma(Bradleyetal.,2008).Thus,thesefindings
suggestthattheearly‐lifeeffectsofCRHR1geneticvariationmaybetosupportthedevelopment
ofadiathesisthatinteractswithearlyadversitytoincreasethelikelihoodofdeveloping
pathologicalanxiety.
MolecularsubstrateswithintheCerelevanttoAT
Asanxietyandaffectivedisorderscanberesistanttocurrenttreatments,andthese
treatmentsarecommonlyassociatedwithsignificantadverseeffects(Bystritsky,2006;Cloosand
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Ferreira,2009;Kessleretal.,2012)thereisgreatneedforidentifyingnewanxiolyticand
antidepressantmoleculartargets.Furthermore,becauseoftheearly‐lifeonsetofanxiety,
establishingnovelearly‐lifeinterventionsaimedatpreventingchronicanddebilitatingoutcomes
wouldbeanidealtreatmentapproach.Todevelopnovelinterventionsforanxietydisorders,itis
necessarytoidentifypotentialtreatmenttargetsandtotesttheirtherapeuticfeasibilityina
speciesthatexpressesanxiety‐relatedpsychopathologythatissimilartohuman
symptomatology.Inthisregard,quantitativemRNAapproachesareparticularlyusefulbecause
theycapturethecombinedimpactofgeneticandenvironmentalepigeneticregulation(Jaenisch
andBird,2003).WithmicroarrayordeepRNAsequencingdatawecanidentifyindividual
differencesinmRNAexpressionlevelsofspecificgenesthatpredictATandalteredmetabolism
withintheATneuralcircuit(Foxetal.,2012;Roseboometal.,2013).
ThemonkeymodelofchildhoodATallowsustodovetailthesamemultimodalimaging
methodsroutinelyusedinhumanswithindepthpost‐mortembrainmolecularanalyses.Our
initialapproachhasbeentocollectbraintissuepunchesfromasubsetofmonkeysphenotyped
forAT.Usingtheimagingdataasaguide,fromthebrainsof24malemonkeysweselectively
biopsiedtheregionofthedorsalamygdalawhereitsmetabolismwasmostpredictiveofAT
(Figure6).AffymetrixrhesusmicroarraychipswereusedtoassessmRNAexpressionthatwas
analyzedinrelationtoindividualdifferencesinATandCemetabolism(seeFigure6).Analyses
controllingforhousingdifferences,hemispheresampled,andagerevealedthatATwas
associatedwithanumberofmRNAsthathadatleastmoderateexpressionlevels[>log2(100)],
andremainedsignificantlycorrelatedwithATaftercorrectingformultiplecomparisons(FDRq
<0.05,two‐tailed;seeFoxetal2012fordetailedmethods).Ageneontologyenrichmentanalysis
ofallthesignificantAT‐relatedmRNAsrevealedthatexpressionlevelsofgenefamilies
associatedwithneuroplasticityandneurodevelopmentsignificantlypredicteddifferencesinAT
(Foxetal.,2012).Specifically,thistranscriptome‐wideanalysisrevealedthatATandincreased
CemetabolismwasassociatedwithdecreasedexpressionlevelsofseveralgenesintheNTF‐3
(neurotrophin‐3)‐NTRK3pathway(seeFigure6).NTRK3(neurotrophictyrosinekinase
receptor‐3,alsotermedTrkC)isofconsiderableinterestbecauseitsactivationcaninitiate
synaptogenesisandneurogenesis(Bernd,2008).Inaddition,NTRK3geneticvariationhasbeen
linkedtohumanpsychopathology(Otnaessetal.,2009)andbecausetheNTRK3proteinisacell
surfacereceptor,NTRK3mayprovideanaccessibledrugtarget.Theseuniquefindingsina
primatespeciessuggestthattheexpressionandmaintenanceofATandthesubsequent
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increasedrisktodevelopanxietyanddepressionmaybeduetoearlymaladaptive
neurodevelopmentalprocesses(Foxetal.,2012).
