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Stress has any effects n the brain. In aitin t prepar-ing an iniial fr the acte cnseqences f angersr threatening sitatins an the retrn t hestasis,an iprtant fnctin f stress is t ince lng-teraaptie respnses
1
. Enhance ery fr stressfl retinally arsing eents is a well-recgnize, highly aaptie phenenn that helps s t reeber ipr-tant infratin. Finings fr experiental stiesinicate that peple hae g recllectin f where they were an what they were ing when they experiencean earthqake
2
r witnesse an accient
3
. Siilarly, ratsreeber the place in a piece f apparats where they receie a ftshck r the lcatin f an escape platfrin a tank fille with water
4,5
. Sch ery enhanceentis nt liite t experiences that are npleasant r aer-sie: pleasrable eents als ten t be well reebere.There is extensie eience that the aygala, a grpf nclei lcate in the eial tepral lbe
(FIG. 1)
, iscrcially inle in reglating stress effects n e-ry 
6
. Finings inicate that stress hrnes an stress-actiate nertransitters enhance the cnsliatin f ery fr etinally arsing experiences thrghactins inling the aygala. Sch aygala actiatinstrengthens the strage f ifferent kins f infratinthrgh the aygala’s wiesprea netwrk f efferentprectins t ther brain regins. Hweer, stress anetinal arsal  nt nly ince strng eries f new infratin: they can als ipair r reeberingthrgh aygala interactins with ther brain regins.Bt the brain is nt a static rgan: it has strctralan fnctinal plasticity that can hae bth aaptie analaaptie cnseqences
7,8
. It is nw eient thatintensely etinal eents r chrnic expsre t stress-fl experiences can create traatic eries an eenreslt in the eelpent f  an anxiety isr-ers, incling pst-traatic stress isrer (PTSD)an ar epressie illness. Anial els inicatethat acte an chrnic stress ince lng-ter fnc-tinal an rphlgical alteratins in specific ayg-ala nclei, tgether with assciate changes in therbrain regins sch as the hippcaps an the prefrn-tal crtex, which ight nerlie the cgnitie changes,increases in anxiety-like behair an  altera-tins that are fn in these cnitins. Iprtantly,stress-ince fnctinal an strctral changes in theaygala hae a pattern that iffers entirely fr thatbsere in these ther brain regins.In this Reiew we first sarize the rle f theaygala in eiating the effects f acte stress nlearning an ery, an the nertransitters anhrnes inle in this prcess.
 
Next we escribe hwacte an chrnic stress expsre inces fnctinalan rphlgical changes in the aygala as well asnernal reelling in ther, assciate brain regins.We then iscss hw sch changes in aygala fnctinan rphlgy, an the assciate changes in thesether brain regins, ight cntribte t alaaptierespnses after expsre t seere r chrnic stress.
The amygdala in memory consolidation
Acte stress expsre inces the actiatin f any if-ferent hrnal an nertransitter systes
9
. Lts f these systes are knwn t inflence ery cnsli-atin prcesses. Extensie eience inicates that thebaslateral cplex f the aygala (BLA; cnsisting f the lateral, basal an accessry basal nclei) is an ipr-tant lcs fr integrating these latry inflences nery cnsliatin
10
.
 A central role for noradrenaline.
Nrarenaline releaseint the aygala in respnse t stressfl r etinalstilatin
11
has a central rle in reglating stress effects
*Department of Neuroscience, Section Anatomy, University Medical Center Groningen, Universityof Groningen, AntoniusDeusinglaan 1, 9713 AV Groningen, te Neterlands.
‡
Laboratory of Neuroendocrinology,Rockefeller University,1230 York Avenue, New York,New York 10065, USA.
§
National Centre for Biological Sciences, TataInstitute of Fundamental Researc, Bangalore560065, India.Correspondence to B.R.e‑mail:b.roozendaal@med.umcg.nl 
doi:10.1038/nrn2651Published online 13 May 2009
Stress, memory and the amygdala
Benno Roozendaal*, Bruce S. McEwen
‡
and Sumantra Cattarji 
§
Abstract | Emotionally significant experiences tend to be well remembered, and theamygdala has a pivotal role in this process. But the efficient encoding of emotional memoriescan become maladaptive — severe stress often turns them into a source of chronic anxiety.Here, we review studies that have identified neural correlates of stress-induced modulationof amygdala structure and function — from cellular mechanisms to their behaviouralconsequences. The unique features of stress-induced plasticity in the amygdala, inassociation with changes in other brain regions, could have long-term consequences forcognitive performance and pathological anxiety exhibited in people with affective disorders.
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© 2009 Macmillan Publishers Limited. All rights reserved
 
