The central extended amygdala in fear and anxiety: Closing...

Whenextreme, fear and anxiety can becomedebilitating [1].2. Anxiety disorders impose a staggering burden on public health; they are common, costly, and contribute to the etiology of depression and

substanceabuse[2–4].Existingtreatmentsareinconsistentlyeffectiveorassociatedwithsignificantadverseeffects[5,6],underscoringtheneedtodevelopadeeperunderstandingofthedistributedneuralcircuits

thatcontroltheexpressionoffearandanxiety.Converginglinesofphysiologicalandmechanisticevidenceindicatethatthecentralextendedamygdala—includingthecentralnucleusoftheamygdala(Ce)andbed

nucleusofthestriaterminalis(BST)—isakeyhubinthiscircuitryandmotivatesthehypothesisthatlocalalterationsinthecentralextendedamygdalacandrivechangesinremoteregionsofthebraininwaysthat

promotethedevelopmentandmaintenanceofanxiety,mood,andsubstanceusedisorders[7–13](Fig.1).

Reviewarticle

Thecentralextendedamygdalainfearandanxiety:Closingthegapbetweenmechanisticandneuroimagingresearch

AndrewS.Foxa,b,⁎⁎,1

dfox@ucdavis.edu

AlexanderJ.Shackmanc,d,e,⁎,1

shackman@umd.edu

aDepartmentofPsychologyandUniversityofCalifornia,Davis,CA95616,UnitedStates

bCaliforniaNationalPrimateResearchCenter,UniversityofCalifornia,Davis,CA95616,UnitedStates

cDepartmentofPsychology,UniversityofMaryland,CollegePark,MD20742,UnitedStates

dNeuroscienceandCognitiveScienceProgram,UniversityofMaryland,CollegePark,MD20742,UnitedStates

eMarylandNeuroimagingCenter,UniversityofMaryland,CollegePark,MD20742,UnitedStates

⁎Correspondingauthorsat:DepartmentofPsychology,UniversityofMaryland,CollegePark,MD20742,UnitedStates.

⁎⁎Correspondingauthorsat:DepartmentofPsychologyand,UniversityofCalifornia,Davis,CA95616,UnitedStates.

1TheseAuthorscontributedequallytothiswork;theorderofauthorswasdeterminedbyacoinflip.

Abstract

Anxietydisordersimposeastaggeringburdenonpublichealth,underscoringtheneedtodevelopadeeperunderstandingofthedistributedneuralcircuitsunderlyingextremefearandanxiety.Recentworkhighlights

theimportanceofthecentralextendedamygdala,includingthecentralnucleusoftheamygdala(Ce)andneighboringbednucleusofthestriaterminalis(BST).AnatomicaldataindicatethattheCeandBSTformatightly

interconnectedunit,wheredifferentkindsof threat-relevant informationcanbe integrated toassemble statesof fearandanxiety.Neuroimaging studies show that theCeandBSTareengagedbyabroad spectrumof

potentiallythreat-relevantcues.Likewise,mMechanisticworkdemonstratesthattheCeandBSTarecriticallyinvolvedinorganizingdefensiveresponsestoawiderangeofthreats.Studiesinrodentshavebeguntoreveal

thespecificmolecules,cells,andmicrocircuitswithinthecentralextendedamygdalathatunderliesignsoffearandanxiety,buttherelevanceofthesetantalizingdiscoveriestohumanexperienceanddiseaseremainsunclear.

Usinga combinationof focalperturbationsandwhole-brain imaging, anewgenerationofnonhumanprimate studies isbeginning to close thisgap.Thisworkopens thedoor todiscovering themechanismsunderlying

neuroimagingmeasures linked topathological fearandanxiety, tounderstandinghowtheCeandBST interactwithoneanotherandwithdistalbrain regions togoverndefensive responses to threat,and todeveloping

improvedinterventionstrategies.

Keywords:Affectiveneuroscience;Anxietydisorders;Bst/bnstBST/BNST (Theseareacronyms:Itshouldbe'BST/BNST');Emotion;Individualdifferences;Neuroimaging;Nonhumanprimate

Here,weprovideanupdatedmini-reviewofthecontributionsoftheCeandtheBSTtofearandanxiety,focusingmostheavilyonstudiesinofhumansandnonhumanprimates(forotherrecentreviews,see

[16,17,10,18,19]. This emphasis reflects the fact that anxietydisorders aredefinedanddiagnosedon thebasis of subjective symptomsandhuman studies are essential for understanding theneuralmechanisms

supportingtheexperienceoffearandanxiety (Pleaseaddthefollowing2references:Pine,D.S.,&LeDoux,J.E.(2017).Elevatingtheroleofsubjectiveexperienceintheclinic:ResponsetoFanselowandPennington.AmericanJournalofPsychiatry,

174,1121-1122.||Zoellner,L.A.,&Foa,E.B.(2016).ApplyingResearchDomainCriteria(RDoC)tothestudyoffearandanxiety:Acriticalcomment.Psychophysiology,53,332-335.).Humanstudiesarealsocrucialforidentifyingthefeaturesof

animalmodelsthatareconservedand,hence,mostrelevanttounderstandinghumandiseaseandtodevelopingimprovedinterventionsforhumansuffering('forwardtranslation;'[20,21].Finally,humanstudiesafford

importantopportunitiesfordevelopingobjectivebiomarkersofdiseaseordiseaserisk[22]—acceleratingthedevelopmentofnewdiagnosticandtreatmentstrategies[23–25]—andforgeneratingnovelhypothesesthat

canbemechanisticallyassessedinanimalmodels('reversetranslation;'[26].Workinmonkeyscanbeconceptualizedasabridge,onethatlinkstheprecisemechanisticstudiesthatcanmostreadilybeperformedin

rodentstothecomplexitiesofhumanfeelingsandhumandisease.Thebrainsofmonkeysandhumansaregenetically,anatomically,andfunctionallysimilar,reflectingthetwospeciesrelativelyrecentevolutionary

divergence(25millionyearsagoformonkeysvs.70millionyearsagoforrodents;[27–30].Homologousbiologicalsubstrates,includingawell-developedprefrontalcortex(PFC),endowmonkeysandhumanswitha

sharedrepertoireofcomplexsocio-emotionalresponsestopotentialthreat[7,31],increasingthelikelihoodofsuccessfultranslationtohumandisease[32,33].

1AnatomyoftheCentralExtendedAcentralextendedamygdalaTheextendedamygdalaencompassesaheterogeneouscollectionofsubcorticalnucleialongthebordersoftheamygdalaandtheventralstriatum.Classicalstudiesofstructuralconnectivityfirstsuggestedthatthecentral

divisionoftheextendedamygdala—includingtheCe,lateralBST(BSTL),andportionsofthesublenticularextendedamygdala(SLEA;aneuronalbridgenestledwithinthesubstantiainnominata)—representsanintegrativeunit[34].