[insertFigure6here]
ThefindingsfromthemicroarrayexperimentalsodemonstratedthatCemetabolismandAT
wereassociatedwithalteredexpressionofsomeexpectedcandidatesgenes(e.g.,5HT2Cand
NPY1R).LevelsofmRNAsforbothofthesegeneswerenegativelycorrelatedwithAT,suchthat
individualswiththelowestexpressionlevelsofNPY1RmRNA,forexample,werethosewiththe
mostextremeAT(Roseboometal.,2013).NYP1Risofinterestbecauseofthenumerousreports
linkingdecreasedNPYsystemactivitytodepression.WhileCeNYP1RmRNAlevelsdidnot
predictCemetabolism,awhole‐brainvoxelwiseanalysisrevealedseveralotherregionswhere
CeNYP1RmRNAexpressiondidpredictmetabolism.Theseregionsincludedthedorsolateral
prefrontalcortex(dlPFC)andperigenualanteriorcingulatecortex,corticalregionsknowntobe
partofthecircuitthatregulatesamygdalaractivity(Davidson,2002;Etkinetal.,2006;Buhleet
al.,2013;Shackmanetal.,2013).ThesedatasuggestthatNPY1RmRNAlevelsintheCemaybe
regulatedbyprefrontalcorticalinputstoNPY1R‐expressingCeneurons.Alternatively,NPY1R‐
expressingCeneuronscouldmodulatemetabolisminthesedistalbrainregionsviadirector
indirectmechanisms.
Livingwithoutanamygdala
Lesionstudiesinhumanandnon‐humanprimatessuggestacausalrolefortheamygdalain
AT.InitialstudiesbyBrown&Schaferdemonstrateddecreasedfearfulnessinmonkeyswith
amygdaladamage(BrownandSchafer,1888).Specificexperimentallesionstotheamygdala
havebeenshowntodecreasethereticencetoactinpotentiallythreateningsituations(Kalinet
al.,2001;MurrayandIzquierdo,2007;MachadoandBachevalier,2008;Chudasamaetal.,2009)
andalterstress‐inducedcortisolrelease(MachadoandBachevalier,2008).Importantly,
amygdalalesionsalsoresultedinlessanxietyinsocialsituationswherehumanATismost
commonlyobserved(Emeryetal.,2001;Machadoetal.,2008).Wenotethatotherstudieshave
usedthehumanintruderparadigmtoassesstheeffectsofamygdalalesionsonbehavior;these
studiesarereviewedinotherchaptersinthisvolume.Alsoreviewedelsewhereinthisvolume
aretheseminalstudiesofpatientS.M.,awomanwithcalcificationoftheamygdalaasaresultof
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Urbach‐Wiethedisease.YearsofclinicalandexperimentalassessmenthavefoundthatS.M.is
moretrustingofandmorelikelytoapproachstrangers(Adolphsetal.,1998),doesnotrecognize
fearinothers(Adolphsetal.,1994),showsa“blindness”forsociallyacceptablephysicalspace
(Kennedyetal.,2009),doesnotreadilylearnnovelPavlovianfearassociations(Becharaetal.,
1995),anddoesnotshowtypicalsignsofanxiety(Feinsteinetal.,2011).Takentogether,these
datasuggestthatSMdisplayslessanxietyinsocialandotherthreateningsituations,andfitwith
datafromadultrhesusmonkeyswithamygdalarlesionsthatdisplayalteredsocialbehavior
(Emeryetal.,2001;Amaral,2002;Machadoetal.,2008).Seealso(Terburgetal.,2012),and
Chapter12inthisvolume,foradifferentinterpretationofthedeficitsassociatedwithhuman
amygdalalesionsresultingfromUrbach‐Wiethedisease.
