Arousal and Stress Effects on Consolidation and Reconsolidation of Recognition Memory

12 Pages·2007·0.28 MB·English

Neuropsychopharmacology(2008)33,394–405
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Arousal and Stress Effects on Consolidation and
Reconsolidation of Recognition Memory
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(cid:1) Mouna Maroun1 and Irit Akirav*,2
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(cid:1) 1Department ofNeurobiology andEtiology, TheBrain andBehavior Research Center, University ofHaifa,Haifa, Israel; 2Department
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(cid:1) ofPsychology,The Brain andBehavior ResearchCenter, University ofHaifa, Haifa,Israel
(cid:1)
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(cid:1)(cid:1) Thisstudyexaminedtheeffectsofthearousalleveloftheratandexposuretoabehavioralstressoronconsolidationandreconsolidation
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(cid:1) of a nonaversive learning paradigm, the object recognition task. Learning was tested under two arousal conditions: no previous
(cid:1)
(cid:1) habituationtotheexperimentalcontext(highnoveltystress/arousallevel)orextensivepriorhabituation(reducednoveltystress/arousal
(cid:1)
(cid:1) level).Resultsindicatedthatinthehabituatedrats,exposuretoanout-of-contextstressor(ie,elevatedplatformstress)impairedlong-
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(cid:1) term consolidation and reconsolidation of object recognition. RU-486, a glucocorticoid receptor (GR) antagonist, infused into the
(cid:1)
(cid:1) basolateral amygdala (BLA), reversed the impairing effects of the stressor. In contrast, the nonhabituated aroused rats were impaired
(cid:1)
(cid:1)(cid:1) whenconsolidationwasexamined,buttheirmemorywasintactfollowingreactivationofthememorytrace.Exposureofnonhabituated
(cid:1)
(cid:1) ratstoanout-of-contextstressorenhancedthelong-termconsolidationofrecognitionmemory,butimpairedreconsolidation,andthe
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(cid:1) effectswerereversedbyaGRantagonistinfusedintotheBLA.Additionally,nonhabituatedcontrolratsshowedintactretrievalfollowing
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(cid:1) microinfusionofpropranololtotheBLAimmediatelyafterthetraining,suggestinganinvolvementofbeta-adrenoceptorsintheBLAin
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(cid:1) thearousal-inducedimpairmentofconsolidation.Thesefindingsdemonstrateoppositeeffects,detrimentalandfacilitative,ofarousaland
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(cid:1) stress on memory consolidation and reconsolidation. In addition, the data suggests that although some general features underlie
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(cid:1) consolidationandreconsolidation,thereisapossibledissimilaritybetweenthetwoprocesses,whichisdependentonthearousallevelof
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(cid:1)
(cid:1) theanimal duringtraining.
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(cid:1) Neuropsychopharmacology (2008)33, 394–405;doi:10.1038/sj.npp.1301401; publishedonline 11April 2007
(cid:1)
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(cid:1) Keywords: stress;basolateral amygdala; RU-486;glucocorticoids; beta-adrenoceptors; propranolol
INTRODUCTION (Akirav and Richter-Levin, 2002; McGaugh, 2002;
Roozendaal, 2003).
Exposuretostress,aswellasthereleaseofstresshormones,
Memory consolidation refers to the progressive post-
for example, epinephrine and glucocorticoids from the
acquisitionstabilizationofthememorytrace(Dudai,2002).
adrenal during or after emotionally arousing experiences
When a memory is reactivated, it must undergo additional
plays a critical role in consolidating lasting memories (de
consolidation (reconsolidation) so as to persist (Alberini,
Kloet et al, 1999; McGaugh, 2002; McIntyre et al, 2003;
2005; Eisenberg et al, 2003; Milekic and Alberini, 2002;
Roozendaal, 2002). Numerous studies found enhancing as
Nader et al, 2000a,b; Sara, 2000). To determine whether
wellasimpairingeffectsonlearningandmemoryfollowing
reconsolidation recapitulates consolidation, several groups
acute stressoracuteglucocorticoidtreatment(Akiravetal,
have recently investigated whether the same molecules and
2001; Diamond et al, 1996; de Kloet et al, 1999; Lupien and
pathways mediate the formation of a memory and its
McEwen, 1997; Roozendaal, 2002; Sandi et al, 1997;
maintenance after reactivation (Akirav and Maroun, 2006;
Trneckova et al, 2005). Additionally, extensive evidence
Anokhinetal,2002;Debiecetal,2002;Kidaetal,2002;Lee
focuses on the role of the amygdala, and specifically the
etal,2004;Naderetal,2000a;PrzybyslawskiandSara,1997;
basolateral amygdala (BLA), as a critical system that
Torras-Garcia et al, 2005).
mediates stress hormone effects on memory consolidation
Hereweusedadifferent approachandaimedtoexamine
whether the arousal level of the animal or exposure to an
out-of-context stressor would differentially affect consoli-
dation and reconsolidation of a nonaversive paradigm, the
*Correspondence: Dr I Akirav, Department of Psychology, The Brain
object recognition task. In other studies comparing
andBehaviorResearchCenter,UniversityofHaifa,Haifa31905,Israel,
consolidation and reconsolidation, a reinforcing stimulus
Tel: [phone],Fax: [phone],
E-mail: [email protected] isusuallypresentduringtheconsolidationphasebutabsent
Received 7 November 2006; revised 5 February 2007; accepted 20 in the reconsolidation phase, thereby confounding the
February 2007 interpretation of the comparison (Nader, 2003). The object
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395
recognition task, on the other hand, does not involve an 1.0mm from the tip of the guide cannula, was inserted.
