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OpinionOpinionTRENDS in Neurosciences Vol.25 No.9 September 2002

Memoryconsolidation and theamygdala: a systemsperspective

James L. McGaugh

The basolateral region of the amygdala (BLA) plays a crucial role in makingsignificant experiences memorable. There is extensive evidence that stresshormones and other neuromodulatory systems activated by arousing trainingexperiences converge in regulating noradrenaline-receptor activity within theBLA. Such activation of the BLA modulates memory consolidation via BLAprojections to many brain regions involved in consolidating lasting memory,including the hippocampus, caudate nucleus, nucleus basalis and cortex.Investigation of the involvement of BLA projections to other brain regions isessential for understanding influences of the amygdala on different aspectsand forms of memory.

Published online: 18 July 2002

the amygdala (acts) directly on cortical neurons

to altertheir responsiveness to the discrete impulsesthat reach the cortexthese deep nuclei could easilymodify the ease and completeness of experiencefixation even if the nuclei were not themselves the lociof engrams. Ralph Gerard 1961 [1]

The hypothesis that the amygdala is involved in theconsolidation of newly created memories is, as thequotation above indicates, not a new idea. But it wasclearly a prescient one. Although findings reportedmore than six decades ago suggested that theamygdala might play a role in learning and memory[2], the amygdala did not figure either prominently or

consistently as a brain region important for memoryin the ensuing decades. The area was for many yearsthe Cinderella of memory research in thebackground and rarely noticed. Lashleys pioneeringinvestigations of cortical function in memory (or lackthereof) [3] dominated research examining brainsystems involved in learning at that time. Theresearch focus shifted abruptly with the publication ofScoville and Milners report of the effects of bilateralsurgical removal of the medial temporal lobes,including the anterior hippocampus and the

James L. McGaugh

amygdala [4]. The finding that the patient H.M. had,

Center for theNeurobiology of Learning and has to this day [5], severe anterograde amnesia

and Memory and Dept of for explicit or declarative memory drew the focus ofNeurobiology and

research attention to the hippocampus [6,7]. The fact


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Behavior, University of

that H.M. also lost his amygdala (bilaterally) mostly

California, Irvine,CA 92697-3800, USA. escaped attention.

For several decades, the intriguing findings ofresearch on the hippocampus stronglyovershadowed interest in the possible involvementof the amygdala in learning and memory. A fewstudies, including those of Weiskrantz [8] and Jonesand Mishkin [9] (which suggested that the amygdalamight play a role in enabling the learning ofassociations between cues and reinforcements), keptthe interest from fading completely. Even Goddardsseminal finding that electrical stimulation of theamygdala produced retrograde amnesia [10] failedto attract significant attention. Gerards suggestionthat the amygdala might directly influence memoryconsolidation in cortical neurons [1] also failed tostimulate inquiry. In those decades, a

word-association test using the word amygdalawould certainly not have produced the short-latencyresponse memory.

Research findings of the past couple of decadeshave now focused a strong spotlight on theamygdala. Cinderella has been invited to thebrain-systems and memory ball, and the amygdalahas joined the select list of brain structures thoughtto be involved in learning and memory. Importantly,the findings suggest that the nuclei of the amygdalacould have several roles in learning and memory,including attention [11], cue-, place- and

object-reward associations [1115], conditioned tasteaversion [16], appetitive conditioning and drugaddiction [17], and conditioned fear and anxiety[18,19]. Moreover, extensive evidence now stronglysupports Gerards long-ignored suggestion [1] thatthe amygdala is involved in modulating memoryconsolidation [20,21].

Much current research is guided by thehypothesis that the amygdala, especially thebasolateral complex of the amygdala (BLA),could be a locus of neuroplasticity underlying theconsolidation of Pavlovian fear conditioning

[18,19,22]. This hypothesis suggests thatunderstanding the cellular mechanisms underlyinglong-term potentiation (LTP) within the amygdalamight reveal how fear-based memory is formed andstored within the amygdala [23,24]. However, it isimportant to note that it is not yet clear how, orwhether, this hypothesis can accommodate theextensive findings that complete lesions of the BLAdo not prevent fear-based learning includingPavlovian fear conditioning [2528]. Additionally,


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such lesions do not prevent Pavlovian appetitiveconditioning or other types of appetitively basedlearning [11]. Thus, it is currently premature to drawany firm conclusion concerning the hypothesis thatthe BLA could be a locus of neuroplasticityunderlying memory for any kind of training.However, it is not premature to conclude that there isstrong support for Gerards suggestion that theamygdala has an important role in regulatingmemory consolidation at other brain loci, even if it isnot the locus of engrams [1].