Indeed,ithaslongbeenrecognizedthattheamygdalaisconnectedtotheBSTviatwomajorfiberbundles:theventralamygdalofugalpathway(VA;sometimestermedtheansapeduncularis)andthestriaterminalis(ST)[35](Fig.2a).

MorerecentstudiesinmonkeyshaveconfirmedthattheCeandBSTLarestructurallyinterconnectedviathesetwodirectpathways(primarilyCe→BSTL)andhaveidentifiedanovelindirectpathwaycenteredontheSLEA(Ce↔

SLEA↔BSTL)[40,41] (Pleaseadd:Fudge,J.L.,Kelly,E.A.,Pal,R.,Bedont,J.L.,Park,L.,&Ho,B.(2017).BeyondtheclassicVTA:ExtendedamygdalaprojectionstoDA-striatalpathsintheprimate.Neuropsychopharmacology,42,1563-1576.

).Inparallel,magneticresonanceimaging(MRI)studieshaverevealedevidenceofbothstructural[42–44]andfunctionalconnectivitybetweentheCeandBST[42,20];Gorkaetal.,inpress;[46,41,47,48],reinforcingthehypothesis

thattheyrepresentafunctionallymeaningfulcircuit[34,8].

Fig.1Thecentralextendedamygdalahelpsorganizedefensiveresponsestothreat.Simplifiedschematicofkeyinputsandoutputstothecentralextendedamygdala(magenta)inhumansandotherprimates.Thecentralextendedamygdalaencompassesthe

centralnucleusoftheamygdala(Ce),whichliesinthedorsalamygdala,andthebednucleusofthestriaterminalis(BST),whichwrapsaroundtheanteriorcommissure.Asshownbythetranslucentwhitearrowatthecenterofthefigure,muchofthesensory

(yellow),contextual(blue),andregulatory(green)inputstothecentralextendedamygdalaareindirect(i.e.,poly-synaptic),andoftenfirstpassthroughadjacentamygdalanucleibeforearrivingattheCeorBST.Inprimates,projectionslinkingtheCewith

theBSTarepredominantlyfromtheCetotheBST.TheCeandBSTarebothpoisedtoorchestrateortriggermomentarynegativeaffectviaprojectionstodownstreamtargetregions(orange),suchastheperiaqueductalgrey(PAG).Inset:Coronalslices

depictingtherelativelocationsoftheCeandtheBST(magenta).Portionsofthisfigurewereadaptedwithpermissionfrom[14].TheCeandBSTregionsdepictedintheinsetisaredescribedin[]and ([47]R.M.Tillman,M.D.Stockbridge,B.M.Nacewicz,S.

Torrisi,A.S.Fox,J.F.SmithandA.J.Shackman,Intrinsicfunctionalconnectivityofthecentralextendedamygdala,bioRxiv2017.)[15].,respectivelyTheCeregiondepictedintheinsetwaskindlyprovidedbyDr.BrendonNacewicz.Abbreviations:Basolateral(BL),

Basomedial(BM),Central(Ce),Lateral(La),andMedial(Me)nucleioftheamygdala;Bednucleusofthestriaterminalis(BST).

alt-text:Fig.1

Fromananatomicalperspective,thecentralextendedamygdalaispoisedtointegratepotentiallythreat-relevantinformationandassemblestatesoffearandanxiety.Invasivetracingstudiesinrodentsandmonkeysshowthat

theCeandtheBSTreceivedirectandindirectprojectionsfrombrainregionsthatencodesensory,contextual,andregulatoryinformation[49](Fig.1).Bothregionsarepoisedtotriggersomatomotorandneuroendocrinesignsoffear

andanxietyviadensemono-andpoly-synapticprojectionstobrainstemandsubcorticaleffectorregions[9,49] (pleaseadd:Fudge,J.L.,Kelly,E.A.,Pal,R.,Bedont,J.L.,Park,L.,&Ho,B.(2017).BeyondtheclassicVTA:ExtendedamygdalaprojectionstoDA-striatalpathsintheprimate.Neuropsychopharmacology,42,1563-1576.)(Fig.1).Leveragingtheincreasedanatomicalresolutionaffordedbyultra-highfieldstrengthfunctionalMRI(7Tesla),humanstudiesindicatethatmanyofthesedownstreamregionsshowrobustfunctionalconnectivitywiththeCe

andtheBSTGorkaetal.,inpress;[48].OtherworkshowsthattheCeandBSTcontaincellswithsimilararchitectonicandneurochemicalfeaturesandthatthetworegionsshowsimilarpatternsofgeneexpression(foradetailed

Fig.2Imagingthecentralextendedamydalainnonhumanprimatesandhumans.(A)Diffusiontensorimaging(DTI).DeterministicDTIrevealstheevolutionarilyconservedwhitematterpathways(yellow)thatlinktheCe(magenta)totheBST(magenta)in

monkeys(left)andhumans(right).ImageskindlyprovidedbyDoTromp.(B)Functionalneuroimagingoffearandanxiety.Inmonkeys(left),metabolicactivityintheCeandtheBST(magentaarrows)isassociatedwithheightenedbehavioralandneuroendocrine

responsesduringprolonged(30min)exposuretoapotentiallythreateninghumanintruder’sprofile(n=592).Likewise,anautomatedmetameta-analysisofhumanimagingstudies(right)revealsactivationintheBSTandtheCeduringstudiesof‘fear’and/or

‘anxiety.’Figuredepictstheminimumconjunction(logical‘AND’)ofthresholdedforward-inferencemaps(q<0.01)automaticallygeneratedusingNeurosynth[36]forstudiestaggedwiththekeywords‘fear’(298studies)and/or‘anxiety’(312studies).Given

thestrengthsandlimitationsofautomatedmetameta-an (metashouldnotbeitalicized)alysis; (pleaseinsertthefollowing3referencesjustpriortothesemi-colon:Muller,V.I.,Cieslik,E.C.,Laird,A.R.,Fox,P.T.,Radua,J.,Mataix-Cols,D.,...Eickhoff,S.B.(inpress).Tensimplerulesforneuroimagingmeta-analysis.NeuroscienceandBiobehavioralReviews.|||Salimi-Khorshidi,G.,Smith,S.M.,Keltner,J.R.,Wager,T.D.,&Nichols,T.E.(2009).Meta-analysisofneuroimagingdata:acomparisonofimage-basedandcoordinate-basedpoolingofstudies.Neuroimage,45,810-823.|||Wager,T.D.,Atlas,L.Y.,Botvinick,M.M.,Chang,L.J.,Coghill,R.C.,Davis,K.D.,...Yarkoni,T.(2016).PainintheACC?ProceedingsoftheNationalAcademyofSciencesoftheUnitedStatesofAmerica,113,E2474-2475.)thisfindingsimply

