Glucocorticoid actions on synapses, circuits, and behavior Implications for the energetics of stress

Glucocorticoid recepter,HPA axis,depression,Hippocampus

Review

Glucocorticoidactionsonsynapses,circuits,andbehavior:Implicationsfortheenergeticsof

stress

BrentMyers1,JessicaM.McKlveen1,JamesP.Herman

DepartmentofPsychiatryandBehavioralNeuroscience,UniversityofCincinnati,Cincinnati,OH,UnitedStates

articleinfoabstract

Environmentalstimulithatsignalrealorpotentialthreatstohomeostasisleadtoglucocorticoidsecretionbythehypothalamic–pituitary–adrenocortical(HPA)axis.Glucocorticoidspromoteenergyredistributionandarecriticalforsurvivalandadaptation.Thisadaptationrequirestheintegrationofmultiplesystemsandengageskeylimbic-neuroendocrinecircuits.Consequently,glucocorticoidshaveprofoundeffectsonsynapticphysiology,circuitregulationofstressresponsiveness,and,ultimately,behavior.Whilegluco-corticoidsinitiateadaptiveprocessesthatgenerateenergyforcoping,prolongedorinappropriategluco-corticoidsecretionbecomesdeleterious.Inappropriateprocessingofstressfulinformationmayleadtoenergeticdrivethatdoesnotmatchenvironmentaldemand,resultinginriskfactorsforpathology.Thus,dysregulationoftheHPAaxismaypromotestress-relatedillnesses(e.g.depression,PTSD).Thisreviewsummarizesthelatestdevelopmentsincentralglucocorticoidactionsonsynaptic,neuroendocrine,andbehavioralregulation.Additionally,these ndingswillbediscussedintermsoftheenergeticintegrationofstressandtheimportanceofcontext-speci cregulationofglucocorticoids.

Ó2014PublishedbyElsevierInc.

Articlehistory:

Availableonline18December2013Keywords:

Hypothalamo–pituitary–adrenocorticalaxisCorticosteronePrefrontalcortexAmygdalaHippocampusHypothalamus

GlucocorticoidreceptorMineralocorticoidreceptor

1.Introduction

Thescienti cunderstandingof‘stress’anditsrami cationsfortheorganismhavecontinuallyevolved.BasedonClaudeBernard’stheoryoftheinternalmilieu,WalterCannon rstusedtheconceptofhomeostasistoexplainthe‘ ght-or- ight’responseofanorgan-ismpresentedwithathreat(Cannon,1932).Inabiologicalsense,HansSelyecoinedtheterm‘stress’asthenon-speci cresponseofthebodytoanyhomeostaticdemand(Selye,1936).Whileitisstillgenerallyacceptedthatthephysiologicalroleofthestressre-sponseistocoordinateautonomic,neuroendocrine,andimmuneresponsestopotentialhomeostaticthreats,anemergingconceptinstressneurobiologysuggeststhattheprimaryroleofstressrespondingistomobilizeenergytopromotecontext-speci csur-vivalandnotnecessarilysustainhomeostaticsystemsatlevelsmaintainedpriortoachallenge(Dallmanetal.,2006;NederhofandSchmidt,2013).Giventhisframework,responsestobothacuteandchronicstressareconsideredadaptive,uptoapoint,andpre-paretheorganismforcurrentandfuturedemands.Thus,forthepurposeofthecurrentreview,stresswillbede nedasastimulusthatmobilizesenergeticsystemstorespondtoanongoingoranticipatedchallenge.

Correspondingauthor.Address:DepartmentofPsychiatryandBehavioral

Neuroscience,UniversityofCincinnati,MetabolicDiseasesInstitute,2170EastGalbraithRoad,Cincinnati,OH45237,UnitedStates.Fax:+15135589104.

E-mailaddress:james.herman@uc.edu(J.P.Herman).1

Authorscontributedequally.