explicit exogenous reinforcer in the consolidation or The injection cannula was connected via PE20 tubing to a
reconsolidation phases. Because no rewarding or aversive Hamilton micro syringe driven by a microinfusion pump
stimulation is used during training, the learning occurs (CMA/100; Carnegie Medicin, Stockholm, Sweden). Micro-
under conditions of relatively low stress or arousal infusion was performed bilaterallyina0.5mlvolumeperside
(Ennaceur and Delacour, 1988). Arousal is not a passive deliveredover2min.Theinjectioncannulawasleftinposition
process and can be regulated by environmental and task before withdrawal for an additional minute to minimize
demands (Robbins, 1997). Accordingly, the placement of dragging of the injected liquid along the injection tract.
rats into an unfamiliar testing apparatus does evoke some
degreeofnovelty-inducedarousal,andrepeatedhabituationof
Object Recognition Task
rats to the experimental context is known to reduce this
arousalresponse(CerboneandSadile,1994;Okudaetal,2004; Objectrecognitionmemoryistheabilitytodiscriminatethe
Roozendaal et al, 2006). Thus, rats habituated to the training familiarity of previously encountered objects. It was tested
apparatus would be expected to be less aroused during the in a paradigm based on spontaneous exploration behavior
training than rats not given prior habituation training. of the rat (Ennaceur and Delacour, 1988). If a rat is
The present study investigated the effects of the arousal presented with both a familiar object and a novel object, it
level of the animal and its interaction with an exposure to willdirectmoreexplorationatthenovelobject.Theobjects
an out-of-context stressor on consolidation and reconsoli- were located in squared black open field (50(cid:2)50(cid:2)50cm)
dation of recognition memory. We present data to suggest underdimlightandwerefixedtotheflooroftheopen-field
that it is the arousal level of the rat during training that arena,10cmfromthewalls.Theobjectsusedinthepresent
playsarole indissociating consolidation from reconsolida- study were children’s toys made of plastic and varied in
tion of recognition memory. shapeandtexture,andwerechosenbasisofweightandsize,
thatis,theywerenolargerthantheratsandwererelatively
immovable.Fromrattorat,therole(familiarornewobject)
MATERIALS AND METHODS
as well as the relative positions of the two objects were
counterbalanced and randomly permuted. The open field
Animals
andtheobjectswerethoroughlycleanedbetweentrialswith
Male Wistar rats (B60 day old, 250–300g) were caged odorous clean wipes.
individually at 22721C under 12-h light/dark cycles. All Explorationwasdefinedassniffingortouchingtheobject
rats were allowed free access to food and water. with the nose and/or forepaws. Turning around or sitting
on the object is not considered as exploratory behavior. A
discrimination index calculated for each animal was
Drugs
expressed as T /(T +T ) (T ¼time spent exploring the
N N F F
The GR antagonist RU-38486 (10ng/0.5ml) and the b- familiarobject;T ¼timespentexploringthenovelobject).
N
adrenergic antagonist propranolol (Prop, 0.75mg/0.5ml) The amount of time spent exploring each object was
were obtained from Sigma (St Louis, MO). RU-38486 was recorded by an observer who was blind to the treatment.
first dissolved in 100% ethanol and subsequently diluted in Intactrecognitionmemoryinthetestphaseisreflectedina
saline to reach the appropriate concentration. The final discrimination score higher than 0.5, which implies greater
concentrationofethanolwas2%.TheRU-486dosewasbased exploration of the novel object.
on previous work showing a significant effect of RU-486 on
memory when microinfused into the BLA (Roozendaal and
Habituation and Handling
McGaugh,1997a;Roozendaaletal,1999).Controlsweregiven
the vehicle (2% ethanol) only. Prop was dissolved in About half of the rats were habituated to the experimental
physiological saline, which was also used as a control. apparatus by allowing them to explore it for 5min twice a
day for 4 days before the experiment was performed
(habituated). No object was placed inside the arena during
Surgery and Drug Administration
habituation. The other half was not habituated to the
Ratswereanesthetizedwith4.8ml/kgequithesin(2.12%(w/ experimentalapparatus,onlyhandledonceadayfor2days
v) MgSO , 10% (v/v) ethanol, 39.1% (v/v) propylene glycol, in their home cage (nonhabituated).
4
0.98% (w/v) sodium pentobarbital, and 4.2% (w/v) chloral It has been recently demonstrated in an object recogni-
hydrate),restrainedinastereotacticapparatus(DavidKopf tion task that animals that were not habituated to the
Instruments,Tujunga,CA),andimplantedbilaterallywitha experimental apparatus showed a twofold increase in
stainless steel guide cannula (23-gauge, thin wall) aimed plasma corticosterone levels as compared with habituated
to the BLA (anteroposterior, (cid:1)3mm relative to bregma; animals (Okuda et al, 2004). Furthermore, the nonhabitu-
lateral, 75mm; ventral, (cid:1)7.4mm). The cannulae were ated animals in the present open-field test were found to
positioned in place with acrylic dental cement and secured exhibit a higher level of anxiety (see Results section).
by two skull screws. A stylus was placed in the guide
cannula to prevent clogging. Animals were allowed 1 week
Consolidation Protocol
to recuperate before being subjected to experimental
manipulations. In the sample phase (day 1), each rat was placed in the
Formicroinfusion,thestyluswasremovedfromtheguide open-field arena and allowed to explore two different
cannula, and a 28-gauge injection cannula, extending objectsfor5min(AandB).Thetestphase(day2)wasgiven
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24hafterthesampletrial.Duringthe5-mintesttrial,therat 1999). Hence, higher anxiety corresponds to less entering
waspresentedwithaduplicateofanobjectfromthesample the center of the arena.