 
Prefrontal cortexHippocampusCaudate nucleusNucleus accumbensLABABLACeAMeAHypothalamusMidbrainPonsBNSTBNSTHypothalamusRegulation of autonomic, behaviouraland hormonal responsesModulationof learningand memory
Inhibitory avoidance task
A learning task in whichanimals are placed in a smallstarting compartment or ona small platform and receive asingle footshock afterentering a largercompartment or steppingdown from the platform.Memory of the one-trial trainingexperience is usually tested byplacing the animals back in thesame position and recordingthe delay before they moveto the place where theyreceived the footshock.
Contextual fear conditioning
A learning paradigm in whichanimals are placed in a piece of apparatus and given a seriesof footshocks. Memory of thetraining experience is typicallyassessed by measuring howlong the animals freeze whenthey are subsequentlyreplaced in the apparatus.
n ery cnsliatin. Infsins f nrarenalineint the BLA, bt nt the aacent central ncles f the aygala (CeA), f ice an rats ieiately aftertraining n etinally arsing learning tasks enhancethe cnsliatin f ery f sch training experi-ences, whereas blcking training-ince nrarenalinewith β-arenceptr antagnists ipairs this cnsli-atin
12,13
. Actiatin f β-arenceptrs in the BLApst-training enhances ery cnsliatin thrghstilatin f the cyclic AmP-epenent prtein kinasepathway 
14
. Actiatin f α1-arenceptrs in the BLAals enhances ery; hweer, actiatin f thisreceptr type sees nt t irectly actiate cAmP, bt tenhance ery cnsliatin thrgh a ptentiatinf the β-arenceptr cAmP respnse
14,15
.Extensie eience inicates that nrarenergicactiity in the BLA is essential in eiating the la-try effects f ther hrnes an nertransitters nery cnsliatin. many sties hae reprte thatintra-BLA infsins f the GABA (γ-ainbtyric aci)-ergic receptr antagnist bicclline enhance ery cnsliatin an that GABAergic receptr agnistsipair ery 
16,17
. Antagnists fr β-arenceptrsinfse int the aygala blck the ery-enhancingeffects f bicclline infse cncrrently 
10
. Stress exp-sre als inces rapi increases in BLA leels f en-cannabinis, a faily f ebrane-erie retrgraeessenger lecles
18
. Recently it has been reprte thatactiatin f the CB1 encannabini receptr in theBLA enhances ery cnsliatin whereas blckaef CB1 receptrs inces ery ipairent
19
. As CB1receptr actiatin is knwn t ecrease GABA releasein the BLA an ther brain regins
20,21
, sch finingssggest that encannabinis ight enhance ery cnsliatin by inhibiting GABAergic actiity in theBLA, thereby presynaptically increasing nrarenergictransissin.
Effects of stress hormones.
The effects f arenal stresshrnes (sch as arenaline an glccrticis) nthe enhanceent f ery cnsliatin als epenn the integrity f the aygala nrarenergic syste
10
.Willias an clleages
22
reprte that arenalineainistere systeically ieiately after
inhibitoryavoidance
training increases nrarenaline leels inthe aygala, whereas thers shwe that infsins f a β-arenceptr antagnist int the aygala blck the ery-enhancing effects f peripherally ain-istere arenaline
23
. As arenaline is a plar sbstancethat es nt reaily crss the bl–brain barrier,a pathway rnning fr the periphery t the CNS isst likely inle in eiating arenaline’s effects naygala latin f ery cnsliatin
24,25
. It isnw well establishe that systeic arenaline can acti- ate peripheral β-arenceptrs lcate n agal affer-ents that terinate in the ncles f the slitary tract.In trn, nrarenergic cell grps in this brain reginsen irect prectins t the aygala. In aitin, thencles f the slitary tract reglates the nrarenergicactiity f the frebrain thrgh inirect prectins tnrarenergic cell grps in the lcs cerles
26
, theain srce f nrarenaline inpts t the BLA
27
.unlike arenaline, glccrtici hrnes rea-ily enter the brain an bin irectly t arenal sterireceptrs in the BLA an ther brain regins
28
. A spe-cific glccrtici receptr (GR) agnist ainistereint the BLA ieiately after inhibitry aiancetraining r
contextual fear conditioning
enhances e-ry cnsliatin, whereas a GR antagnist ipairsthe cnsliatin f ery f these an ther learningexperiences
29,30
. Frtherre, nertxic lesins f theBLA, bt nt the CeA, blck the ery enhanceentthat is ince by systeically ainistere glccr-ticis
31,32
. Glccrticis als reqire nrarenergicactiity in the BLA t enhance the cnsliatin f ery fr etinally arsing training
33,34
: pst-training actiatin f GRs in the BLA facilitatesery cnsliatin thrgh a rapi ptentiatinf the nrarenaline signalling cascae
34
; cnersely,intra-BLA infsins f a GR antagnist attenate these–respnse effects f a β-arenceptr agnist nretentin enhanceent fr inhibitry aiance train-ing
34
. These finings sggest that glccrticis facili-tate the effects
 