InaninitialstudyaimedatunderstandingtheroleofamygdalainmonkeyAT,we
lesionedtheentireamygdalawiththeneurotoxinibotenicacid(Kalinetal.,2001).Lesioned
animalsdisplayedlessfear‐relatedbehaviorinthepresenceofalivesnakeornoveladult
conspecific.However,noreductioninfreezingbehaviorwasobservedinresponsetothehuman
intruder.Inhindsight,webelievethatthisnullresultreflectsanunintendedconsequenceofthe
factthatthelesionedmonkeysinthisstudywererepeatedlyexposedtothehumanintruder
paradigmpriortosurgery.Otherworkbyourgroup(Foxetal.,2012)indicatesthatalthough
individualdifferencesinfreezingaremoderatelystable,absolutelevelsoffreezingtendto
decreasewithrepeatedexposuretothehumanintruderparadigm.Thus,itispossiblethatthe
apparentlackofeffectofthelesionsonfreezinginthisexperimentwasduetorepeatedexposure
associatedhabituation.
Alterationsinsleepwerealsoobservedinthemonkeyswithlargeamygdalalesions
(Bencaetal.,2000).Specifically,lesionedandcontrolmonkeyswereadaptedtoEEGrecording
duringtheirnocturnalsleepperiod.Despiteapparentadaptation,thesleeppatternsofcontrol
animalswerepunctuatedbyfrequentarousals.Monkeyswithlargebilaterallesionsofthe
amygdalahadmoresleepandahigherproportionofREMsleepcomparedtocontrolanimals,
suggestingthattheamygdalamaybeimportantinmediatingtheeffectsofstressonsleep.Thisis
interestingconsideringthatanxietyisthepsychiatricsymptommostoftenassociatedwith
insomnia,andthegrowingrecognitionofthatsleepdisturbancesaccompanyalmostallformsof
psychopathology(Bencaetal.,1992).
Inafollow‐uplesionstudywefocusedmorespecificallyontheCe.Inthatstudy,the
monkeyswereintentionallykeptnaïvetothehumanintruderparadigmandwereexposedtoit
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onlyonce,followingrecoveryfromthelesionsurgery(Kalinetal.,2004).Smallselectivelesions
intheCeregionwereproducedtoexaminetheextenttowhichtheCemediatesunconditioned
fear,AT‐relatedbehavioralresponses,andstress‐inducedpituitary‐adrenalactivity(Figure7).
Thereweretwoexperimentalgroups[bilaterallesion(n=9)andunilateral(n=5)Celesions)and
anage‐matchedunoperatedcontrolgroup(n=16).
[insertFigure7here]
TheCelesionssignificantlyaffectedcoovocalizationsandfreezingduration,thetwo
behavioralcomponentsofAT.Comparedwiththeage‐matchedcontrols,cooingwasincreasedin
thebilateral‐lesionandunilateral‐lesiongroups(p<0.04).Thebilateral‐lesiongroupshowed
significantlylessfreezingbehaviorcomparedtotheothergroups(p<0.023).Thebilateral
lesionedanimalsalsodisplayedlessfearwhenexposedtoalivesnake,suggestingthatthese
effectsgeneralizebeyondthehumanintruderparadigm.Decreasesinadrenocorticotropin
releasinghormone(ACTH)andcerebrospinalfluidlevelsofcorticotropinreleasinghormone
(CRH),thetwokeyupstreammediatorsofcortisolreleasewereobserved,andindividual
differencesintheextentofthelesionsignificantlypredictedstress‐relatedcortisollevels(Kalin
etal.,2004).InconjunctionwiththeFDGimagingresults,thesefindingsindicateamechanistic
rolefortheCeinmediatingthebehavioralandpituitary‐adrenalcomponentsofAT,aswellas
otherfear‐relatedbehaviors,earlyinlife.