trial and a novel object (A and C). Exposure to the stressor
or microinfusion of vehicle, RU-486 or Prop, to the BLA
Histology
took place immediately following the sample phase on day
1. All figures show discrimination index in the test phase. At the end of the experiments, rats were anesthetized, and
theirbrainswereremoved,frozen,sectioned,andinspected
forcannulaplacementusingNisslstaining.Thelocationsof
Reconsolidation Protocol
cannula tips for the drugs and saline groups are shown in
In the sample phase (day 1), each rat was placed in the Figure 1.
open-field arena and allowed to explore two different
objectsfor5min(AandB).Twenty-fourhourslater(day2),
Statistics
they were exposed to the same two sample objects for a
5-minperiodinordertoreactivatethememorytrace(Aand Differences between the groups were determined using
B). The test phase (day 3) was given 24h after the ANOVA and t-tests. All post hoc comparisons were made
reactivation trial. During the 5-min test trial, the rat was using the least significant difference multiple comparison
presented with a duplicate of an object from the sample/ test (LSD).
reactivation trial andanovelobject(A andC).Exposureto
thestressorormicroinfusionofvehicle,RU-486orProp,to
Approval
the BLA took place immediately following the reactivation
phaseonday2.Allfiguresshowdiscriminationindexinthe The experiments were approved by the Ethics and Animal
test phase. Care Committee of the University of Haifa and were
performed in accordance with the National Institute of
Health Guidelines for the Care and Use of Laboratory
Elevated Platform Stress
Animals.
In this behavioral stressor, the animals are placed on an
elevated platform (EP; 12(cid:2)12cm) for 30min in a brightly
lit room (Xu et al, 1998). The rats exhibit behavioral RESULTS
‘freezing’, that is, immobility for up to 10min, defecation,
Nonhabituated Rats Spend Less Time in the Center of
and urination. This stressor was found to increase plasma
the Open Field
corticosterone levels by 38% as compared with na¨ıve rats
(KavushanskyandRichter-Levin,2006).Ithasalsorecently We assessed the level of arousal in habituated and
been found to impair long-term potentiation in the CA1 nonhabituatedratsusingtheopen-fieldtest.Nonhabituated
area of the hippocampus and in the BLA-medial prefrontal rats spent significantly less time exploring the central areas
pathway (Maroun and Richter-Levin, 2003). as compared with the habituated rats (t(10)¼4.533,
po0.001;n¼6each;Figure2).Thissuggestshigheranxiety
levels in the nonhabituated rats compared with the
Open-Field Test
habituated rats.
Theopenfieldwaslocatedinasmall,quietroomfittedwith
a video camera 25cm above the apparatus. The rats were
tested under a low-illumination red light to simulate
darkness and minimize stress levels. The open-field
consisted of a base and black walls (50(cid:2)50(cid:2)50cm)
divided into 25 (5(cid:2)5) identical sectors by white stripes.
The squares were subdivided into peripheral and central
sectors, where the central sector included the nine central
squares (3(cid:2)3) and the peripheral sector contained the
squares close to the wall. Both the habituated and the
nonhabituated rats were placed in the central sector, and
theiractivitywasrecordedfor5minbyavideocameraand
taped for further analysis. The open-field arena was
thoroughly cleaned between each test using odorous clean
wipes. Open-field activity was manually scored from a TV
screen by an observer who was blind to the treatment. We
quantified the percent time spent in the center and in the
corners of the open-field arena.
In an open-field arena, rats prefer the periphery to the
centerof the apparatus. Entering the center, which assesses
approach-avoidance toward novel stimuli, is considered a
reliable index of anxiety; it responds to anxiolytic agents
(Ramos et al, 1997) and is sensitive to stress-induced Figure 1 Schematic drawing of BLA cannulae tip positions. A coronal
anxiety states (Pare, 1994; Izumi et al, 1997; Durand et al, viewisshownatposition3.14and3.30mmposteriortobregma.
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Differential Performance of Habituated and the stressed nonhabituated group (EP) spent significantly
Nonhabituated Rats in the Consolidation of Object more time exploring the new object as compared with the
Recognition nonhabituatedgroups(cont andRU groups: po0.0001,RU
+EP:po0.01)(t-testfordifferencefrom0.5inthestressed
Eight groups of rats that were habituated to the experi-
nonhabituated group: t(6)¼5.153, po0.01). Thus, in
mental context before training (habituated) or just handled
contrast to the habituated rats, the nonhabituated control
(nonhabituated) were exposed to the sample phase on day
ratsshowedimpairedperformanceinthetest,andexposure
1. Immediately afterwards, they were either microinfused
to stress enhanced the recognition memory consolidation.
with vehicle to the BLA and taken to their home cage
Microinfusing RU-486 to the BLA reversed the enhance-
(habituated cont, n¼10; nonhabituated cont, n¼7);
ment of the stressor and merely microinfusing RU-486 to
exposed to the EP stress (habituated EP, n¼13; nonhabi-
the BLA in the nonstressed rats did not affect their
tuatedEP,n¼7);microinfusedwithRU-486andexposedto
performance. Further, there was no significant difference
the EP (habituated RU+EP, n¼9; nonhabituated RU+EP,
between the groups in discrimination index (F(7,56)o1,
n¼7);ormicroinfusedwithRU-486(habituatedRU,n¼6;
NS) during the sample phase (day 1; data not shown).
nonhabituated RU, n¼5), without exposure to the stressor
A significant difference in total exploration time was
(Figure 3a).