http://tins.trends.com 0166-2236/02/$ see front matter 2002 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(02)02211-7


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TRENDS in Neurosciences Vol.25 No.9 September 2002http://tins.trends.comOpinion 457Modulation of memory consolidation by the amygdalaThere is considerable evidence that drugs andneurotransmitters infused into the amygdalamodulate memory consolidation. Gallagher andcolleagues [29,30] were the first to report that drugsinfused into the amygdala influence consolidationof memory for inhibitory avoidance training.Administration of -adrenaline-receptor antagonistsinto the amygdala impaired 24 h retention whenadministered immediately after training but had noeffect when administered 6 h after training.Intra-amygdala infusions of noradrenaline, whenadministered together with the -adrenaline-receptorantagonists, attenuated the memory impairment.Importantly, many subsequent studies found thatnoradrenaline produces dose-dependent andtime-dependent enhancement of memoryconsolidation when infused into the amygdala shortlyafter inhibitory avoidance training, or training onseveral other kinds of tasks [3134].

Post-training peripheral infusions of adrenaline,as well as either peripheral or intra-amygdalaadministration of drugs affecting the GABA-,opioid-, glucocorticoid- or muscarinic ACh-receptorsystems in the amygdala, also have dose- andtime-dependent influences on memory consolidation[15,30,3545]. These effects, with the exception ofthe influences of ACh, involve modulation ofnoradrenaline activation within the amygdala[30,31,4648]. Moreover, the BLA is the crucialregion of the amygdala for mediating theseneuromodulatory influences on memoryconsolidation [4345,49,50]. Drug infusions

administered selectively into the immediatelyadjacent central amygdala do not affect memoryconsolidation [38,47,51]. Furthermore, selectivelesions of the BLA (but not the central nucleus) blockthe memory-modulating effects of peripherallyadministered drugs and hormones [20,5254].Modulation of memory consolidation by the BLA:the role of efferent projections from the amygdalaThe BLA does not work alone in performing its role inmodulating memory consolidation. The BLA projectsto many brain regions, including various corticalregions, the hippocampus, basal forebrain, thenucleus accumbens (NAc) and the striatum [5557]

(Fig. 1). There is now considerable evidence that theseprojections are crucial in mediating BLA influenceson the consolidation of different forms of memory.Lesions of the stria terminalis (ST), a majorpathway connecting the amygdala to other brainregions (including the NAc and dorsal striatum),block the effects of electrical stimulation of theamygdala on memory for inhibitory avoidancetraining but do not otherwise impair acquisition orretention [58]. Lesions of the ST also block the


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memory-enhancing effects of noradrenaline infusedinto the amygdala after training [32] as well as thememory-modulating effects of adrenaline and thoseof drugs affecting the opiate, glucocorticoid andmuscarinic-ACh systems [46,5861]. Findings ofseveral studies indicate that the BLA projections tothe NAc via the ST are crucial for mediating BLAinfluences on memory consolidation. As was foundwith ST lesions, NAc lesions block the memoryenhancingeffects of the synthetic glucocorticoiddexamethasone when this is administeredsystemically after inhibitory avoidance training.Furthermore, combination of a unilateral NAc lesionwith a contralateral BLA lesion also blocksdexamethasone-induced memory enhancement [62].Modulation of memory consolidation by the amygdala:the roles of the caudate nucleus and hippocampusThe BLAST pathway provides a major efferentprojection enabling BLA influences on other brainregions involved in memory consolidation. It is wellestablished that injection of drugs affecting AChreceptors into the striatum influences theconsolidation of memory for inhibitory avoidancetraining [63,64]. The amygdalaSTstriatum

connection is crucial for this influence, as ST lesionsblock the memory enhancement that is induced byinfusions of the muscarinic ACh-receptor agonistoxotremorine directly into the striatum immediatelyafter training [65]. There is also extensive evidencethat the amygdala influences hippocampal memoryconsolidation processes. Packard and Chen [66]reported that infusions of glutamate administeredinto the hippocampus after training on afood-rewarded maze task enhanced memoryconsolidation and that concurrent inactivation of theamygdala with lidocaine blocked the enhancement.Lesions of the ST or of the BLA also block the

memory-enhancing effects of systemicallyadministered dexamethasone [52,60]. As glucocorticoidreceptors are densely located in the hippocampus, thehippocampus is one likely locus of the glucocorticoidinfluence on memory consolidation. Lesions of the BLATRENDS in NeurosciencesOthercortical regionsCaudatenucleusNucleusaccumbensBasolateral

amygdalaHippocampusEntorhinalcortexBasalismagnocellularisFig. 1. Projections fromthe basolateral complexof the amygdala to otherbrain areas involved in


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memory consolidation.