indicatesthattheseregionsareroutinelyrecruitedbyavarietyofpotentiallythreat-relevantcues.Itdoesnotindicatethattheseregionsareconsistentlyco-activatedinparticularstudiesanditdoesnotimplythattheseregionsaresimilarlyresponsiveto

particularkindsofthreat(e.g.;uncertainordiffusedanger).(C)TheCeandtheBSTshowphasicandsustainedresponsestopotentiallythreat-relatedcuesinhumanimagingstudies.Left:TheBSTandneighboringregions(whitering)showsustained(<118-s)

activationduringtheuncertainanticipationofaversiveimages.Middle:TheCeshowssustainedactivation(30-s)duringexposuretoavirtualrealitycontextpairedwithunpredictableelectricshock.Right:TheCeandtheBST(blackarrows)bothshowphasic

responsestovideoclipsofanapproachingtarantula(4-s).Portionsofthisfigurewereadaptedwithpermissionfrom[37,8,9,38,12,13,39].

alt-text:Fig.2

review,see[8] (thereshouldbeaparenthesisafterthereference:[8])).Collectively,theseanatomicalobservationssuggestthattheCeandtheBSTrepresentanevolutionarilyconserved,functionallycoherentcircuitthatispoisedtouse

informationaboutthreat,context,andinternalstatestoinitiatearangeofdefensiveresponses.

2PhysiologyoftheCentralExtendedAcentralextendedamygdalaStudiesofnonhumanprimatesaffordanimportantopportunitytoobtainconcurrentmeasuresofnaturalisticdefensivebehaviors,neuroendocrineactivity,andbrainmetabolisminresponsetoarangeofethologicallyrelevant

threats,includingexplicitcues(i.e.,anunfamiliarhumanintruder’sprofile)andmorediffusecontexts(i.e.,anoveltestingcage)[7,10,31].Usingacombinationof18-fluorodeoxyglucose-positronemissiontomography(FDG-PET)and

well-establishedbehavioralassays,wehavedemonstratedthattheCeandBSTareexquisitelysensitivetopotentialdanger.Instudiesincludingbetween238and592monkeys,elevatedlevelsofmetabolicactivityintheCeandBST

areassociatedwithheightenedsignsoffearandanxiety(e.g.,freezing,cortisol)duringsustained(30-min)exposuretointruderthreat[9,50](Fig.2b).HeightenedmetabolicactivityintheCeandBSTisalsoassociatedwithelevated

defensiveresponsesduringsustainedexposuretoanunfamiliartestingcage(i.e.,intheabsenceofintruderthreat;[51,52].

Consistentwithworkinmonkeys,imagingresearchinhumanssuggeststhattheCeandBSTarebothengagedbyabroadrangeofthreat-relatedcuesandcontexts.Theamygdalarespondstoavarietyofthreat-relatedstimuli

[53–57]3andworkusinghigh-resolutionfMRIindicatesthatthedorsalregionoftheamygdalainthevicinityregionoftheCeisparticularlysensitivetoaversivevisualstimuli[58].Increasedactivationinthedorsalamygdalais,inturn,

associatedwithelevatedsignsandsymptomsofarousalinresponsetoacutethreat(e.g.,Pavlovianthreatcues;[59–65].Likewise,multi-voxelclassifieranalysessuggestthatthedorsalamygdalaisanimportantcomponentofalarger

circuitthatunderliesnegativeaffectelicitedbyaversiveimages[66].

LiketheCe,theBSTisrecruitedbyavarietyofpotentiallythreat-relevantcuesinhumans,includingemotionalfacesSladkyetal., inpress).Infact,asshowninFig.2banddescribed inmoredetail intheaccompanying

caption,anautomatedmetameta ('meta'shouldNOTbecapitalized)-analysisgeneratedusingNeurosynth[36]revealsthatstudiestaggedwiththekeywords‘fear’and/or‘anxiety’consistentlyrevealactivationinthevicinityoftheCeand

theBST, although the latter region is rarely labeled as such for a variety of reasons (e.g., omission fromautomated anatomical labeling tools; [8,9,19] (There is an extra reference inserted here. The 2015PNASpaper shouldNOTbe

included).4.LiketheCe,BSTactivationandfunctionalconnectivityco-varywiththreat-elicitedchangesinperipheralphysiologyandself-reportedfearandanxiety[68–70,39].

Amongresearchersfocusedonhumans,itiswidelybelievedthattheCeandBSTarefunctionallydissociable(forcriticalreviews,see[19,13].Inspiredbyanearliergenerationoflesionandinactivationstudiesinrodents[71],

thishypothesissuggeststhattheCe,ortheamygdalamoregenerally,rapidlyassemblesphasicresponsestoclear-and-immediatethreats(e.g.,acueassociatedwiththeimminentdeliveryofshock),whereastheBSTcomeson-line

moreslowlyandisresponsiblefororchestratingsustainedresponsestodangersthatarediffuse,uncertain,orremote.Thishypothesishasbeenadoptedwithminormodificationsbymanyinvestigatorsandcommentatorsandhaseven

beenincorporatedintotheNationalInstituteofMentalHealth(NIMH)ResearchDomainCriteria(RDoC)asAcuteThreat(‘Fear’)andPotentialThreat(‘Anxiety’) (https://www.nimh.nih.gov/research-priorities/rdoc/constructs/acute-

threat-fear.shtml;https://www.nimh.nih.gov/research-priorities/rdoc/constructs/potential-threat-anxiety.shtml;https://www.nimh.nih.gov/research-priorities/rdoc/negative-valence-systems-workshop-proceedings.shtml). (spaces should beinsertedaftereachofthesemi-colons)