0091-3022/$-seefrontmatterÓ2014PublishedbyElsevierInc.http://wendang.chazidian.com/10.1016/j.yfrne.2013.12.003

Respondingtostressinvolvestheconcertedactivityofmultiple,interactingcentralstress-regulatorysystemstomobilizeenergyfortheorganism.Activationofthestressresponseoccurseitherasaconsequenceof,orinanticipationof,achallenge(Myersetal.,2012b).Anticipatoryresponsesrequiretheorganismtoref-erencepriorexperiencestopredicttheneedforenergymobiliza-tion,primarilymediatedbymulti-synapticforebrainprojectionstothemedialparvocellularparaventricularnucleus(PVN)ofthehypothalamus.Systemicchallengesarelargelyre exiveresponsestophysiologicaldisruptiongeneratedbydirectprojectionsfromthehindbraintothePVN,thoughthereisconsiderableoverlapandintegrationatvariousnodesthroughoutthebrain(Hermanetal.,2012,2003;Ulrich-LaiandHerman,2009).Thus,theneuro-endocrineresponsetostressisahighly-regulated,temporalpro-cess,involvingtheintegrationofsensoryinformationfrommultiplemodalitiestorapidlyactivate,aswellasinhibitthesecre-tionofglucocorticoids.

Theneuroendocrinestresscascade,comprisingthehypotha-lamic–pituitary–adrenocortical(HPA)axis,beginswiththereleaseofadrencorticotropichormone(ACTH)secretagoguesfromneuro-secretoryneuronsinthemedialparvocellularPVN,whichprojecttohypophysialportalvesselsintheexternalzoneofthemedianeminance(Bruhnetal.,1984).Secretagoguestravelviatheportalveinstotheanteriorpituitary,wheretheycanaccesscorticotropes(DeWiedetal.,1957;GibbsandVale,1982;McCannandFruit,1957;SaffranandSchally,1956).ThepioneeringworkofWylieValeandcolleaguesprovidedinitialidenti cationofcorticotropin

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B.Myersetal./FrontiersinNeuroendocrinology35(2014)180–196181

releasingfactor(CRF)astheprimarydriverofpituitaryACTHre-lease(BaleandChen,2012;Rivieretal.,1983a,b;Rivieretal.,1982;Spiessetal.,1981;Swansonetal.,1983;Valeetal.,1981).Subsequentstudies,alsobyValeandcolleagues,revealedtheexis-tenceofseveralco-secretagoguesthatsynergizewithCRF,includ-ingargininevasopressin(AVP)(RivierandVale,1983a,1983b;Sawchenkoetal.,1984;Valeetal.,1981,1983).Bywayofthesys-temiccirculation,ACTHactsattheleveloftheadrenalcortextoin-ducethereleaseofglucocorticoids,cortisolinsomespecies(e.g.,humans,non-humanprimates)andcorticosteroneinothers(e.g.,rats,mice)(DallmanandJones,1973;Dallmanetal.,1987).Attheadrenal,cortisol/corticosteroneisreleasedinpulses,thetimingofwhichdictatestheoverallmagnitudeofbothbaselineactivityandstressresponses(Lightmanetal.,2008;Youngetal.,2004).Pulsatilepatternsofglucocorticoidreleasearedictatedbyultra-dianrhythms(forreviewseedeKloetandSarabdjitsingh,2008;Sarabdjitsinghetal.,2012a).Thisrhythmicityofglucocorticoidre-leaseisessentialformaintainingcellularresponsivenessandpro-moteswide-rangingglucocorticoidactionsfromgenetranscriptiontobehavior(Conway-Campbelletal.,2010;Sarabd-jitsinghetal.,2010b).Glucocorticoidsthentravelthroughoutthebody,exertingamultitudeofeffectsintheperipheryincludinggly-cogenbreakdownandgluconeogenesis(Coderreetal.,1991;Ex-ton,1979;Muncketal.,1984;fordetailedreviewsofbraincircuitsregulatingglucosehomeostasisseeSchwartzetal.,2000;SeeleyandWoods,2003;Woodsetal.,1998).Glucocorticoidscrosstheblood–brain-barrier,andprimarilybindtomineralocorticoid(MR)andglucocorticoidreceptors(GR)inneuronsand/orglia.Inthebrain,MRhashigh-bindingaf nityforcorticosteroidsand,consequently,isactivatedatbasallevels(deKloetandSarabdjit-singh,2008;deKloetetal.,1998).Thus,MRisthoughttosenserestinglevelsofglucocorticoidsandpromotekeyfunctionsassoci-atedwithlowglucocorticoidlevels,includingcircadiandriveoftheHPAaxisandmnemonicfunction(deKloetetal.,2005).Con-versely,GRhasalowerbindingaf nityforglucocorticoidsandislargelyunoccupiedatbasallevels.Thus,GRisthoughttobepartic-ularlyimportantinsignalingmediatedbystresslevelsofglucocor-ticoids(Boyleetal.,2005;deKloetandReul,1987;deKloetetal.,2005;ReulanddeKloet,1985).GRisabundantlyexpressedthroughoutthebrain,includingtheprimarystress-regulatorysitesdiscussedinthisreview:medialprefrontalcortex(mPFC),hippo-campus,amygdala,bednucleusofthestriaterminalis(BST),hypo-thalamus,andhindbrain(Fuxeetal.,1987;Meaneyetal.,1985;ReulanddeKloet,1986).MRhasamorerestricteddistributionthatoverlapswiththatofGRinseveralkeyregions,includingthemPFC,hippocampus,andamygdala(deKloetandReul,1987;ReulanddeKloet,1985).