CorticalandsubcorticalsystemsinteractingwithCeinrelationtoAT
Psychiatricdisorderslikelyreflectalterationsinthecoordinatedactivityofdistributed
functionalcircuits.WhiletheresultsofourFDGandlesionstudiessuggestthattheCeisakey
substrateforstableindividualdifferencesinAT,theydonotdirectlyaddressthelarger
functionalnetworkinwhichtheCeisembedded.Tounderstandthelong‐rangeneuralnetworks
thatmayinteractwiththeCeinrelationtoAT,weusedfMRItoassessfunctionalconnectivityof
theCeregion.Basedonworkdemonstratingtheabilitytoreliablyassessfunctionalconnectivity
inanesthetizedrhesusmonkeys(Vincentetal.,2007),weusedtheCeasaseedregionto
examinetemporalcorrelationsoftheBOLDsignalinasubsetofthemonkeysfromthelarge‐
sampledescribedabove(Oleretal.,2010).Bycombiningdatafrommultiplemodalities(FDG‐
PETandfMRI)wefoundthatgreaterCeglucosemetabolismwasassociatedwithdecreased
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functionalcouplingbetweentheCeanddlPFC,andthatdecreasedfunctionalcouplingbetween
theCeanddlPFCwasalsoassociatedwithhigherlevelsofAT(Birnetal.,2014).DecreasedCe‐
dlPFCconnectivitywasalsoobservedinasampleofpre‐adolescentchildren(ages8‐12)with
anxietydisorders,furthervalidatingthemonkeyATmodel,suggestingaroleforaltereddlPFC‐
amygdalafunctionalcouplinginthepathogenesisofchildhoodanxietydisordersand
demonstratingthatthemodulatoryinfluenceofdlPFConamygdalafunctionisevolutionarily
conserved(Birnetal.,2014).Importantly,themonkeyFDG‐PETdataprovidedevidencethat
elevatedCemetabolismstatisticallymediatestheassociationbetweenCe‐dlPFCconnectivityand
elevatedAT(Birnetal.,2014).Thus,thesefunctionalconnectivitydatasuggestthatcoordinated
activitybetweendlPFCandCeisanimportantmodulatorofindividualdifferencesinthe
expressionofAT.Thishighlightsanimportantbenefitofassessingfunctionalconnectivity,as
findingsarenotconstrainedbydirectneuroanatomicalconnections.Futurestudiesaimedat
directlymodulatingdlPFC‐Cefunctionalconnectivitywouldhelpinfurtherunderstandingthe
roleofdlPFCinregulatingamygdalafunctionandATaswellasinchildrenwithanxiety
disorders.Inthisregard,transcranialmagneticstimulationisanoninvasivestrategythatcould
beusedinbothhumanandnon‐humanprimatestostimulatethedlPFCandexamine
downstreameffectsonamygdalafunctionaswellasonaffectingdlPFC‐amygdalaconnectivity.
Inadditiontotheamygdala,FDG‐PETimagingstudiessuggestthatATreflectsindividual
differencesinanumberofregionsthatincludetheanteriorhippocampus,BST,anterior
temporalcortexandPAG.Thecaudalorbitofrontalcortex(OFC)alsoappearstoplayarole(FDR
q<.05,corrected;unpublishedanalysesofthen=238sampledescribedbyOleretal2010).
Furthermore,aspirationlesionsoftheOFCreducefreezinginresponsetotheNECchallenge
(Kalinetal.,2007).Importantly,whole‐brainFDG‐PETimagingprovidedevidencesuggesting
thatthereductioninfreezingobservedinOFC‐lesionedanimalsreflectsanindirectconsequence
oflesion‐inducedalterationsintheextendedamygdala.Specifically,OFClesionsreducedNEC‐
relatedmetabolismintheBST(Foxetal.,2010).ItisimportanttoemphasizethatwhileOFC
lesionsattenuatefreezinganddecreaseBSTmetabolism,thecorrelationbetweenBSTactivity
andfreezingbehavior,evidentpriortothelesions,remainedsignificantafterthelesions(Foxet
al.,2010).ThissuggeststhatdecreasedfreezingbehaviorinOFClesionedanimalswasdirectly
relatedtodecreasedactivityintheBST,andsupportspreviouslyreportedfindingsthat
individualdifferencesinBSTmetabolicactivityarepredictiveofindividualdifferencesin
freezingand/orATinyoungmonkeys(Kalinetal.,2005;Foxetal.,2008).Thus,futurestudies
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examiningthemechanisticroleofBSTinprimateanxietyshouldemployselectiveBSTlesion
techniquessimilartothosedescribedabove,andinotherchaptersinthisvolume,todissociate
theselectiverolethatthiscomponentoftheextendedamygdalamayplayinnormaland
pathologicalanxiety.