f nrarenergic stilatin in the BLAn ery cnsliatin thrgh an interactin withthe β-arenceptr–cAmP cascae.
Figure 1 |
T man bn  t amygala an t ntn an xtn nntn.
The basolateralcomplex of the amygdala (BLA) consists of the lateral amygdala (LA) and basal amygdala (BA) and projects to manydifferent brain regions involved in learning and memory, including the prefrontal cortex, the hippocampus, the caudatenucleus and the nucleus accumbens. The BA also projects to the central amygdala (CeA) and the medial amygdala (MeA).The CeA projects to autonomic, behavioural and hormonal regulatory centres in the hypothalamus, the midbrain, the ponsand the bed nucleus of the stria terminals (BNST). The MeA sends efferents to the BNST and hypothalamus.
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 Training trialRetention trial
IntervalDayDayA1 A2
A3 B?
With habituationWith habituationWithout habituationWithout habituation
1 2 3 4 5 6 7 8 91 2 3 4 5 6 7 8 9
Cort (sc)Cort (sc)
   D   i  s  c  r   i  m   i  n  a   t   i  o  n   i  n   d  e  x   (   %   )
VehicleCort 0.3 mg per kgCort 1.0 mg per kgCort 3.0 mg per kg
–1001020304050
   D   i  s  c  r   i  m   i  n  a   t   i  o  n   i  n   d  e  x   (   %   )
–1001020304050
Propranolol(3.0 mg per kg)Yohimbine(0.3 mg per kg)Habituation to test caseTraining in test caseRetention in test case******
Water-maze task
A spatial learning and memorytask that depends on thehippocampus. Rodents aretrained to learn the location of an escape platform that ishidden beneath the surface ina pool of water. The cuedversion of the water maze taskmeasures a form of implicitlearning and memory thatdepends on the caudatenucleus; here, animals aretrained to swim to a visibleplatform that is moved fromone location to another acrosstrials.
Recent finings inicate that the ery-latingeffects f the nerpeptie crtictrpin-releasing factr(CRF), which is release in the aygala after stress,
 
alsepen n interactins with the β-arenceptr–cAmPcascae in the BLA
35
. mreer, it was fn that theCRF an glccrtici systes in the BLA interact ininflencing β-arenceptr–cAmP effects n ery cnsliatin: a blckae f GRs in the BLA preentscncrrently ainistere CRF fr enhancing ery cnsliatin f inhibitry aiance training
35
.
Role of emotional arousal.
The eience that arsal-ince nrarenergic actiatin in the BLA is essentialin eiating the latry effects f stress hrnesan any nertransitters n ery cnsliatinhas iprtant cnseqences. Fr exaple, recent fin-ings inicate that arenal stress hrnes latethe cnsliatin f ery fr etinally arsingexperiences that ince the release f nrarenalineint the aygala, bt  nt affect ery cnslia-tin f netral infratin
36–38
. A sty that exainethis isse in rats reprte that crticsterne ain-istere systeically ieiately after bect recgni-tin training enhance the cnsliatin f ery f this experience in etinally arse rats that hant been habitate t the cntext
39
 