Thereisavitalneedforglucocorticoidactivitytobetightlyregulated,requiringsystemscoordinationfromcellulartobehav-iorallevels.Inresponsetostress,glucocorticoidsignalingpro-motesorganismaladaptationtoenvironmentalconditionsandhelpstomeettheresultingenergeticdemands.Thisadaptationrequirestheintegrationofmultiplesystemsandengageskeylimbic-neuroendocrinecircuits.Forebrain,hypothalamic,andhindbraincircuitsareactivatedbyglucocorticoidsandpartici-pateinthecoordinationofphysiologicalandbehavioraloutput.However,whenenergeticdrivedoesnotappropriatelymatchenvironmentaldemand,ortheorganismischronicallyactivatingthesesystems,riskfactorsemergeforavarietyofstress-relatedpathologies.Thepresentarticlewillreviewtheactionsofgluco-corticoidsincentralstress-regulatorycircuits,focusingonthero-dentliterature,inthecontextoftheadaptiveroleofthestressresponsefortheorganism.Thereviewwillsummarizetheroleofcentralglucocorticoidactionsonsynaptic,neuroendocrine,andbehavioralregulation,highlightedbyadiscussionoftheenergeticintegrationofstressandtheimportanceof

context-speci cregulationofglucocorticoids.Theenergymobi-lizingeffectsofglucocorticoidsrequireintegrationofcellularactivity,circuitconnectivity,andbehavioraloutputtocoordinatecontext-appropriateadaptation.Weproposethatglucocorticoid-mediatedenergeticdrivegeneratesanadaptivecapacityinresponsetoenvironmentaldemand;however,thecostofrepeat-edlyorexcessivelydrivingadaptivesystemsmaycompromiseperformanceunderconditionsofelevatedenvironmentalpressure.Thus,wewillexaminetheintegrativeactionsofgluco-corticoidsontheprimarylimbicsitesmediatingorganismalstressresponsivenesswithintheframeworkofcontext-speci cadaptation.

2.Synapticactionsofclucocorticoids

ThecellularactionsofglucocorticoidsarelargelydependentonbrainsiteandtherelativeexpressionofGRandMR(deKloet,2013a)(Table1).Glucocorticoidsalsoactinconcertwithmonoam-inergicandpeptideneurotransmitters,particularlynoradrenergic(Quirarteetal.,1997;Roozendaaletal.,2008,2006a,b,2002)andCRFsystems(BaleandVale,2004;Bale,2005;Mengetal.,2011),whichhavebeenreviewedelsewhere(deKloet,2013b;FerryandMcGaugh,2000;HeinrichsandKoob,2004;Roozendaal,2000).Further,thesynapticactionsofglucocorticoidsarecriticallyaf-fectedbytherecentstresshistoryoftheorganism,aconceptknownas‘metaplasticity’,whichwillbeexpandedoninthefol-lowingsection(forreviewsee:Schmidtetal.,2013).Acuteandchronicstressoftenyielddifferenteffectsoncellularfunctiontomeetcontext-speci cenergeticdemandsplacedontheorganism.Thus,wewilldiscusstheeffectsofglucocorticoidsoncellularfunc-tioninlightoftheseconsiderations.2.1.Medialprefrontalcortex

ThemPFCistheexecutivecontrolcenterofthebrain,providingtop-downregulationofbehavioralfunction.Thus,itisakeysiteforglucocorticoidactionsandregulationoftheHPAaxis(Akanaetal.,2001;Diorioetal.,1993;McKlveenetal.,2013).TherodentmPFCiscomprisedofthreesubdivisions,basedonconnectivityandcyto-architecture:theanteriorcingulate,prelimbic(plPFC),andinfra-limbic(ilPFC)cortices(Uylingsetal.,2003;Vertes,2004).Onthebasisofstructureandfunction,theseregionsarethoughttobehomologoustohumanBrodmannareas24b,32,and25,respec-tively(Gabbottetal.,2005;Uylingsetal.,2003).