ConcludingRemarksandFutureDirections
ThefunctionalneuroimagingdatainintactanimalsandbehavioraldatafromCe‐lesioned
animalsreviewedaboveextendpriorstudiesonthefunctionoftheCe.First,wedemonstrateda
mechanisticrolefortheCeinthebehavioralandpituitary‐adrenalcomponentsofATusing
selectiveibotenicacidlesions.Then,buildingonearlierstudies,wedemonstratedthatCe
metabolismstronglypredictsindividualdifferencesinAT.Inthislargesample,wedemonstrated
thatpolymorphismsintheCRHreceptorsystemareassociatedwithheightenedanxietyand
elevatedmetabolicactivityintheCeinresponsetopotentialthreat.Inasubsample,wefound
thatmRNAexpressionofneurodevelopment‐relatedgenesisdecreasedintheCeofanxious
monkeys,whichsuggeststhatlearning‐relatedneuroplasticityphenomenaintheamygdalamay
becompromisedinindividualswithextremeanxiousphenotypes.Additionally,weuncovered
evidencesuggestingthatdorsolateralandorbitalregionsofthePFCinfluenceAT‐relatedactivity
withintheextendedamygdala.Takentogether,thesedataindicatearoleforacircuitcenteredon
theextendedamygdala,encompassingtheCeandBST,intheestablishingandmaintaining
normativeandextremeanxietyearlyinlife.
Futurestudiesemployinglesionorreversibleinactivationtechniquesthattargetspecific
neuronalsub‐populationswilllikelydeepenourunderstandingoftheamygdalarmicrocircuits
thatunderlieprimateAT.Furthermore,rapidimmunohistochemicalstainingtoidentifyspecific
cellpopulationsformicro‐dissectionandsubsequentdeepRNAsequencingisapromising
methodforunderstandingthecell‐specificmolecularmechanismsrelatedtoAT.Genedelivery
withviralvectorstoinduceorsuppressexpressionofspecificmoleculesisanothertechnique
withthepotentialtoenrichourunderstandingofprimateamygdalarmicrocircuitfunctionand
theroleoftheextendedamygdalaintemperamentalanxiety.Withtheultimateaimof
developingmoreeffectiveearly‐lifeinterventionstotreatandpreventanxiety‐related
psychopathology,itisourhopethatsuchstudieswillshedlightontheriskforanxiety‐related
psychopathologyaswellasdeepenourunderstandingofamygdalafunctionandnormal
variationintemperament.
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Table1.Parallelsbetweenmonkeyanxioustemperament(AT)andchildhoodbehavioralinhibition(BI).