found between the groups during the test phase
A three-factor ANOVA conducted on discrimination
(F(7,56)¼8.183, po0.0001; Table 1). Post hoc comparisons
index on day 2 (arousal: habituated/nonhabituated; drug:
revealed that the nonhabituated groups spent significantly
RU-486/vehicle; stress: stress/no-stress) revealed a signi-
more time exploring the new object compared with the
ficant arousal, drug and stress (F ¼25.2, po0.001)
(1,56) habituated groups (po0.05). The difference in exploration
interaction,indicatingthatthepatternoftheeffectsofstress
time between habituated and nonhabituated animals is
and drug depended on the arousal level. There was a main
consistent with reports in the literature suggesting a
effect of arousal (F ¼5.953, p¼0.018), but not drug
(1,56)
(F ¼1.756, NS) or stress (F o1, NS). The interac-
(1,56) (1,56)
tions between arousal and drug (F ¼24.964, po0.001),
(1,56)
arousal and stress (F ¼27.865, po0.001), drug and
(1,56)
stress (F ¼4.942, p¼0.03) were all significant. Further
(1,56)
analysisofthedatashowedasignificantdifferencebetween
the groups in discrimination index in the test on day 2
(F(7,56)¼16.822, po0.0001). Post hoc comparisons re-
vealed that the stressed habituated group (EP) spent
significantlylesstimeexploringthenewobjectascompared
with the other habituated (po0.0001) and nonhabituated
groups (cont: po0.01; EP: po0.0001; RU: p¼0.051;
RU+EP: po0.001) (t-test for difference from 0.5 in
the habituated group: cont: t(9)¼5.91, po0.001; RU:
t(5)¼8.69, po0.001; RU+EP: t(8)¼3.628, po0.01). Thus,
exposuretostressimpairedtheconsolidationofrecognition
memory in the habituated rats, and microinfusing RU-486
to the BLA reversed the impairment. Merely microinfusing
RU-486 to the BLA in the nonstressed rats did not affect
their performance. Post hoc comparisons also revealed that
Figure3 Differentialperformanceofhabituatedandnonhabituatedrats
in the consolidation of object recognition. (a) Habituated rats that were
exposed to the stressor after the sample phase showed impaired
performance on day 2 compared with the other groups (*po0.001).
Nonhabituated rats that were exposed to the stressor after the sample
phase showed intact performance on day 2 compared with the other
groups (*po0.001). RU-486 into the BLA reversed the impairing
(habituated) and enhancing (nonhabituated) effects of the stressor. (b)
Habituatedandnonhabituatedratsthatwereexposedtothestressor3h
Figure2 Nonhabituatedratsspendlesstimeinthecenteroftheopen afterthesamplephasewerenodifferentfromtheircontrolcounterparts,
field.Nonhabituatedratsspentsignificantlylesstimeexploringthecentral thatis,habituatedanimalsshowedintactperformanceinthetestonday2
areasascomparedwiththehabituatedrats(*po0.001),suggestinghigher and nonhabituated animals showed poor performance (*po0.001
anxietylevelsinthenonhabituatedratscomparedwiththehabituatedrats. indicatesadifferencebetweenhabituatedandnonhabituatedgroups).
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398
Table 1 Total Exploration Time in Habituated and Non- ones, results from the different treatment they received
habituated Animals before the training (handling instead of being exposed
extensively to a context). Thus, in another experiment, we
Figure# Group Testexploration examinedwhetheranexposureofthenonhabituatedratsto
anothercontext,similartothecontextinwhichthetraining
3a Habituated-Cont 25.5471.85
takes place, would still result in poor performance.
Habituated-EP 26.1971.20 Accordingly, two groups of animals were habituated to
Habituated-RU 30.2074.89 another experimental apparatus (another open field,
Habituated-RU+EP 27.9674.55 50(cid:2)50(cid:2)50cm; context A) by allowing them to explore it
Nonhabituated-Cont 48.7376.42 for 5min twice a day for 4 days before the experiment was
Nonhabituated-EP 39.6574.16 performed.
Theseratswereexposedtothesamplephaseonday1and
Nonhabituated-RU 43.5374.03
immediately afterwards were either taken to their home
Nonhabituated-RU+EP 52.9472.46
cage (cont, n¼7) or exposed to the EP stress (EP, n¼7)
4a Habituated-Cont 39.1973.97 (datanotshown).t-Testanalysisofperformanceduringthe
Habituated-EP 40.2872.70 test revealed that the stress group spent significantly more
Habituated-RU 38.2572.11 timeexploringthenewobjectascomparedwiththecontrol
Habituated-RU+EP 45.7675.11 group (t(12)¼4.473, po0.001) (t-test for difference from
Nonhabituated-Cont 58.1777.82 0.5:EP:t(6)¼4.771,po0.01).Thissuggeststhatinorderto
Nonhabituated-EP 55.0875.33 performwellinthetest,animalsshouldbehabituatedinthe
specificcontextofthearenaofthetask(likethehabituated
Nonhabituated-RU 51.0773.40
animals),andnotinasimilarcontext.Further,therewasno
Nonhabituated-RU+EP 4873.59
significant difference between the groups in discrimination
index (t(12)o1, NS) during the sample phase (day 1;
Explorationtimes(s)ofthedifferentexperimentalgroupsinthetestphase.