MolecularandfunctionalstudiesindicatethatglucocorticoidsacutelyincreaseglutamatergicoutputfromthemPFC(Popolietal.,2012).Microdialysisandmicroelectrodesamplingexperi-mentsindicateincreasedextracellularglutamateinvivointhemPFCfollowingacutestress(BagleyandMoghaddam,1997;Has-cupetal.,2010;Moghaddam,1993).Acutefootshockincreasesdepolarization-evokedreleaseofglutamateinisolatedsynapto-somesviaaGR-dependentmechanismandincreasestheampli-tudeofexcitatorypostsynapticcurrents(EPSCs)inmPFCpyramidalneurons(Musazzietal.,2010).Inadolescentrats,acutestressalsoincreasesNMDA-andAMPA-mediatedexcitatorycur-rentsbyup-regulatingtheexpressionofthesereceptorsonthepostsynapticmembrane(viaserum-andglucocorticoid-induciblekinases)(Yuenetal.,2011,2009).Thus,existingdatasuggestthatacutestressactivatesmPFCneurons,permittingdown-streamacti-vationoftargetregions(seebelow).

Veryfewstudieshaveassayedinhibitoryneurotransmissionafteracutecorticosteroneapplication.Arecentstudyinmicefoundthatcorticosteronedecreasedminiatureinhibitorypostsynapticcurrents(mIPSCs)andincreasedpairedpulseinhibition,suggest-ingthatacuteglucocorticoidexposuredisinhibitsglutamatergic

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182B.Myersetal./FrontiersinNeuroendocrinology35(2014)180–196

Table1

Site-speci ceffectsofglucocorticoidsonsynaptictransmissionandplasticity.ReferenceYuenetal.(2009)

BrainsitemPFC

GR/MRmanipulationCORT

Stresscondition

RestraintorPlatformorCORTRapideffects

Delayedeffects"eEPSCamplMusazzietal.(2010)mPFCHilletal.(2011)plPFCYuenetal.(2012)

mPFC

PFCcultures

Karstetal.(2005)

CA1

KarstandJoëls(2005)CA1

Olijslagersetal.(2008)CA1

Pavlidesetal.(1996)CA1Alfarezetal.(2002)CA1Alfarezetal.(2003)CA1Yangetal.(2004)CA1Krugersetal.(2006)

CA1

Wiegertetal.(2006)CA1Alfarezetal.(2003)DGPasrichaetal.(2011)DG

MaggioandSegalDorsalHipp

(2009a)

VentralHipp

MaggioandSegalVentralHipp

(2009a)

MaggioandSegal(2007)DorsalHipp

VentralHipp

MaggioandSegalDorsalorVentral(2009b)

Hipp

DorsalHipp

DorsalorVentralHipp

VentralHipp

DuvarciandParé(2007)BLAKarstetal.(2010)

BLA

Karstetal.(2010)

BLA

GRAntagonisti.p.

None

CORT

CORT+CB1AntagonistNone

CORTi.c.

GRAntagonisti.p.ormPFCCORT

CORT+GRAntagonistCORTorCORT:BSAGRAgonist

CORT+GRAntagonistorCORT+GRKO

MRAgonist+GRAntagonistMRKO+CORTCORT

GRAgonist

CORT+MRAntagonistCORT

GRAgonists.c.MRAgonists.c.CORTNone

None

GRAntagonisti.p.None

GRAntagonist(oral)CORTCORTNoneCORT

CORTorGRAgonistCORT+MRAntagonistCORT

GRAgonistorCORT+MRAntagonist

MRAgonistorCORT+GRAntagonist

CORT

CORT+GRAntagonistCORT

CORT+MRAntagonistGRAgonistGRAntagonists.c.MRAgonistMRAntagonists.c.GRAntagonists.c.CORTCORTCORT

GRKO+CORTMRKO+CORT

MRAgonist+GRAntagonistGRAgonist

CORT+CycloheximideCORT

i.p.