Consistentwiththe‘double-dissociation’or‘strict-segregation’model,severalhumanimagingstudieshavedemonstratedthattheBSTshowspersistenthemodynamicresponsesduringtheuncertainanticipationofnoxious

stimuli,suchasshockoraversiveimages,whereasthedorsalamygdalashowstransientresponsesthataretime-lockedtotheonsetofthethreat-anticipationperiodortheactualdeliveryofthenoxiousstimulus7[72–75];Klumperset

al.,inpress (Klumpers,F.,Kroes,M.C.W.,Baas,J.,&Fernandez,G.(2017).Howhumanamygdalaandbednucleusofthestriaterminalismaydrivedistinctdefensiveresponses.JournalofNeuroscience,37,9645-9656.);[70,39].Inoneofthemore

compellingexamples,Somervilleandcolleaguespresentedeitheraversiveorneutralimages(3-secs)inrelativelylongblocks(118-secs)wherethetimingofimagepresentationswaseithercertainoruncertain(Fig.2c).Theseunique

designfeaturesareimportantbecausetheyaffordacrucialopportunitytodouble-dissociatephasic(to3-secscertainthreat)fromsustained(i.e.,to118-secsuncertainthreat)responsesinthesameindividuals.Analysesrevealed

transientactivationintheamygdalainresponsetothenegativeimages.Incontrast,theBSTshowedpersistentactivationfornegative-vs.-neutralblocksandforuncertain-vs.-certainblocks.Moreover,thelevelofsustainedactivation

intheBSTcloselytrackedmeandifferencesinself-reportedfearandanxietyacrossthefourblockedconditions(i.e.,uncertain-negative>certain-negative>uncertain-neutral>certain-neutral).Despitesomeimportantlimitations

(e.g.,perceptualconfounds,failingtotesttheRegion×Conditioninteraction),theseresultsareoftentakenasstrongsupportforthe‘strict-segregation’model.

Ontheotherhand,agrowingnumberofimagingstudiesaredifficulttoreconcilewiththehypothesisofstrictfunctionalsegregationbasedonthreatuncertaintyorduration(Fig.2c).Severalstudieshavereportedincreased

amygdalaactivationduringtheanticipationofuncertainthreat,bothinchildren[77]andinadults[37,78].Forexample,Andreattaandcolleaguesobservedsustainedactivation—confirmedusingafiniteimpulseresponseapproach—in

theregionof therightCeduringexposuretoavirtual-realitycontext (30-secs)pairedwithunpredictableelectricshocks.Leveragingagame-like ‘virtualpredator’paradigm,Mobbsandcolleaguesobserved significantlygreater

activationinthedorsalamygdalawhenthepredatorwasfirstencounteredandpresentednoimmediatedanger,relativetoasubsequentperiodwhenshockdeliverywasimminentandsignsandsymptomsoffearandanxietywere

maximal[79],whichrunscounter to the idea that thattheamygdala isprimarilyresponsible fororganizing transientresponses to immediateacutedanger.Herryandcolleaguesobservedpersistentlyelevatedamygdalaactivity in

humans(60-s)andmice(120-s)exposedtoatemporallyunpredictable,anxiogenictrainofauditorystimuli[]. (Herry,C.,Bach,D.R.,Esposito,F.,DiSalle,F.,Perrig,W.J.,Scheffler,K.,...Seifritz,E.(2007).Processingoftemporalunpredictability

inhumanandanimalamygdala.JournalofNeuroscience,27,5958-5966.)Other (pleaseinsertanewparagraphbreakhere,justbeforetheword'Other')workhasrevealedphasicresponsesintheregionoftheBSTtobriefthreats,suchasa4-secsvideoclipofanapproachingtarantula[80,74,38,81].Likewise,

Brinkmann and colleagues very recently demonstrated that the CeBST and the BSTCe show statistically indistinguishable responses to briefly presented (800 ms) aversive images Brinkmann et al., under review/personal

communication7/20/2017 (Brinkmann,L.,Buff,C.,Feldker,K.,Neumeister,P.,Heitmann,C.Y.,Hofmann,D., . . .Straube,T. (2018). Inter-individualdifferences in traitanxietyshapethe functionalconnectivitybetweenthebednucleusof thestria

terminalisandtheamygdaladuringbriefthreatprocessing.Neuroimage,166,110-116.)).Thelatterresultisparticularlycompellinggiventherelativelylargesample(n=93)andformaltestoftheRegion×Conditioninteraction.Itimplies

that themagnitudeofregionaldifferences (i.e.,Cevs.BST) ismuchsmaller than impliedbythestrictsegregationhypothesis,conditionalonunknownmoderators,or issimplynon-existent,at least forbrieflypresentedaversive

images.Another,relativelylargeimagingstudy(n=168)reportedphasicactivationoftheBSTinresponseto4-secsshock-predictivecues[83],indicatingthattheBSTissensitivetocertainthreat.Otherrecentworksuggeststhatthe

BSTismaximallyengagedwhenshock-threat ispsychologically imminent [84].These imagingobservationsarebroadlyconsistentwithevidence fromrecordingand loss-of-functionstudies in rodents indicating thata substantial

proportionofBSTneuronsexhibitshort-latencyresponsesduringexposuretobothacutethreat(e.g.,foot-ortail-shock)anddiffuselythreateningenvironments[85,17,86].

Onbalance, thebrain imaging literaturesuggests that theCeandBST,whilecertainlynot interchangeable,aremorealike thandifferent. Inaddition to theanatomical similaritiesdescribed in theprevioussection (e.g.,

connectivity,geneexpression),bothregionsrespond toabroadspectrumof threat-relatedcuesandcontextsandbotharecorrelatedwithconcurrentchanges inphysiologyandsubjectiveexperience.Variation in thestrengthof

functionalconnectivitybetween the tworegionshasbeenassociatedwith individualdifferences indispositionalanxiety inhumans []andmonkeys [Fox,Oler,Birn,Shackman,Alexander&Kalin,unpublishedobservations]. (the 1streference[]is:Brinkmann,L.,Buff,C.,Feldker,K.,Neumeister,P.,Heitmann,C.Y.,Hofmann,D.,...Straube,T.(2018).Inter-individualdifferencesintraitanxietyshapethefunctionalconnectivitybetweenthebednucleusofthestriaterminalisandtheamygdaladuringbriefthreatprocessing.Neuroimage,166,110-116.)Inhumans,theCeandtheBSTbothshowtransientresponsestoclear-and-immediatethreatandsustainedactivationincontextsassociatedwithuncertain,longer-lastingthreat.Both

regionsshowheightenedactivationinpatientswithanxietydisordersandindividualsatriskfordevelopingsuchdisordersBrinkmannetal.,inpress; (Brinkmann,L.,Buff,C.,Feldker,K.,Tupak,S.V.,Becker,M.P. I.,Herrmann,M.J.,&