(FIG. 2)
. By cntrast,pst-training ainistratin f crticsterne i ntenhance the retentin f bect recgnitin in habitaterats, which shwe an attenate arsal respnse r-ing the training. Habitatin f rats t the experientalcntext significantly rece nrarenergic actiity inthe BLA ring bect recgnitin training, as assesseby rece actiity f tyrsine hyrxylase, the rate-liiting enzye in the bisynthesis f nrarenaline
40
.In nn-habitate (that is, etinally arse) rats, theβ-arenceptr antagnist prpranll, ainisteresysteically r irectly int the BLA, blcke the cr-ticsterne-ince ery enhanceent
41
. T eter-ine whether the failre f crticsterne t enhanceery cnsliatin ner lw-arsal cnitinswas e t insfficient training-ince nrarenergicactiatin, lw ses f the α2-arenceptr antagnistyhibine, which increases nrarenaline leels in thebrain, were c-ainistere with the crticsterne twell-habitate rats ieiately after bect recgni-tin training. The crcial fining f this sty was thatsch an agente nrarenergic tne was sfficient tiic the effects f etinal arsal, in that silta-nesly ainistere crticsterne enhance ery cnsliatin
41
. Frther, in habitate rats crticsterneactiate BLA nerns, as assesse by phsphrylateCRE-bining prtein inreactiity leels, nly inanials that als receie yhibine. Finings f hansties are cnsistent with thse f anial sties anhae prie eience that stress hrne effects nery enhanceent f etinally arsing trainingreqire nrarenergic
42,43
an aygala actiity 
44
.
BLA interactions with other brain regions.
many f theexperients that inestigate BLA inleent in e-ry cnsliatin se inhibitry aiance an fearcnitining training an testing, bt cparable effectsf pst-training aygala treatents hae been btainein experients sing ifferent kins f aersie r appe-titie training tasks. Seeral recent sties hae inicatethat the BLA can inflence the cnsliatin f e-ry f ifferent kins f infratin thrgh its any efferent prectins t ther brain regins
10
 
(FIG. 3)
.
 
TheBLA prects irectly t the caate ncles an bthirectly an inirectly t the hippcaps
45,46
, anthere is cnsierable eience that these tw areas areinle in ifferent kins f learning
47,48
. In sties f rats gien
water-maze
training, Packar an clleages
49
 fn that aphetaine infse pst-training intthe caate ncles selectiely enhance ery f  isally ce training, whereas infsins int the rsalhippcaps selectiely enhance ery f spatialtraining. By cntrast, aphetaine infse int theaygala pst-training enhance ery fr bth
Figure 2 |
Glt t n mmy nlatn  bjt gntntanng q aal-n nang atatn.
Rats were eitherhabituated to the training context for 7 days or not habituated. On day 8 they weregiven a 3 min training trial during which they could freely explore two identical objects,followed by systemic drug administration. Retention was tested 24 h later by placingthe rats back into the apparatus for 3 min; now one object was similar to that exploredduring training whereas the other object was novel. Corticosterone (Cort) injectionsselectively enhanced memory consolidation in context-naive rats, which showedgreater emotional arousal response during training. Systemic post-trainingadministration of the
β
-adrenoceptor antagonist propranolol blocked this memoryenhancement in naive (emotionally aroused) rats. Co-administration of the
α
2-adrenoceptor antagonist yohimbine with corticosterone enhanced objectrecognition memory in habituated (emotionally non-aroused) rats. The data representthe discrimination index (%) on a 24 h retention trial, expressed as the mean ± thestandard error. The discrimination index was calculated as the difference in time spentexploring the novel and the familiar object, expressed as the ratio of the total timespent exploring both objects. ** p<0.0001 vs vehicle
41
.
 
Figure is modified, withpermission, from
REF. 41
 
(2006) National Academy of Sciences.
REVIEWS
NATuRE REvIEWS
|
 
NeuroscieNce 
voLumE 10
|
juNE 2009
|
 
 425
focu
 
S on StRESS
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