ForcedSwimmingAcuteFootShock20minSliceIncubation20minSliceIncubationChronicStressChronicCORTmPFCChronicStress

7dCORTIncubation7dCORTIncubationBathApplicationBathApplicationBathApplicationBathApplicationBathApplication20minSliceIncubation20minSliceIncubationBathApplicationBathApplicationNoneNone

20minSliceIncubationChronicStressInescapableShockInescapableShockChronicStressChronicStress

20minSliceIncubationBathApplicationChronicStressBathApplicationBathApplicationBathApplicationBathApplicationBathApplicationBathApplication1hSliceIncubation1hSliceIncubation1hSliceIncubation1h

Slice

Incubation

1hBathApplicationForcedSwimming1hBathApplicationForcedSwimmingForcedSwimming20minIncubationBathApplication20minPulseBathApplicationBathApplicationBathApplicationBath

Application

BathApplication2PulseApplication

MeEPSCampl

"sEPSCamplitude

;mIPSCfreqMmIPSCfreq

;mEPSCamplandfreq,;eEPSCampl

;eEPSCamplMeEPSCampl

;mEPSCamplandfreqMmEPSCamplandfreq

"mEPSCfreqMmEPSCfreq"mEPSCfreq"mEPSCfreqMmEPSCfreq

"mEPSCampl,"eEPSCampl"mEPSCampl

MmEPSCfreqandampl

MmIPSCfreqandampl

;LTP"LTP;LTP;LTP

;LTP,"LTDMLTP,MLTD;LTPMLTP;LTP

"LTP

;LTP

"mEPSCfreq

"sIPSCAmpl"sIPSCAmpl;sIPSCFreq"sIPSCAmpl;sIPSCFreq;LTP"LTP"LTPMLTP"LTD

LTDconvertedtoLTPLTDconvertedtoLTP"LTD

LTDconvertedtoLTP;eIPSPs

"mEPSCFreq

"mEPSCFreq(severalhourslater)

"mEPSCFreqMmEPSCFreqMmEPSCFreqMmEPSCFreq"mEPSCFreqMmEPSCFreq;mEPSCFreq;mEPSCFreq"mEPSCFreqMmEPSCFreq

;mEPSCFreq

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B.Myersetal./FrontiersinNeuroendocrinology35(2014)180–196

Table1(continued)Reference

Brainsite

GR/MRmanipulationCORT

GRKO+CORTGRAgonist

GRAntagonist+MRAgonistCORT+CyclohexamideCB1Antagonist

Hubertetal.(2013)Vouimbaetal.(2004)Maroun(2006)Sarabdjitsinghetal.(2012b)

BLABLABLABLA

NoneNoneNoneNone

GRAntagonisti.p.MRAntagonisti.p.GRAntagonisti.p.MRAntagonisti.p.

Karstetal.(2010)

CeA

CORT

StressconditionAcuteRestraint+BathApplication

AcuteRestraint+BathApplication

AcuteRestraint+BathApplication

AcuteRestraint+BathApplication

AcuteRestraint+BathApplication

AcuteRestraint+BathApplicationChronicStressPlatformStressChronicStressElevatedPlatformAcuteRestraintAcuteRestraintNoneNone

BathApplication

;LTPMLTPMLTPMLTP

MmEPSCFreqRapideffects;mEPSCFreqMmEPSCFreq;mEPSCFreqMmEPSCFreq;mEPSCFreqMmEPSCFreq

Delayedeffects;mEPSCFreqMmEPSCFreqMmEPSCFreqMmEPSCFreq;mEPSCFreqMmEPSCFreq"mEPSCFreq"LTP;LTP"LTP,MLTD;LTP

;LTP(Gradual)MLTP

;LTP(Gradual)MmEPSCFreq

183

outputfromthemPFC(Hilletal.,2011).Theeffectsofcorticoste-roneonmIPSCswerepreventedbyCB1antagonism,suggestingthattheeffectofacutestressondisinhibitionofmPFCpyramidalneuronsislikelyendocannabinoid-dependent(Hilletal.,2011).Overall,thepresentdatasuggestthatglucocorticoidsacutelyin-creaseglutamatergicneurotransmissionanddecreaseinhibitoryneurotransmissioninthemPFC.ItremainstobedeterminedwhetherreducedinhibitioncontributestoenhancedmPFCexcitability.