Straube,T.(2017).Distinctphasicandsustainedbrainresponsesandconnectivityofamygdalaandbednucleusofthestriaterminalisduringthreatanticipationinpanicdisorder.PsychologicalMedicine,47,2675-2688.)[73];Buffetal.,inpress (Buff,C.,Brinkmann,L.,Bruchmann,M.,Becker,M.P.I.,Tupaka,S.,Herrmann,M.J.,&Straube,T.(2017).ActivityalterationsinthebednucleusofthestriaterminalisandamygdaladuringthreatanticipationinGeneralizedAnxietyDisorder.SocialCognitiveandAffectiveNeuroscience, 12, 1766-1774.); [89,90,12,91–93], although the studies to date have been small in size, have frequently relied on data acquisition and processing techniques that are less than optimal for resolving subtle

differencesinregionalfunction(e.g.,linearspatialnormalizationalgorithms,largesmoothingkernels),andprospectivelongitudinaldataaremostlylacking.Inmonkeys,individualsexpressingmoreintensesignsoffearandanxiety

show increasedFDGmetabolism in theCe andBSTduring sustained exposure to novel contexts andpotential threat. AlthoughFDG-PET lacks the temporal resolution needed to cleanly dissociate phasic from sustainedneural

responses,workinmonkeyshintsatsomepotentialdifferencesbetweenthetworegions—activityintheBSTisassociatedwithheritableindividualdifferencesinfearandanxiety2[8,9]andtheBSTappearstobeinvolvedinorganizing

persistentlyelevatedsignsoffearandanxietyfollowingthreatexposure(i.e.,mood‘spillover;'[94].Nevertheless,thecriticaltestsofregionaldifferenceshaveyettobeperformedinmonkeys(e.g.,Region×Condition;Foxetal.,in

press (Fox,A.S.,Lapate,R.C.,Davidson,R.J.,&Shackman,A.J.(2018).Thenatureofemotion:Aresearchagendaforthe21stcentury.InA.S.Fox,R.C.Lapate,A.J.Shackman,&R.J.Davidson(Eds.),Thenatureofemotion.Fundamentalquestions(2nd

ed.).NewYork:OxfordUniversityPress.);[19].Theupshotofthisworkisthattheavailableimagingliteratureprovides,atbest,mixedevidenceforclaims—includingthoseembodiedinRDoC—ofstrictfunctionalsegregationbetweenthe

CeandtheBSTonthebasisofthreatuncertaintyorduration(i.e.,‘theCemediatesphasicresponsestoclear-and-imminentdanger;theBSTmediatessustainedresponsestouncertainthreat’)—aconclusionthatechoesthatreached

byGungorandParéonthebasisofmechanisticworkinrodents[86].

Understandingtheneurobiologyofhumanfearandanxietyisimportant,bothconceptuallyandclinically.AsreviewedelsewhereFoxetal.,inpress (Fox,A.S.,Lapate,R.C.,Davidson,R.J.,&Shackman,A.J.(2018).Thenatureof

emotion:Aresearchagendaforthe21stcentury.InA.S.Fox,R.C.Lapate,A.J.Shackman,&R.J.Davidson(Eds.),Thenatureofemotion.Fundamentalquestions(2nded.).NewYork:OxfordUniversityPress.);[8,9,19],drawingstronginferenceabout

theneuralcircuitssupportingphasicandsustainedresponsestodifferentdimensionsofthreatrequirestheuseofwell-matchedtasks.Parametricmanipulationsofthreatprobability(ifthreatwilloccur),imminence(whenorwhereit

willoccur),andduration(asin[96,84,79,97,38]wouldbeparticularlyuseful.Theuseofdynamicparametrictasks(e.g.,wherethreatimminenceorprobabilityissmoothlyandcontinuouslyvaried)wouldalsoaffordpowerfulnew

opportunitiesforunderstandingthekindsofuncertaintymostrelevanttofearandanxietyandforidentifyingcircuitsinvolvedintriggeringbehavioralandphysiological‘phasetransitions’(e.g.,fromvigilancetobehavioralinhibitionto

activedefense;[98];[99].PutativedoubledissociationsneedtoberigorouslyassessedusingtheappropriateRegion×Conditioninteraction(asin[73,100],preferablyinadequatelypoweredsamples[101–103].Absentthat,claimsof

anatomicaldissociationareunwarranted.Likewise,concludingthataparticularbrainregionis‘notinvolved’inacomplex,multidimensionalpsychologicalfunction,like‘fear’or‘anxiety,’basedonanullstatisticaltestorasingleassay

isunwarranted.Givenmountingevidencethatfearandanxiety,likeotheremotions,reflectwidelydistributedneuralcircuits(e.g (Theother'uncited'referenceissupposedtobeincludedinthisblockofreferences:Shackman,A.J.,Fox,A.S.,&

Seminowicz,D.A.(2015).Thecognitive-emotionalbrain:Opportunitiesandchallengesforunderstandingneuropsychiatricdisorders.BehavioralandBrainSciences,38,e86.).,[104];NummenmaaandSaarimakiinpress;[106];ShackmanandFox,

inpress (Shackman,A.J.,&Fox,A.S.(2018).Howareemotionsorganizedinthebrain?InA.S.Fox,R.C.Lapate,A.J.Shackman,&R.J.Davidson(Eds.),Thenatureofemotion.Fundamentalquestions(2nded.).NewYork,NY:OxfordUniversityPress.);

[108],oneofthemostimportantchallengesforfutureresearchwillbetoextendmodelsoffearandanxietytoencompassinteractionsbetweenthecentralextendedamygdalaanddistalregionsofthebrain,apointthatwediscussin

moredetailinthefinalsection.

3MechanisticStudiesoftheCentralExtendedAstudiesofthecentralextendedamygdalaThere is ample evidence that that theCe and theBST are critical for assembling states of fear and anxiety. Summarizing the data available nearly a decade ago, just prior to thewidespread adoption of high-precision

optogeneticandchemogenetictechniques,Davisandcolleaguesoutlineda‘partial-dissociation’model,hypothesizingthattheCeplaysacriticalroleinorganizingbothimmediateandlonger-lastingresponsestothreat[85].Thismodel

suggeststhatphasicresponsesaremediatedbycircuitscoursingfromthebasolateralamygdala(BL)tothemedialdivisionoftheCe(CeM)andfromtheretodownstreameffectorregions.Incontrast,responsestomorepersistent

kindsofdanger—thosethatareuncertain,psychologicallydiffuse,orremoteintimeintimeorspace—werethoughttobemediatedbycircuitspassingfromthelateraldivisionoftheCe(CeL)tothelateraldivisionoftheBST(BSTL)

and,ultimately,toeffectorregions.

Morerecentworkinrodentmodelshasrefinedourunderstandingofthebrainbasesoffearandanxiety(e.g.,[109,110],whilehighlightingtheanatomicalandfunctionalcomplexityofthecentralextendedamygdala(e.g.,

[111,86,112,113]. Ithasbecomeabundantlyclear that theCeand theBST, likemanyotherbrain regions,harboravarietyofdistinctcell ‘types’—groupsofneurons that canbedistinguishedbasedonproteinexpression, firing

characteristics,connectivity,andotherfeatures—andthatdifferentcelltypeswithinthesameregionofthecentralextendedamygdala(e.g.,Ce)arefunctionallydissociable(e.g.,[112,113].Someoftheseneuronsareresponse-specific,

whileothersarethreat-specific.Forexample,PAG-projectingcellsintheCeMtriggerfreezing,whereasanindependent,butanatomicallyintermingled,setofmedulla-projectingneuronstriggerchangesincardiovascularactivity[113].