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OpinionTRENDS in Neurosciences Vol.25 No.9 September 2002

or NAc block the memory enhancement that is inducedby infusions of a glucocorticoid-receptor agonistdirectly into the hippocampus after inhibitoryavoidance training [61,67]. These findings stronglysuggest that BLASTNAc projections are animportant pathway mediating BLA influences onmemory consolidation involving the hippocampus.Asdiscussed above, activation of noradrenaline receptorswithin the BLA appears to be essential for theamygdala to influence memory consolidation. Thefinding that infusions of -adrenaline-receptorantagonists into the BLA also block the memory-enhancing effects of a glucocorticoid-receptor agonistadministered into the hippocampus after training [68]provides further evidence of the role of noradrenalinein the BLA as well as of the influence of the BLA onhippocampal function in memory consolidation. Thereport that lesions of the amygdala block the impairingeffects of acute stress on hippocampal LTP andwater-maze spatial learning [69] provides additional

evidence of amygdalahippocampus interactions inmemory formation [70].

Many studies have reported findings suggestingthat the caudate nucleus and hippocampus areinvolved in consolidating different forms or types ofmemory. Several double dissociation studies [7174]have reported that drug treatments and lesionsaffecting the caudate nucleus selectively influencecued learning and memory, whereas the sametreatments affecting the hippocampus selectivelyinfluence spatial and relational learning. Thus, thecaudate nucleus and hippocampus appear to be

dedicated to the consolidation of different kinds ofinformation or forms of memory. By contrast, there isevidence that the amygdala is promiscuous in itsinfluence on the consolidation of different forms ofmemory. Amphetamine infused into the amygdalaafter training enhances both cued andspatial/relational memory [75,76]. Furthermore,infusions of lidocaine into the caudate nucleus aftertraining prevent the amygdala-induced enhancementof memory for cued water-maze training, whereaslidocaine infused into the hippocampus after trainingprevents the amygdala-induced enhancement ofmemory for spatial water-maze training [76]. These

findings indicate that the amygdala modulates theconsolidation of memory for cued training byinfluencing the caudate nucleus, and theconsolidation of spatial and relational memory byinfluencing the hippocampus.

Modulation of memory consolidation and hippocampalLTP by the BLA

Other recent findings provide further evidence


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consistent with the hypothesis that the amygdalaprovides a modulatory and time-limited influence onhippocampal functioning in memory consolidation [77].Infusions of the protein kinase II (CaMKII) inhibitorKN-62 induce retrograde amnesia when administeredinto the amygdala or CA1 region of the hippocampus

immediately after inhibitory avoidance training.Infusions of drugs that stimulate protein kinaseA(PKA) (e.g. noradrenaline and the cAMP analog 8-BrcAMP)enhance memory when administered into thehippocampus, but not the amygdala, 3 h after training.As noradrenaline or 8-Br-cAMP infused into thehippocampus 3 h after training also attenuates theamnesia induced by KN-62 administered into theamygdala immediately after training, the amygdalainducedamnesia appears to reflect disruption ofmodulatory influences rather than disruption ofmemory consolidation within the amygdala. Bycontrast, the hippocampus does appear to be crucial formemory consolidation. Noradrenaline or 8-Br-cAMPinfused into the hippocampus 3 h after training doesnot attenuate amnesia induced by KN-62 infused intothe hippocampus immediately after training [78].

Activation of CaMKII and PKA cascades in thehippocampus appears to be crucial for LTP [79] aswell as for memory consolidation [80,81]. Many recentstudies have reported that the BLA modulates LTP inthe hippocampus in vivo. Lesions of the BLA oradministration of -adrenaline-receptor antagonistsinto the BLA block the induction of LTP in the dentategyrus [8284]. Moreover, stimulation of the BLAeither before or within 30 min following LTPinduction enhances LTP [8587]. It remains to bedetermined, of course, whether such LTP is causallylinked to memory [88].

Influences of BLAcortical connections onmemory consolidation

It is now well established that the cortex is also acrucial locus of memory consolidation. Functionalinactivation of cortical regions after training with theGABA-receptor agonist muscimol, with the Na2+channelblocker tetrodotoxin or by infusion of drugsaffecting the cAMPPKA signaling pathway producesretrograde amnesia for training in several kinds oflearning tasks [8992]. Drug infusions administeredinto cortical regions can also enhance memory

consolidation [90].Additionally, and importantly,evidence from several recent studies indicates that theBLA modulates cortical functioning in memoryconsolidation.All nuclei within the BLA complexproject directly to the entorhinal cortex [57,93] andfiring of BLA neurons activates neurons in theentorhinal cortex [94,95].As is shown in Fig. 2a,infusions of 8-Br-cAMP into the entorhinal corteximmediately after inhibitory avoidance trainingenhance retention. Projections from the BLA are


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essential in enabling the modulation of memoryconsolidation mediated by the entorhinal cortex, aslesions of the BLA block the memory enhancement [96].