ThesynapticeffectsofglucocorticoidsinthemPFCduringchronicstressarenotaswellestablished,andtheeffectsonexcit-atoryandinhibitoryneurotransmissionarelargelyunknown.Re-peatedrestraintstress,chronicunpredictablestress,orchroniccorticosteronetreatmentdecreaseapicaldendriticcomplexityofpyramidalneurons(Cerqueiraetal.,2007,2005;CookandWell-man,2004;Goldwateretal.,2009;Listonetal.,2006;Radleyetal.,2004,2006;Wellman,2001).Conversely,repeatedrestraintstressincreasesthecomplexityandtranscriptionalactivityofpre-frontalGABAergicinterneurons(Gilabert-Juanetal.,2012).Whilethefunctionalconsequenceofthesemorphologicmodi cationsisunknown,thedirectionofchangessuggestsbothdecreasedpyra-midalcellexcitabilityandincreasedcapacityforinterneuron-med-iatedinhibition.

Inadolescentrats,chronicstressdecreasesNMDA-andAMPA-mediatedcurrentsinthemPFCthroughincreaseddegradationofpostsynapticglutamatereceptors(Yuenetal.,2012).Notably,ado-lescenceisadevelopmentalperiodmarkedwithpruningofpre-frontalglutamatergicsynapses,particularlythosetothebasolateralamygdala(BLA)(Cressmanetal.,2010).Therefore,itre-mainstobedeterminedwhetherincreaseddegradationofgluta-matereceptorsisduetochronicstressorstress/developmentinteractions(forreviewonadolescentsynapticplasticityseeSelemon,2013).Inadultanimals,chroniccorticosteroneadminis-trationdecreasesexpressionofNMDAsubunitNR2BandAMPAsubunitsGluR2/GluR3intheventralmPFC(Gourleyetal.,2009).However,theimpactofchronicstressoninhibitoryneurotrans-missioninthemPFChasnotbeendirectlytested,furtherhighlight-ingtheneedforabetterunderstandingofchronicglucocorticoideffectsonsynapticphysiologyinadultanimals.

2.2.Hippocampus

Thehippocampusiscriticalforprocessesrelatedtomemory,particularlyspatialandcontextuallearningandmemoryretrieval(RoozendaalandMcGaugh,1997a;Roozendaaletal.,2001).Thehippocampusconsistsofmultiplesubregions,includingtheCA1andCA3regions,thedentategyrus,andtheventralsubiculum(SwansonandCowan,1977).Theactionsofglucocorticoidsinthehippocampushavelongbeenrecognized(McEwenetal.,1968)andhavebeenstudiedingreatdetail.BothMRandGRareabun-dantlyexpressedinhippocampus,andmemoryprocessingisheav-ilyin uencedbycirculatinglevelsofglucocorticoids(Fuxeetal.,1987;Meaneyetal.,1985;OitzlanddeKloet,1992;ReulanddeKloet,1986).Moreoverinadditiontoaroleinmemoryprocesses,thehippocampus(speci callytheventralsubiculum)inhibitsHPAaxisresponsestopsychogenicstressors(Hermanetal.,2003;Her-manetal.,1998,1989).

Thecellularactionsofglucocorticoidsinthehippocampus(pre-dominantlyCA1pyramidalneurons)havebeenverywellcharac-terized,particularlybyJoëlsandcolleagues(forreviewseeJoëlsetal.,2012).Therapid,non-genomiceffectsofglucocorticoids(occurringwithinminutes)aremediatedprimarilybythemem-brane-associatedMRatthepre-andpostsynapticmembrane(Joëlsetal.,2008;Karstetal.,2005;Olijslagersetal.,2008;Pasrichaetal.,2011).ActivationofMRincreasesneuronalexcitabilitybyincreasingtheprobabilityofglutamaterelease,suppressingpotas-siumconductance,andincreasingglutamatereceptortraf cking(Grocetal.,2008;Karstetal.,2005;Olijslagersetal.,2008).Con-versely,thedelayedeffectsofglucocorticoidsaremediatedprimar-ilybyGR(KarstandJoëls,2005).ActivationofGRcausesdelayedsuppressionofneuronalexcitability(duetoenhancedcalciumin- ux,decreasedcalciumef ux,andincreasedcalcium-dependentpotassiumcurrent)andsynapticplasticity(impairedlong-termpotentiation(LTP)duetolateraldiffusionofglutamatereceptors),presumablytonormalizehippocampalactivityafterstressandprotectinformationacquiredduringthestressfulexperience,respectively(Bhargavaetal.,2002;Chameauetal.,2007;Grocetal.,2008;JoëlsanddeKloet,1989,1990;Joëls,2006;Joëlsetal.,2007,2009;Karstetal.,1994;KimandDiamond,2002;

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184B.Myersetal./FrontiersinNeuroendocrinology35(2014)180–196