These response-specificneuronscanbeactivatedbydifferent threat-specificneurons.Forexample, serotonin receptor2a-expressingneurons in theCeLplayakey role in regulating thecompetitionbetween innateand learned

defensiveresponses:amplifyingfreezingelicitedbysustainedexposure(10-min)toinnatethreat(i.e.anodorderivedfromfoxfeces)andattenuatingfreezingtolearnedthreat(i.e.,aneutralodorassociatedwithfoot-shock)[114].

Thesekindsofobservationsunderscoretheconceptualimportanceofunderstandinghowdifferentcelltypesinthecentralextendedamygdalacontributetofearfulandanxietyousstatesandtraits.

Despitethiscomplexity,mechanisticworkinrodentsreinforcesthegeneralconclusionthatthemicrocircuitsresponsibleforassemblingphasicandsustainedresponsestothreatoverlapinthecentralextendedamygdala3

[115,86,116].Forexample,theCeandtheBSThavearebothbeenshowntobeimportantforassemblingsustainedresponsestodiffusethreat10(e.g.,[117–121,112];Mazzoneetal.,inpress;[123–125].ProjectionsfromtheBLtothe

Ceexertbi-directionalcontroloverdefensiveresponsestotheelevated-plusmaze(EPM)andopen-fieldtest,whichcanbeconsidereddiffuselythreateningcontexts[126];chemicalinactivationoftheCereducesdefensiveresponsesto

theelevated-plusmaze [127];andCRF-expressingneurons in theCemodulateconditioned freezing to threateningcontextsand longer-lasting (30-s) threatcuesAsoket al., inpress;[129].With regard to theBST, serotonergic

projectionsfromthedorsalraphetotheBSTmodulatetherecallofconditioneddefensiveresponsestobothcontextualandcuedthreats[130].Moreover,wWorkusingtemporallyunpredictableshockparadigmsdemonstratesthat

cannabinoidprojectionsfromtheBLandtheCetotheBSTarenecessaryforsustaineddefensiveresponsesinresponsetouncertaindanger[131].Thisobservation,whichharnessesataskadaptedfromthatofdevelopedbyDavis,

Walker,andcolleagues[132–134],providesimportantevidencethattheBL,Ce,andBSTallplayaroleinrespondingtouncertainordiffusethreat,consistentwithotherrecentwork(e.g.,[135–137].Whileourunderstandingremains

farfromcomplete,takentogether,theseobservationsshowthatspecificmicrocircuitswithinandbetweentheCeandtheBSTareimportantfororchestratingdefensiveresponsestoavarietyofthreats.

AlthoughthecausalcontributionoftheBSTtofearandanxietyhasyettobeexploredinhumansorotherprimates,monkeyswithfiber-sparingexcitotoxiclesionsoftheCeshowamarkedreductionindefensivebehaviorsand

endocrineactivityduringsustainedexposuretohumanintruderthreatandduringacuteexposuretoalivesnake[10,138,31].Likewise,humanswithamygdaladamageexhibitaprofoundlackoffearandanxietyinresponsetoboth

diffuselythreateningcontexts(e.g.,walkingthroughahauntedhouse,foraginginthepresenceofuncertainthreat)andacutethreat(e.g.,spiders,snakes,conditionedthreatcues)[139–141] (Areferenceismissingandshouldbeadded.

Thisisoneofthe'uncitedreferences'identifiedbythecopyeditor.Feinstein,J.S.,Adolphs,R.,&Tranel,D.(2016).AtaleofsurvivalfromtheworldofPatientS.M.InD.G.Amaral&R.Adolphs(Eds.),Livingwithoutanamygdala.NewYork:Guilford.).A

majorcaveatisthatsuchdeficitsmayreflectdamagetoaxonalfiberspassingthroughtheCeenroutetootherregions,suchastheBST,ormoresubtlekindsoflong-rangefunctionaldisconnection[142],apointthatwetakeupmore

fullyinthenextsection.

4ClosingtheGapbetweenMechanisticandImagingRgapbetweenmechanisticandimagingresearchTheCeandtheBSTareanatomicallycomplexandcanbepartitionedintomultiplesub-regions(Fig.1),eachcontainingavarietyofintermingledcelltypes[8,86].Althoughunfamiliartomanybrainimagers,recentlydeveloped

opto-andchemogenetictoolsprovidenumerousopportunitiesfordecipheringthiscomplexityandidentifyingthespecificcircuitcomponentsthatcontroldefensiveresponsestothreat[143–147].Developingabasicunderstandingof

thesemethods isakeysteptodissolvingartificialacademic ‘silos’anddevelopingmorethoughtfulhypothesesabouttheroleof thecentralextendedamygdala inhumanemotionandemotionaldisorders.Typically,aDNAvector

encodinga target ligandor receptor isengineered intoavirus.Thevirus is injected into thebrain, inducingexpressionof the targetprotein in the infectedregion (e.g.,BST).Regionalandcell-typespecificity isachievedusing

recombinase-dependentvirusesorcelltype-specificpromoterviruses.Forexample,aviruscontainingaCre-dependentvectorcanbeinjectedintotheCeoftransgenicmiceengineeredtoexpressCrerecombinaseinsomatostatin-

expressingneurons,resultinginselectiveexpressionofthetargetedreceptorproteininsomatostatin-expressingneuronsintheCe.Moresophisticatedapproachesenabletheinclusion(BooleanAND)orexclusion(BooleanNOT)of

cellswithspecificefferentorafferentprojections,specificbehavioralprofiles(e.g.,activatedbyrewardvs.punishment),orcombinationsofthesecriteria.Byoverexpressingreceptorsthatrespondtolight('optogenetics')ordesigner

drugswithminimallimitedoff-targeteffects('chemogenetics'),itispossibletoreversiblyactivateorsilencespecificcellpopulationsondemand.Theapplicationoftheseapproachestorodentmodelsoffearandanxietyhasrevealeda

levelofarchitecturalintricacyinthecentralextendedamygdalafarbeyondwhatcanberesolvedusingexistingneuroimagingtechniques,includingmutuallyinhibitorycircuitswithintheCethatcontrolfreezingandfleeing[111,114]

andneuronalpopulationswithintheBSTthatcanpromoteordampensignsoffearandanxietyGarcia-Garciaetal.inpress;[112].