Dataarepresentedasmeans7standarderrorofthemean. data not shown). No significant differences in total
exploration time were found between the groups during
either the sample phase (t(12)o1, NS) or the test phase
(t(12)¼1.01, NS).
decrease in exploratory activity as a function of repeated
exposure to the same environment (Hui et al, 2005) and
Similar Performance of Habituated and Nonhabituated
enhanced the exploration and novelty seeking following
Rats in the Reconsolidation of Object Recognition
exposure to stress (Thorsell et al, 2006). However, no
differences were found between the different treatments in Eight groups of rats that were habituated to the experi-
the habituated and nonhabituated groups suggesting that mental context before training (habituated) or just handled
the exposure to the stressor and the drugs had no (nonhabituated) were exposed to the sample phase on day
discernible effects on locomotor activity or the normal 1. Twenty-four hours afterwards, animals were exposed to
tendency for exploration of objects. the same two objects (reactivation) and, immediately
In the following experiment, we aimed to demonstrate afterwards, were either microinfused with vehicle to the
that when there is a delay between the training and BLA and taken to their home cage (habituated cont, n¼7;
exposure to the stressor (ie, exposure to the stressor is 3h nonhabituated cont, n¼7); exposed to the EP stress
aftertraining),thestressorwillnotaffectperformance.This (habituated EP, n¼8; nonhabituated EP, n¼7); micro-
will indicate that recognition memory consolidates by this infused with RU-486 and placed on the EP (habituated RU
time point and that the effects obtained are owing to +EP, n¼70; nonhabituated RU+EP, n¼9); or micro-
interactionbetweenthearousallevelandtheout-of-context infused with RU-486 (habituated RU, n¼6; nonhabituated
stressor. Thus, habituated and nonhabituated animals were RU, n¼5), with no exposure to the stressor (Figure 4a).
placedontheEP3h(3hEP)afterthesamplephaseorwere A three-factor ANOVA conducted on discrimination
taken to their home cage (control; Figure 3b; n¼5 each). index on day 3 (arousal: habituated/nonhabituated; drug:
A two-way ANOVA conducted on discrimination index RU-486/vehicle;stress: stress/no-stress) revealed significant
on day 2 (arousal: habituated/nonhabituated; stress: effectsofthedrug(F ¼23.266,po0.001),andthestress
(1,48)
stress/no-stress) revealed a significant effect of arousal (F ¼41.287, po0.001), but not arousal (F o1, NS).
(1,48) (1,48)
(F ¼92.031,po0.001),butnotstress(F o1,NS)or The interaction between drug and stress was significant
(1,16) (1,16)
the interaction between arousal and stress (F o1, NS). (F ¼32.706, po0.001), but not between arousal and
(1,16) (1,48)
Further analysis of data showed a significant difference drug (F o1, NS), arousal and stress (F o1, NS), or
(1,48) (1,48)
between the groups in discrimination index in the test on between arousal, drug, and stress (F o1, NS). Further
(1,48)
day 2 (F(3,16)¼30.82, po0.0001). Post hoc comparisons analysis of data showed a significant difference between
showed that the habituated groups (control and stressed) the groups in discrimination index in the test on day 3
spent significantly more time exploring the new object (F(7,48)¼14.909, po0.0001). Post hoc comparisons re-
comparedwiththe nonhabituatedgroups(po0.001).Thus, vealed that the stressed habituated and nonhabituated
3h after the sample, exposure to the stressor has no effect groups (EP) spent significantly less time exploring the
on consolidation. new object compared with the other groups (po0.0001 for
It might be argued that the poor performance of the all groups) (t-test for difference from 0.5: habituated: cont:
nonhabituated animals as compared with the habituated t(5)¼8.863,po0.001;RU:t(5)¼10.142,po0.001;RU+EP:
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(control; Figure 4b; n¼6 each). A two-way ANOVA
conducted on discrimination index on test day 3 (arousal:
habituated/nonhabituated; stress: stress/no-stress) did not
show significant effects of arousal (F o1, NS), stress
(1,21)
(F ¼1.793, NS) or the interaction between arousal and
(1,21)
stress (F o1, NS). Thus, 3h after the reactivation, the
(1,21)
reconsolidation window has closed.
Control Experiments for the Reactivation of the
Memory Trace
The nonhabituated control rats showed intact memory in
the test 24h following reactivation (Figure 4a). It could be
argued that their good performance was a result of their
exposure to the arena twice before the test (sample phase
and reactivation), as opposed to only one exposure in the
consolidation protocol. To verify that their good perfor-
mance in the test was derived from the reactivation of the
memory trace and not merely from being exposed twice to
the arena, three experiments were performed. In these
experiments, there is no reactivation of the memory trace,
thus, we expect nonhabituated control animals to perform
the task poorly, as seen in the consolidation experiment.
In the first experiment, the nonhabituated rats were
exposed to the arena on day 1 (with no objects) and then
exposed to two different objects for 5min (sample phase)
on day 2. Immediately afterwards, they were taken to their
Figure 4 Similar performance of habituated and nonhabituated rats in
the reconsolidation of object recognition. (a) Habituated and nonhabi- home cage (cont, n¼7) or placed on an EP (EP, n¼7;
tuatedratsthatwereexposedtothestressorafterthereactivationofthe Figure 5a, day 1 Arena). t-Test results revealed that the
memory trace showed impaired performance in the test on day 3 control rats spent significantly less time exploring the new
compared with the other groups (*po0.01 for habituated, po0.001 for object compared with the stressed rats (t(12)¼5.391,
nonhabituated). In both habituated and nonhabituated rats, RU-486 into
po0.001) in the test on day 3 (t-test for difference from
theBLAreversedtheimpairingeffectsofthestressoronperformance.(b)
0.5: EP: t(6)¼5.039, po0.01). Thus, merely being exposed
Habituatedandnonhabituatedratsthatwereexposedtothestressor3h
after the reactivation phase were no different from their control twicetothearenaisnotenoughforintactretrieval.Further,
counterparts,thatis,showedintactperformanceinthetestonday3. there was no significant difference between the groups in
discrimination index (t(12)o1, NS) during the sample
phase (day 1; data not shown).