The nucleus basalis magnocellularis (NBM)provides cholinergic projections to the cortex. Thefinding that functional inactivation of the NBMwith infusions of lidocaine impairs the acquisitionof conditioned taste aversion indicates thatACh-mediated activation of the cortex is crucial for

http://tins.trends.com


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Basolateral amygdalaVehicle0.3 g Noradrenaline1.0 g Noradrenaline3.0 g NoradrenalineSham IgG-saporin lesionsRetention latencies (s)050100150200250300350NMDA lesions*****(a)

Entorhinal cortexVehicle0.25 g 8-Br-cAMP1.25 g 8-Br-cAMPRetention latencies (s)250200150100500(b)Sham

Basolateral amygdala

Acknowledgements

I thank Larry Cahill,Ivan Izquierdo,Richard Morris,Benno Roozendaal,Georg Striedter andNorman Weinberger fortheir thoughtful andhelpful comments on aprevious draft of this

paper, and Ann Power andNancy Collett forassistance in preparingthe manuscript.

References

Fig. 2. Interactions of the basolateral complex of the amygdala (BLA)with the cortex in memory consolidation. (a) Lesions of the BLA blockthe memory-enhancing effects (in a 48 h retention test) of 8-Br-cAMP


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infused into the entorhinal cortex immediately after training on a one-trial inhibitory avoidance task. *P < 0.05 and **P < 0.01 compared to thecorresponding control group [96]. P < 0.05 and P < 0.01 compared tocorresponding 8-Br-cAMP sham-lesion control groups. (b) Lesions ofnucleus basalis magnocellularis (NBM) induced by infusions of 192IgG-saporin block the memory enhancement (in a 48 h retention test),as induced by post-training infusions of noradrenaline administeredinto the basolateral amygdala immediately after inhibitory avoidancetraining. *P < 0.01 and **P < 0.001 compared to vehicle sham-lesioncontrol groups. P < 0.05 and P < 0.001 compared to correspondingsham-lesion animals receiving the same noradrenaline dose [34].

this form of learning a form that is also known toinvolve the BLA [97]. Activation of the NBM and theconsequent release of ACh in the auditory cortex areessential for the consolidation of changes in corticalfunction (receptive field plasticity) induced byPavlovian conditioning using tone-shock pairing[98101]. The BLA is a principal source of afferents tothe NBM [102]. Several lines of evidence suggest thatthe BLA modulates cortical activity via projections tothe NBM mediated largely by the ST. Dringenbergand Vanderwolf [103] reported that BLA stimulationactivates cortical EEG activity (i.e. induces low voltage

high frequency activity) and that lidocaine infusedinto the NBM blocks the BLA-induced activation.Moreover, BLA stimulation potentiates the corticalEEG activation evoked by somatosensory stimulation[104]. These findings suggest that BLA activation ofthe NBM and consequent ACh-mediated activation ofthe cortex could be important, and possibly essential,for modulation of memory consolidation. This issuewas investigated in a recent study of BLA influenceson memory in rats with lesions of the NBM induced by192 IgG-saporin, a p75 nerve growth factor

Symp. Soc. Exp. Biol. 4, 454482

Nucleus basalis magnocellularis

TRENDS in Neurosciences

receptor-mediated neurotoxin that selectivelydestroys cholinergic projections to the cortex [42]. As isshown in Fig. 2b, the dose-dependent enhancement ofmemory consolidation induced by noradrenalineadministered into the BLA after training wascompletely blocked in animals with 192 IgG-saporinlesions [34]. These findings provide strong support forthe hypothesis that BLANBMcortical cholinergic

projections play an important, if not crucial, role inmediating the memory-modulating influence ofadrenaline-receptor activation of the BLA.

BLA: connections and consequences

The BLA makes good use of its many connectionswith other brain regions in regulating memoryconsolidation. Some of the brain regions influenced bythe BLA (e.g. the hippocampus and possibly the


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entorhinal cortex) could regulate the consolidation oflong-lasting memory in circuits elsewhere in thebrain, whereas others (e.g. the caudate nucleus andNBM-activated cortical regions) might serve as theloci of lasting memories. Learning-inducedneuroplasticity within the amygdala [23,24] couldplay a role in enabling the prolonged post-trainingmodulatory influences of the BLA on memoryconsolidation in other brain regions.

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