Theseexcitingobservationsraisetwoveryimportantquestions.First,arethesemechanismsconservedinhumansandotherprimates?Ifso,thentheyarelikelytoberelevanttoourunderstandingofanxietydisordersand

couldguidethedevelopmentofimprovedtreatments[21].Second,whatroledotheseextendedamygdalamechanismsplayinthekindsoflarge-scalebraincircuitsthathavebeenlinkedtomaladaptivefearandanxietyinhumansand

monkeys?Whichmoleculesandmicro-circuitsunderlieheightenedactivationinthecentralextendedamygdalaandhowdotheyinfluencethefunction(i.e.,activity,functionalconnectivity)ofdistalregionsofthebrainimplicatedin

pathologicalfearandanxiety?Reconcilingthesetwolevelsofanalysis—oneglobal,theotherlocal—ismandatory,ifwearetodevelopacompleteandclinicallyusefulunderstandingoffearandanxiety.

Nonhumanprimateresearchprovidesapowerfulopportunitytocombinefocalperturbationtechniqueswithwhole-brainsurveysofbrainfunctionandhasbeguntoaddresssomeofthesefundamentalquestions.Forexample,

imagingstudiesinmonkeysdemonstratethatmetabolicactivityintheposteriororbitofrontalcortex(OFC)/anteriorinsulaisassociatedwithheightenedpassiveavoidanceofthreat(i.e.,freezing;[8].Althoughsurgicallesionsofthe

OFCmarkedlyreducethreat-elicitedfreezing,suggestingacausalrole[149,150],neuroimagingmeasurescollectedbeforeandaftersurgerysuggestthatthisanxiolyticeffectisproximallymediatedby‘downstream’alterationsinBST

metabolism[151](Fig.3a).ReducedBSTactivityhasalsobeenobservedinhumanswithOFCdamage[152],suggestingthatthiscircuitisconservedacrossprimatespecies(Fig.3b).Inmorerecentwork,Kalin,Fox,andcolleagues

haveextendedthisstrategytogain-of-functionstudies[153].Harnessingaviralvectorapproach,theydemonstratedthatoverexpressionofcorticotropin-releasinghormone(CRH)inthedorsalamygdalaincreasesdefensivebehaviors

duringsustainedexposuretopotentialthreat,consistentwithworkinrodentshighlightingtheimportanceoftheCeCRHsystemforrespondingtodiffuselythreateningcontexts,suchastheelevatedplus-maze[154].Thesebehavioral

changeswere associatedwith increasedmetabolism in the dorsal amygdala and posterior OFC aswell as enhanced functional connectivity between the two regions, highlighting the importance of a distributed brain network

underlyingfearandanxiety(Fig.4a).

Fig.3FocaldamagetotheventralPFCisassociatedwithdistalchangesinBSTfunction.(A)Monkeys.ExperimentallesionsoftheOFCreducethreat-elicitedfreezing(notdepicted)andBSTmetabolism(magentaarrow).Theorbitofrontalregionstargetedby

thesurgery(maroon)canbeseenfromthelateral(farleft)andbasalviews(middle).Bar-plotdepictsthesignificantGroup×TimeinteractionforBSTmetabolism.(B)Humans.DamagetotheventromedialPFC(vmPFC)isassociatedwithreducedperfusionin

theBST(magentaarrow).Theventromedialregionsshowingdamagecanbeseenfromthemid-sagittal(farleft)andbasalviews(middle).Bar-plotdepictsthesignificantreductioninrightBSTperfusioninthepatientgroup.Portionsofthisfigurewereadapted

withpermissionfrom[151,152].

alt-text:Fig.3

Otherrecentworkdemonstratesthefeasibilityofusingopto-andchemogeneticapproachesinnonhumanprimates(e.g.,[156–161]—includingcell-typespecificperturbationsinwild-type(i.e.,geneticallyunmodified)monkeys

[162]—andhighlightsthevalueofcombiningmechanisticinterventionsandcellularrecordingswithwhole-brainimagingtechniquesMazzoneetal.,inpress;[163];Parketal.,inpress (Park,S.H.,Russ,B.E.,McMahon,D.B.T.,Koyano,K.W.,Berman,R.A.,&Leopold,D.A.(2017).Functionalsubpopulationsofneuronsinamacaquefacepatchrevealedbysingle-unitfMRImapping.Neuron,95,971-981.);Shibaetal.,inpress (Shiba,Y.,Oikonomidis,L.,Sawiak,S.,Fryer,T.,Hong,Y.T.,Cockcroft,G.,...Roberts,A.C.(2017).Convergingprefronto-insula-amygdalapathwaysinnegativeemotionregulationinmarmosetmonkeys.BiologicalPsychiatry,82,895-903.)).Inalandmarkstudy,Graysonandcolleaguesshowedthattransientchemogeneticinactivationoftheamygdalaproduceswidespreadalterationsinintrinsicfunctionalconnectivity,includingdecreasedamygdala-BSTconnectivity,

decreased amygdala-OFC connectivity, and increases in corticocortical coupling [155] (Fig. 4b). This finding is consistent with work in rodents [26,166] and neurological patients [167–169] demonstrating that the behavioral

consequencesoffocalbraindamagecanemergefromphysiologicalalterationsindistalbrainregions(forarelatedperspective,see[106]. (aparenthesisshouldbeadded[106]).)Thesefindingshighlighttheimportanceofadistributed

circuitcenteredon,butnotlimitedto,thecentralextendedamygdalaandtheyunderscoretheaddedvalueofcombiningthefocalperturbationstrategiesthatarewidelyusedinrodentstudieswiththewhole-brainimagingtechniques

thatareroutinelyusedinbasicandclinicalresearchinhumans.

5ConclusionsThecentralextendedamygdalaplaysacrucialroleinevaluatingandrespondingtoabroadspectrumofthreat-relatedcuesandcontexts.Whiletheyarecertainlynotinterchangeable,theCeandtheBSTshowsimilarpatterns

ofconnectivity,cellularcomposition,neurochemistry,andgeneexpression.Botharesensitivetouncertainor temporallyremotethreat;bothco-varywiththreat-elicitedchanges inbehavior,physiology,andexperience;bothshow

phasic responses to acute threat; andboth showheightenedactivity during sustainedexposure todiffusely threatening contexts.Work in rodents indicates that both regionsplay a critical role in organizing sustaineddefensive

responsestoarangeofpotentiallythreateningcuesandcontexts.Moregenerally,studiesleveragingopto-andchemogenetictechniqueshavebeguntorevealthespecificmolecules,cells,andmicrocircuitswithinthecentralextended