t(6)¼4.204, po0.01; nonhabituated: cont: t(6)¼7.1223, In the second experiment, nonhabituated animals were
po0.001; RU: t(4)¼7.22, po0.01; RU+EP: t(8)¼11.671, exposed to different objects on day 1 and day 2. In the
po0.001). Thus, exposure to stress impaired reconsolida- classicalreconsolidationprotocol,animalswereexposedon
tion in the habituated and nonhabituated rats, and day 1 and day 2toobjects AB, and on day 3to the familiar
microinfusingRU-486totheBLAreversedtheimpairment. object A and to a new object C. In the present experiment,
MerelymicroinfusingRU-486totheBLAinthenonstressed animals were exposed on day 1 to objects AB, on day 2 to
rats did not affect their performance. Further, there was no objects CD, and on day 3 to the familiar object C and to a
significant difference between the groups in discrimination new object E. Thus, immediately after the exposure to
index during the sample phase (day 1; F(7,48)o1, NS; data objects on day 2, nonhabituated rats were taken to their
notshown)orthereactivationphase(day2;F(7,48)o1,NS; home cage (cont, n¼7) or exposed to the EP stress (EP,
datanotshown).Thus,allgroupsexhibitedsimilarlevelsof n¼7) (Figure 5a, AB–CD–CE). t-Test revealed that the
performance during the reactivation session. No significant stress group spent significantly more time exploring the
differencesintotalexplorationtimewerefoundbetweenthe new object compared withthe controlgroup (t(12)¼5.145,
groups during the test phase (F(7,48)¼1.945, p¼0.082; po0.001)inthetestonday3(t-testfordifferencefrom0.5:
Table 1). EP: t(6)¼5.99, po0.001). Thus, when there was no
In the following experiment, we aimed to demonstrate reactivation of the memory for a familiar object on day 2,
that when there is a delay between the reactivation and control animals did not perform well in the test. Further,
exposure to the stressor (ie, exposure to the stressor is 3h there was no significant difference between the groups in
after reactivation), the stressor will not affect performance. discriminationindexduringthesamplephasesonday1and
This will indicate that recognition memory reconsolidates day 2 (t(12)o1, NS; data not shown).
bythistimepointandthattheeffectsobtainedareowingto In the third experiment, we aimed to confirm that
the interaction between the arousal level and the out-of- recognition memory is consolidated at the time of
contextstressor.Tothatend,habituatedandnonhabituated reactivation. To that end, habituated and nonhabituated
animals were placed on the EP 3h (EP 3h) after the animalswereexposedtothesamplephaseonday1.Onday
reactivation phase or were taken to their home cage 2, habituated and nonhabituated rats were exposed to the
Neuropsychopharmacology
Stresseffectsonrecognitionmemory
MMarounandIAkirav
400
groups in discrimination index (F(3,26)o1, NS) during the
sample phase (day 1).
Beta-Adrenoceptors in the BLA Mediate the
Performance of Nonhabituated Rats in the
Consolidation,butNotintheReconsolidation,ofObject
Recognition Memory
In the next experiment, we sought to examine whether the
poor performance of the nonhabituated control rats in the
consolidation test would be reversed by a b-adrenoceptor
blocker into the BLA. Immediately after the sample phase,
nonhabituated rats were either microinfused with saline to
theBLAandtakentotheirhomecage(cont);exposedtothe
EP stress (EP); microinfused with Prop and placed on the
EP (Prop+EP); or microinfused with Prop, with no
exposure to the stressor (Figure 6a; n¼7 each). A two-
way ANOVA conducted on discrimination index on day 2
(drug: prop/vehicle; stress: stress/no-stress) revealed sig-
nificant effects of drug (F ¼8.949, p¼0.006), and the
(1,24)
interactionbetweenthedrugandthestress(F ¼24.433,
(1,24)
po0.001), but not stress (F ¼2.382, NS). Further
(1,24)
analysis of data showed a significant difference between
the groups in discrimination index (F(3,27)¼13.772,
po0.001) in the test on day 2. Post hoc comparisons
Figure5 Reactivationofthememorytrace.(a)Left:nonhabituatedrats revealed that thecontrolgroupspentsignificantly less time
wereexposedtothearenaonday1(withnoobjects)andexposedtotwo exploring the new object compared with the other groups
different objects for 5min (sample phase) on day 2. The control rats (EP and Prop+EP: po0.001, Prop: po0.001) (t-test for
showed impaired performance in the test on day 3 compared with the
difference from 0.5: EP: t(6)¼7.53 po0.001; Prop:
stressed rats (*po0.001). Right: nonhabituated rats were exposed to
t(6)¼7.405, po0.001; Prop+EP: t(6)¼5.148, po0.01).
different objects on day 1 (sample) and day 2. The control rats showed
Furthermore, a significant difference was found between
impairedperformanceinthetestonday3comparedwiththestressedrats
(*po0.001). (b) Habituated and nonhabituated rats were exposed to two the Prop+EP and the Prop group (po0.05). Thus,
differentobjectsfor5min(samplephase)onday1.Onday2,theratswere microinfusing Prop to the BLA after the sample phase
exposedtothecontextofthearenaandweretakentotheirhomecageor reversedthepoorperformanceofthenonhabituatedratsin
exposed to the stressor. Exposure to the stressor did not impair or facilitate the test on the next day. In addition, there was no
performanceinthehabituatedandnonhabituatedrats,respectively.
significant difference between the groups in discrimination
index(F(3,27)o1,NS)duringthesamplephase(day1).No
context of the arena (with no specific reactivation of the
significant differences in total exploration time were found
memory trace) and, immediately afterwards, they were
between the groups during either the sample phase
either taken to their home cage (habituated cont, n¼8;
(F(3,27)o1, NS) or the test phase (F(3,27)o1, NS).
nonhabituated cont, n¼7) or exposed to the EP stress
Next, we examined whether the b-adrenoceptor blocker
(habituated EP, n¼8; nonhabituated EP, n¼7; Figure 5b).
would affect the good performance of the nonhabituated
A two-way ANOVA conducted on discrimination index
rats in the reconsolidation protocol. Immediately after the
on day 3 (arousal: habituated/nonhabituated; stress:
reactivation of the memory trace, rats were either micro-
stress/no-stress) revealed a significant effect of arousal
infusedwithvehicle(cont),orProptotheBLAandtakento
(F ¼78.017,po0.001),butnotstress(F o1,NS)or
(1,26) (1,26) their home cage (Figure 6b; n¼7 each). t-Test did not
the interaction between arousal and stress (F o1, NS).