Pavlidesetal.,1996).Theventralpartofthehippocampusre-spondstoglucocorticoidsmuchdifferentlythanthedorsalhippo-campus.Uponcorticosteroneapplication,theventralhippocampushasreduced ringfrequencyaccommodationandmoredepolar-ization-associatedspikes(MaggioandSegal,2009a).Further,un-likeCA1,stressdoesnotleadtoimpairedLTPintheventralsubiculum(MaggioandSegal,2010,2009b,2007).Thesedifferen-tialeffectsintheventralhippocampusmayallowforalongerwin-dowofacquisitionwhenthisbrainregionisactivatedduringastressfulexperience(Joëlsetal.,2012).Theprominentroleoftheventralhippocampus/subiculumininhibitingHPAaxisstressresponsesraisesthepossibilitythatdifferentialactionsofstress/glucocorticoidsonsynapticfunctionmayberelevanttostressregulation.

Theeffectofchronicstressoncellularphysiologyinthehippo-campusisfairlywellcharacterized.Inchronicallystressedanimals,LTPintheCA1hippocampalareaanddentategyrusisimpairedatbasallevelsofcorticosteroneandisnotfurtherimpairedintheCA1hippocampalareaordentategyrusfollowingcorticosteroneappli-cation(Alfarezetal.,2003).Theeffectsofchronicstressonsynap-ticplasticityintheCA1hippocampalareaarelikelyGR-mediated,asblockadeofGRduringthelast4daysofchronicstressblockstheeffectsofstressonLTP(Krugersetal.,2006).Further,animalswithahistoryofchronicstresshaveGR-dependentincreasesincalciumin uxintoCA1neuronsatbasallevelsofcorticosterone,whichmaycontributetoimpairedsynapticplasticity(KarstandJoëls,2007).Theseimpairmentsofsynapticplasticityinthehippocam-pusfollowingchronicstresslikelyunderliesomeofthecognitiveimpairmentsobservedwithchronicstressexposure.2.3.Amygdala

Theamygdalaintegratesemotionalandsensoryinformationfortheexpressionoffearandanxiety(CharneyandDeutch,1996;Davis,1997;PhelpsandLeDoux,2005;Weiskrantz,1956).Addi-tionally,theamygdalaisinvolvedinthelearningandconsolidationofemotionalmemoriesandhasanessentialroleinconditionedresponses(Davis,1992;LeDoux,2012).Theamygdalaiscomposedofmultiplesubnucleithatareanatomicallyandphysiologicallyheterogeneous.Ofthesesubnuclei,thebasolateral(BLA),central(CeA),andmedial(MeA)cellgroupsappeartobemostcloselylinkedtoregulationofstressresponses(Sahetal.,2003;SwansonandPetrovich,1998;Ulrich-LaiandHerman,2009).

Similartothehippocampus,glucocorticoidsrapidlyincreasemEPSCsintheBLAviathemembraneassociated-MR(Karstetal.,2010).Incontrasttothesuppressiveandnormalizingeffectsofglucocorticoidsoncellularresponsesinthehippocampusfollow-ingacutestress,glucocorticoidsintheBLAprolongexcitatorysyn-apticresponsesviaGR(DuvarciandParé,2007;Karstetal.,2002;Liebmannetal.,2008;Rainnieetal.,2004).Further,subsequentcorticosteroneapplicationoracutestresspriortoslicepreparationdecreasesmEPSCfrequencyintheBLAviatheGRandCB1receptor(Karstetal.,2010).Thus,thecellularresponsesofBLAneuronstoglucocorticoidsdependontherecenthistoryofstressexposure,aneffectknownasmetaplasticity(Joëlsetal.,2012;Karstetal.,2010).Inresponsetoacutenoisestress,amygdalarc-fosmRNAexpressionincreasesonlyduringtherisingphaseofpulsatileglu-cocorticoidinfusioninadrenalectomizedanimals,asopposedtothefallingphaseorduringconstantinfusionofcorticosterone,furthersuggestingthatrapidreactivityoftheamygdalatogluco-corticoidsishighlydependentonrecentchangesinglucocorticoidstatus(Sarabdjitsinghetal.,2010a).StressalsoimpairsLTPinprojectionsfromtheBLAtotheplPFCandintheventralhippocam-pus–mPFCpathway(MarounandRichter-Levin,2003;Richter-Le-vinandMaroun,2010).Thestress-inducedimpairmentofLTPintheventralhippocampus–mPFCpathwaydoesnotoccurin