Fig.4Nonhumanprimateresearchprovidesapowerfulnopportunitytocombinefocalmanipulationsoftheamygdalawithwhole-brainsurveysofbrainfunction.(A).Molecularactivation.UsingMRI-guidedinjectionsofaviralvector(upperleft),Kalin,Foxand

colleaguesoverexpressedcorticotropin-releasinghormone(CRH)inthedorsalamygdala.MRIimagedepictsthegadoliniumflume(white)inthetargetregion.PhotomicrographshowsCRH-expressingcellsinthesameregion(upperright).CRH

overexpressionintheamygdalaenhancedthreat-eliciteddefensiveresponses(notshown)andincreasedmetabolism(yellowclusters)inthedorsalamygdala(magentaarrow)andtheposteriorOFC(greenarrows).CRH-inducedincreasesindefensiveresponses

andmetabolismwerecorrelatedinbothregions(redclusters).(B)Chemogeneticinhibition.Leveragingachemogeneticapproach,GraysonandcolleaguesreversiblyinhibitedtheamygdalawhileusingfMRItoassessintrinsicfunctionalconnectivityacrossthe

brain.Aviralvectorencodinganinhibitorydesignerreceptorexclusivelyactivatedbyadesignerdrugwithminimaloff-targeteffects(DREADD)wasinjectedintotheamygdala(upperleft).Systemicadministrationofthedesignerdrugreversiblyinactivated

theamygdala(upperright).DREADDs-mediatedinhibitionoftheamygdalawasassociatedwithdecreasedamygdala-BSTconnectivity(magentaarrow),decreasedamygdala-OFCconnectivity,andincreasedcorticocorticalcoupling(lowerpanels).Inthecoronal

section,clusters(yellow)depicttheminimumconjunction(logical‘AND’)ofregionssignificantforfourdesigner-drugvs.vehiclecontraststhatweremadeavailablebyGraysonandcolleaguesonthepublisher’swebsite.Portionsofthisfigurewereadapted

withpermissionfrom[155,153].(Forinterpretationofthereferencestocolourinthisfigurelegend,thereaderisreferredtothewebversionofthisarticle.) (shouldthislastcommentbeaddedtotheothercolorimages???)

alt-text:Fig.4

amygdalathatsupportsignsoffearandanxietyinratsandmice.Amajorchallengeistounderstandtherelevanceofthesediscoveriestohumanexperienceandhumandisease.Recentworkinnonhumanprimatesprovidesabridgeto

addressingthisfundamentalissue.Usingacombinationoffocalperturbationsandwhole-brainimaging,thisnewgenerationofnonhumanprimateresearchsetsthestagefordiscoveringthemechanismswithinthecentralextended

amygdalathatunderlieneuroimagingmetricslinkedtoextremefearandanxietyinhumans;forunderstandinghowtheCeandBSTfunctionallyinteractwithoneanotherandwithremoteregionsofthebrain,suchastheOFC;and

ultimatelyforacceleratingthedevelopmentofimprovedstrategiesfordiagnosing,treating,andpreventingpathologicalfearandanxiety.

ConflictofinterestAuthorsdeclarenoconflictsofinterest.

Uncitedreferences[170]and[171].

AcknowledgementsWegratefullyacknowledgeassistancefromL.Brinkmann,L.Friedman,B.Nacewicz,andD.Tromp;criticalfeedbackfromJ.Blackford,L.Pessoa,S.Padmala,and3anonymousreviewers;andfinancialsupport

fromtheCaliforniaNationalPrimateCenter;NationalInstituteofMentalHealth (NationalInstitutesofHealth)(DA040717,MH107444);UniversityofCalifornia,Davis;andUniversityofMaryland,CollegePark.

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Footnotes2Ithasbecomeincreasinglycommontodrawadistinctionbetween‘fear’and‘anxiety’(e.g.,[172].Yetlaypeople,scholarsinotherareas,theAmericanPsychiatricAssociation’sDiagnosticandStatisticalManual[173],andevendomain

expertsoftenusethesetermsininterchangeable,inconsistent,oroverlyinclusivewaysKagan,inpress;[12,13,175].Toavoidmisunderstanding,wehaveadoptedtheundifferentiatedterm‘fearandanxiety’(foramoredetailed

discussionofnomenclature,seeFoxetal.,inpress; (Fox,A.S.,Lapate,R.C.,Davidson,R.J.,&Shackman,A.J.(2018).Thenatureofemotion:Aresearchagendaforthe21stcentury.InA.S.Fox,R.C.Lapate,A.J.Shackman,&R.J.Davidson(Eds.),The

natureofemotion.Fundamentalquestions(2nded.).NewYork:OxfordUniversityPress.)[19].UnderstandingtheneurobiologyoffearandanxietyisboththeoreticallyandclinicallyimportantandrequiresthatwedeterminehowtheCe,the

BST,andotherbrainregionsworktogethertoevaluateandrespondtodifferentkindsofthreat.Weurgeotherresearcherstoeschewpotentiallyproblematicredefinitionsofeverydaylanguageand,instead,focusonthespecific

parametersofthethreat,thecontextinwhichitoccurs(e.g.,prospectsforescape),andtheneurobehavioralresponse(e.g.,timecourse),includingsubjectiveexperience.

3Interestingly,theamygdalaisnotconsistentlyrecruitedbyconditionedthreatcuesinhumanfMRIstudies[176,177],contrarytoelectrophysiologicalandmechanisticworkinrodents,monkeys,andhumans[178,139,116].Inaddition,

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severalgroupshavereported‘de-activation’oftheamygdalainavarietyofaversiveparadigms[80,179,180,70,84,79,181–183].Themechanismsunderlyingtheseeffectsremainenigmatic.

4AlthoughautomatedanatomicallabelingtoolsdonotyetincludetheBST,probabilisticmasksarenowavailableforthesupracapsularportion[15,48],asshowninFig.1.ItcanalsobehelpfultoassesswhetherprovisionalBSTclusters

lieoutsideofneighboringregionsincorporatedinprobabilisticatlases(aBooleanNOTwithnucleusaccumbens,pallidum,caudate,putamen,thalamus,andventricles)(Klumpers,Kroes,Baas,&Fernandez,inpress (Klumpers,F.,Kroes,M.C.W.,Baas,J.,&Fernandez,G.(2017).Howhumanamygdalaandbednucleusofthestriaterminalismaydrivedistinctdefensiveresponses.JournalofNeuroscience,37,9645-9656.);[19].

Highlights

• Centralextendedamygdala(EAc)encompassesCeandBST.

• EAcisengagedbyarangeofthreat-relevantcues.

• Optogenetic/chemogeneticstudiesrevealkeymoleculesandmicrocircuits.

• Next-generationnonhumanprimatestudies….

• …bridgethegapbetweenmechanisticworkinrodentsandimagingstudiesinhumans.