(1,26) reveal a significant difference between the groups in
Further analysis of data showed a significant difference
discrimination index during the sample phase (day 1;
between the groups in discrimination index (F(3,26)¼
t(12)o1,NS;datanotshown),thereactivationphase(day2;
13.772,po0.001)inthetestonday3.Posthoccomparisons
t(12)o1, NS; data not shown), or the test (day 3; t(12)o1,
showed that the nonhabituated control and stress groups
NS). Both groups performed the task well in the test (t-test
spent significantly less time exploring the new object
for difference from 0.5: cont: t(6)¼7.159, po0.001; Prop:
compared with the habituated control and stress groups
t(6)¼10.934, po0.001). No significant differences in total
(po0.001) (t-test for difference from 0.5: habituated cont:
explorationtimewerefoundbetweenthegroupsduringthe
t(7)¼6.642 po0.0001; habituated EP: t(7)¼13.4,
sample phase (t(12)o1, NS), the reactivation phase
po0.001). Importantly, the stress did not impair or
(t(12)o1, NS), or the test phase (t(12)o1, NS).
facilitate performance in habituated and nonhabituated
rats, respectively, and the nonhabituated control animals
showed impaired performance as in the consolidation
DISCUSSION
protocol. Thus, when the memory trace is not reactivated,
exposure to the stressor has no effect on performance. In The results of this research showed that the novelty stress/
addition, there was no significant difference between the arousal experienced by the rats during training dissociated
Neuropsychopharmacology
Stresseffectsonrecognitionmemory
MMarounandIAkirav
401
explaintheeffectsofthestressoronrecognitionmemory.It
should be noted that although we used a small infusion
volume(0.5mlvolumeperside),thedrugsmayhavespread
to adjacent areas, such as the central nucleus of the
amygdala.
Importantly, we showed that when we placed habituated
andnonhabituatedanimalsontheEP3hafterthesampleor
thereactivationofthememorytrace,therewasnoeffecton
either consolidation or reconsolidation of memory. Thus,
the exposure to the stressor should be within the time
window of consolidation and reactivation to affect the
memory trace. This confirms that recognition memory is
consolidated at the time of reactivation and it corresponds
to previously reported data that show that reconsolida-
tion could be manipulated only following reactivation
of the specific memory trace (Akirav and Maroun, 2006;
Nader et al, 2000a).
Differential Effects of Arousal Level on Recognition
Memory
The emotional state of the animal during training has a
considerable effect on memory, as seen by the dissimilar
performance of the habituated and the nonhabituated rats.
The response to novelty is a complex mechanism that
involves several processes, including arousal, attention,
anxiety,andstress-relatedfactors.Arousalandattentionare
Figure 6 The involvement of b-adrenoceptors in the BLA in the necessary when the animal is exposed to a novel environ-
consolidation and reconsolidation of object recognition of nonhabituated mentinordertogetacquaintedwithit(CerboneandSadile,
rats.(a)Nonhabituatedcontrolratsshowedimpairedperformanceinthe
1994; Hui et al, 2005; Thiel et al, 1998). The open-field test
test on day 2 compared with the other groups (*po0.01; #po0.05
showed that the nonhabituated rats spent significantly less
indicates a difference between Prop nonhabituated and Prop+Stress
nonhabituated).PropintotheBLAreversedtheimpairedperformanceof time exploring the center of the open-field arena as
nonhabituated control rats in the test. (b) Prop into the BLA of comparedwiththehabituatedrats,indicatingahigherlevel
nonhabituated rats after the reactivation of the memory trace did not of anxiety. Furthermore, nonhabituated animals showed
affect their performance in the task. Thus, the intact performance of the twofoldincreaseintheirtotalexplorationtimeinthearena
nonhabituated rats in the reconsolidation protocol is probably not
comparedwiththehabituatedanimals.Thissupportsother
mediatedbybeta-adrenoceptorsintheBLA.
studies suggesting a decrease in exploratory activity as a
function of repeated exposure to the same environment
consolidationfromreconsolidationofrecognitionmemory. (Hui et al, 2005) and enhanced exploration and novelty
Accordingly, rats with no previous habituation to the seeking following the exposure to stress (Thorsell et al,
experimental context (ie, highly aroused) demonstrated 2006). Taken together, these findings corroborate those of
impaired performance when consolidation was examined, other studies showing that nonhabituated animals are
and good reconsolidation memory when the memory trace emotionally different from their habituated counterparts
was reactivated. The impairment in consolidation in (Cerbone and Sadile, 1994; Okuda et al, 2004). It is
nonhabituated rats was found to be mediated by beta- important to note that there was no difference in total
adrenoceptors in the BLA, as the Prop microinfused to the exploration time between controls and animals that were
BLAimmediatelyaftertrainingresultedinintactconsolida- exposedtotheEPwithinthehabituatedandnonhabituated
tion. Prop microinfused to the BLA immediately after the groups. Thus, the stressor did not have a notable effect on
reactivationofthememorytracedidnotaffectreconsolida- the animals’ exploration time and thus it opposes the
tion, thus, further supporting the dissociation effect. In argument that the exposure to the stressor might have
contrast, rats that had reduced novelty stress/arousal confounded with the object recognition task.