previouslystressedanimalsiftheBLAisstimulatedorifanimalsreceiveasecondboutofstress(Richter-LevinandMaroun,2010),anotherexampleofmetaplasticity.WhilestressimpairsLTPinBLAprojections,LTPinafferentstotheBLAisstrengthened,includ-inginputfromtheentorhinalcortex,externalcapsule,andplPFC(Kavushanskyetal.,2006;Maroun,2006;RodríguezManzanaresetal.,2005;Vouimbaetal.,2004).Further,unpredictablefootshockfacilitatesLTPintheBLA,whichmaybeduetoastress-inducedincreaseinGluR1inspinesfromdendriticstores(Lietal.,2011;Hubertetal.,2013).TheeffectsofstressonLTPintheBLAappeartobeprimarilymediatedbyGRasMRisinvolvedinthemainte-nanceofLTP,regardlessofcirculatingglucocorticoidlevels(Sarabdjitsinghetal.,2012b).

3.Connectivityandintegrationofglucocorticoid-responsivecircuits

Stressintegrativefunctionsareregulatedbyforebraincircuits,primarilyinvolvingtheabovementionedregions(mPFC,hippo-campus,andamygdala)(Ulrich-LaiandHerman,2009)(Table2).Notably,theseinterconnectedlimbicforebrainsitesdonotsendsubstantialprojectionstostress-effectorneuronsinthePVN.Thus,theirin uenceonHPAaxisoutputiscommunicatedthroughinter-veningPVN-projectingneurons.InhibitoryGABAergicinputstothePVNemanatefromseveralstructuresinthebasalforebrainandhypothalamus,includingtheBST,preopticarea(POA),anddorso-medialhypothalamus(DMH)(Boudabaetal.,1996;Radleyetal.,2009;RolandandSawchenko,1993).Incontrast,glutamatergicinputstothePVNoriginatepredominantlyfromhypothalamicnuclei,includingtheventromedialhypothalamus(VMH),posteriorhypothalamus(PH),aswellasDMH(Ulrich-Laietal.,2011).Neuronsintheseregions,includingthosethatprojecttothePVN,showpronouncedactivationbystressfulstimuli(Cullinanetal.,1995,1996),consistentwitharoleinstressregulation.Allhypo-thalamicPVN-projectingregionsreceivemixedGABAergicandglutamatergicinputfromotherhypothalamicnuclei(Myersetal.,2013),whichmayberesponsibleforintra-hypothalamicmechanismsgoverningtheintegrationofforebrainlimbicinputsandstressresponsivenessbasedonmetabolicdemand.

Importantly,GRisexpressedinnumeroushypothalamicPVN-projectingneurons,includingthePOA,DMH,andarcuatenucleus(Fuxeetal.,1987).InthePVN,glucocorticoidssignalbynon-geno-micmechanismstorapidlyinhibitactivationofparvocellularneu-ronsandconsequentdriveontheHPAaxis(Evansonetal.,2010;TaskerandHerman,2011).These‘fastfeedback’glucocorticoideffectsarenon-genomicinnature,actingthroughanendocannab-inoid-dependentmechanismtoinhibitglutamatergicdrive(TaskerandHerman,2011).FastinhibitoryeffectsofglucocorticoidsareattenuatedinanimalswithPVNGRdeletion,consistentwithactionviaGR(Haametal.,2010).However,theroleofGRinotherPVN-projectinghypothalamiccellgroupsremainstobedetermined.3.1.Medialprefrontalcortex

PreviousstudiesdeterminedthatglucocorticoidsactatthemPFCtoinhibitHPAaxisresponsestopsychogenicstress(e.g.re-straint)(Akanaetal.,2001;Diorioetal.,1993).Morerecently,weestablishedthatglucocorticoidsbindspeci callytoGRintheplPFCorilPFCtoregulateglucocorticoidresponsestoacutepsy-chogenicstress(McKlveenetal.,2013).Glucocorticoidsalsomobi-lizeendocannabinoidsinthemPFCinresponsetoacutestress,andcannabinoidreceptor1(CB1)antagonismdisinhibitstheHPAaxis(Hilletal.,2011).Thus,glucocorticoidsacutelyinhibittheHPAaxisviaGRandconsequenteffectsonendocannabinoidsignaling.Ourlabhasalsodemonstratedthatchronicstressselectivelyrecruits