Phenotypic features AT in Juvenile Monkeys BI in Children
Increased freezing/reduced motor activity/passive
avoidance in the presence of adult strangers
YES (Kalin and Shelton, 1989; Kalin et al., 1998; Fox et al., 2008; Oler et al., 2010; Fox et
al., 2012; Shackman et al., 2013)
YES (Fox et al., 2005; Hirshfeld‐Becker et al., 2008; Degnan et
al., 2010)
Less frequent vocal communication
YES (Kalin and Shelton, 1989; Fox et al., 2008; Oler et al., 2010; Fox et al., 2012; Shackman et al., 2013)
YES (Fox et al., 2005; Hirshfeld‐Becker et al., 2008; Degnan et
al., 2010)
Moderate stability across
time and context
YES (Fox et al., 2008; Fox et al., 2012; Shackman et al., 2013)
YES (Pfeifer et al., 2002; Fox et al., 2005; Hirshfeld‐Becker et al., 2008; Degnan et al., 2010;
Brooker et al., 2013)
Significant functional impairment or distress
Unknown
Variable (Fox et al., 2005; Hirshfeld‐Becker et al., 2008;
Degnan et al., 2010)
Heritable YES (Williamson et al., 2003;
Oler et al., 2010) YES (Rickman and Davidson, 1994; Hirshfeld‐Becker et
al., 2008)
Reduced by anxiolytic administration
YES (Kalin and Shelton, 1989; Davidson et al., 1992; Davidson
et al., 1993)
Unknown
Increased pituitary‐adrenal
activity (cortisol)
Not consistently observed (Kalin et al., 1998; Fox et al., 2008; Oler et al., 2010; Fox et
al., 2012; Shackman et al., 2013)
Not consistently observed (Schmidt et al., 1997; de Haan et al., 1998; Fox et al., 2005)
Right‐lateralized frontal EEG activity
YES (Davidson et al., 1993; Kalin et al., 1998)
YES (Davidson and Rickman, 1999; Buss et al., 2003; Fox et
al., 2005) Increased or sustained
amygdala activity to novelty and potential threat
YES (Fox et al., 2008; Oler et al., 2010; Fox et al., 2012; Shackman et al., 2013)
YES (some data are from retrospective studies in adults)
(Schwartz et al., 2003; Blackford et al., 2011)
Altered functional connectivity between the amygdala and prefrontal
cortex
YES (Birn et al., 2014)
YES (Hardee et al., 2013)
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Figure1
Figure 1. The three experimental conditions of the human intruder paradigm elicit distinct fear‐relatedbehaviors in young rhesus monkeys. When alone and separated from their cagemate (left), youngmonkeysactivelyexplorethetestcageandspontaneouslyemit“coo”calls,thoughttoreflectanattempttoattracthelpfromtheirmothersorotherconspecifics.Inthenextconditionahumanintruderpresentshisor her profile while avoiding direct eye contact with the monkey (NEC, center). In this situation themonkeystypicallyorienttheir focusonthe intruder, tryingtoevadediscoverybyremainingcompletelystill(freezing)orhidingbehindtheirfoodbin(opaqueboxinthecenterpanel).Inthethirdcondition,thehumanintruderenterstheroomandstaresattheanimal(right).Thisdirectthreatconditionoftenelicitsaggressive behaviors (e.g., barking, threatening gestures, cage rattling). This figure was reprintedwithpermission(Kalin,1997).
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Figure2
A. B.
Figure2. (A)AT is calculatedas themeanz‐scoresofNEC‐induced freezing, coovocalizations [reverse‐scored], and plasma cortisol levels. (B) To measure NEC‐induced regional brain metabolism, monkeyswere injectedwith a radiotracer (18‐FDG) immediately prior to exposure of the 30‐minNEC challengedepicted in Figure 1. FollowingNEC exposure themonkeyswere anesthetized, bloodwas collected forcortisol, and the animals were placed in a high‐resolution microPET scanner to measure FDG uptake,integratedacrossthe30‐minNECchallenge.
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Figure3
Figure3.TounderstandtherelationbetweenindividualdifferencesinregionalbrainmetabolismandAT,whole‐brainvoxelwiseregressionanalysiswasperformedin238youngmonkeyswhilecontrollingfornuisanceeffectsofage,sexandvoxelwisegray‐matterprobability.ResultsrevealedapeakFDG‐ATcorrelation in theregionof theCe(significanceofcorrelations:yellow,p<0.05; lightorange,p<0.01;darkorange,P<0.001,adjustedformultiplecomparisonsusingtheŠidákcorrection.)Theareainpinkrepresentsthe95%spatialconfidenceintervalofthepeakFDG‐ATcorrelationintheamygdala.ThisfigurewasadaptedwithpermissionfromOleretal.,2010).
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Figure4
Figure 4.Invivo serotonin transporter (5‐HTT) binding localized the dorsal amygdalacluster to the Ce. (Top) A low‐power photomicrograph of ex vivo 5‐HTTimmunohistochemistry showing substantial immunoreactivity in the lateraldivisionofCe[adaptedwithpermissionfromO'RourkeandFudge(2006)CopyrightElsevier].Highlevels of 5‐HTT are a chemoarchitectonichallmarkof the lateral subdivisionof the Ce(CeL). (Middle)Overlapbetween the amygdala 95%spatial confidence interval of thepeak FDG‐AT correlation (pink) and in vivo 5‐HTT availability (dark blue = 250Xbackground 5‐HTT binding). High 5‐HTT availability was also observed within thesubstantia innominata,which canbe seen just below the anterior commissure,medialanddorsaltotheCeandintheregionofthedorsalraphenucleus(notshown).(Bottom)Magnified coronal view of the overlap between 5‐HTT binding and the FDG‐PETcorrelationasshowninthemiddlepanel.
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Figure5
Figure5.OverlapbetweenregionalmetabolicactivitypredictiveofAT (yellow)andregionsthatare significantly heritable. No significantly heritable voxels were observed in the dorsalamygdalaregion(top),althoughwithinthesameslicesignificantheritabilitywasdetectedinthesuperiortemporalsulcus.(Bottom),Glucosemetabolismwassignificantlyheritableinboththerightandleftanteriorhippocampus,whereitoverlapswiththeleftanteriorhippocampalregionthat correlated with AT (yellow, regions predictive of AT; dark green to light green, falsediscoveryrate:q=0.05,q=0.01,q=0.001).ThisfigurewasadaptedwithpermissionfromOleretal.,(2010).
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Figure6
Figure6.MicroarraydatademonstratedthatindividualswithhigherlevelsofCeNTRK3mRNAexpressionexhibitedlowerAT.(Top)CeregionspredictiveofdispositionalATwereusedtoguideamygdalabiopsyforanalysisofAT‐relatedRNAexpression.Aslicethroughthefunctionallydefinedamygdalaregionjuxtaposedwitharepresentativesingle‐subjectslabinwhichthedorsalamygdalawasbiopsied.(Middle)NTRK3expressionnegativelypredictsCemetabolism.IndividualsshowinghigherlevelsofNTRK3mRNAexpression,indexedbyqRT‐PCR,showreducedCemetabolisminvivo(green)[FDR‐correctedwithinthestableAT‐relatedregion(pink)].(Bottom)Portrayaloftheneuroplasticity‐associated,NTRK3(Trkreceptor,green)pathway.AsimilarpatterninrelationtoATwasfoundforIRS2(orange)andRPS6KA3(pink),twodownstreamtargetsofNTRK3.OthermoleculesintheNTRK3pathwayaredepictedingray.FigurewasadaptedfromFoxetal.,(2012)andreprintedwithpermission.
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Figure7
Example CeA Lesion
Ce LesionGroup
ControlGroup
Stress‐induced plasm
a ACTH
(+/‐ SEM
)*
Cooing Frequency
square‐root transform
ed (+/‐ SEM)
*
Freezing Duratio
n
log transform
ed (+/‐ SEM)
*
Figure7.TheeffectsofCelesionsoncomponentsof AT.Left,arepresentativelesionisdisplayedonfourcoronalsectionsthroughtheanterior–posterior(toptobottom)extentofCe.TheintactCeisdepictedinblue,theareaofthetotallesionisdisplayedinyellow,andtheCeregionthatislesionedisdepictedbytheoverlapingreen.Right,monkeyswithCelesionsdisplayedlessfreezing(top),emittedmorecoocalls(middle),andreleasedlessACTH(bottom)duringexposuretothehumanintruderparadigm.FiguremodifiedfromKalinetal.,(2004)andreprintedwithpermission.
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