because of extensive prior habituation performed well in It has been reported (Okuda et al, 2004) that nonhabi-
both consolidation and reconsolidation memory tests. tuated animals have higher levels of corticosterone than
Ourdata furtherdemonstratethatexposuretoanout-of- habituated animals. Additionally, post-training corticos-
context stressor facilitated memory consolidation, but terone injections enhanced the performance of the
impaired reconsolidation in the nonhabituated rats. How- nonhabituated rats in a test given 24h after training.
ever, in the habituated rats, the stressor impaired both This corresponds with our finding of an enhancing effect
consolidation and reconsolidation of recognition memory. of stress in nonhabituated rats. Why is it that the
A GR antagonist infused into the BLA reversed the nonhabituated rats do not learn? We suggest that the
impairing as well as the facilitating effects of the stressor arousal/stress induced by the novel context impairs their
on memory in both the habituated and the nonhabituated memory. The most apparent difference seen between
rats. Thus, GR mechanism in the BLA might potentially habituated and nonhabituated animals is their total
Neuropsychopharmacology
Stresseffectsonrecognitionmemory
MMarounandIAkirav
402
exploration time during the test and sample. Although rats. It is interesting why microinfusing Prop to the BLA
nonhabituated animals spent more time exploring the two and then exposing the animals to a stressor resulted in not
objects,theirconsolidationwasimpaired.Thisissurprising as much of an enhancement as Prop induced by itself. The
as in the recognition task, more total exploration time actions of Prop to reduce arousal may have interacted with
results in strong novel object preference. For example, theeffectsofstress,butwecannotinferonthebasisofthis
several studies set a criterion for minimal exploration time result whether the actions of Prop to reduce arousal and
that has to be achieved by all the animals (eg until it had stress are unitary or dissociable.
accumulated30sormoreofobjectexploration;Aingeetal,
2006; Hammond et al, 2004). Furthermore, nonhabituated
Opposite Effect of the Stressor on the Consolidation of
animals showed high levels of exploration when reconso-
Recognition Memory in Habituated and Nonhabituated
lidation was tested and their performance in this task was
Animals
intact. Taken together, these suggest that the difference
between habituated and nonhabituated animals cannot be Considerable evidence indicates enhancing as well as
attributed to differences in total exploration time. impairing effects following acute stress or acute glucocorti-
coid treatment (de Kloet et al, 1999; Lupien and McEwen,
1997; Roozendaal, 2002). The finding that memory con-
Dissociation of Consolidation from Reconsolidation of
solidation was enhanced in nonhabituated rats following
Recognition Memory as a Function of the Novelty
exposure to the stressor corresponds with studies showing
Arousal Experienced during Training
that if an animal learns a stressful task, then the
The differentiation between the performance of nonhabi- consolidation of this task may be enhanced by stress and
tuated rats in the consolidation and the reconsolidation of thatitsendproduct,corticosterone,maybesecretedduring
recognition memory seems to be dependent on the arousal thetask(deKloetetal,1999,1998;Roozendaal,2003).Thus,
level experienced by the animal and mediated by adreno- thelevelofstressappliedinourexperimentisapparentlyin
ceptors in the BLA. It has been proposed that memories the range that provokes a facilitation of memory retention.
require intact beta-receptors to reconsolidate the memory This was found to be the case in a variety of emotionally
trace after use (Sara, 2000). Prop, administered after arousing tasks, such as inhibitory avoidance, spatial
reactivation, has been shown to impair the reconsolidation learning, discrimination learning, and fear conditioning
ofapositivelyreinforcedradialmazetask,aswellaspassive (CorderoandSandi,1998;Floodetal,1978;Huietal,2004;
avoidanceandfearconditioning(DebiecandLeDoux,2004; Kovacs et al, 1977; Pugh et al, 1997; Roozendaal and
Przybyslawski et al, 1999). In our study, Prop into the BLA McGaugh, 1996; Sandi et al, 1997).
after reactivation did not affect the performance of the However, it seems that the enhancing effect is more
nonhabituated rats. Perhaps a systemic microinfusion relevant to aversive tasks (Wolf, 2003) than to nonaversive
would have resulted in a different outcome, and this tasks, asthestressor wasfoundtoimpairtheconsolidation
should be addressed in future studies. In a recent paper of object recognition in the habituated rats. Repeated
(Roozendaal et al, 2006), it has been reported that habituationisknowntoreducethenovelty-inducedarousal
endogenous noradrenergic activation of the BLA induced response, and under these circumstances, stress can have
by the emotional arousal of nonhabituated animals is detrimental effects on memory. There are reports that if an
essential in enabling glucocorticoid enhancement of recog- animal is placed in a stressful environment immediately
nition memory. This supports our argument that the following training, performance in delayed recall may be
arousal level of nonhabituated animals is mediated by impaired(CabibandCastellano,1997;Diamondetal,2006;
noradrenergicmechanismsintheBLA.Furthermore,itmay Klenerova et al, 2003; Meere and Borrell, 1988; Rudy, 1996;
suggest that the enhancing effect of the out-of-context Trneckova et al, 2005). Overall, these findings suggest that
stressor on memory consolidation in nonhabituated ani- the level of arousal or stress experienced by the animal
mals is because of an interaction between noradrenergic during training is an important factor in determining
and glucocorticoid factors in the BLA. Nevertheless, the whether stress will enhance or impair memory consolida-
involvement of the beta-adrenergic blocker in the con- tion. Yet, another explanation may be that a stressor may
solidation, but not the reconsolidation, of the object enhance memory consolidation in animals with otherwise
recognition task further supports our claim that there is a poormemorywhereasthesamestressorimpairsmemoryif
dissociationofconsolidationfromreconsolidationthatmay thecontrolsalreadyshowgoodmemory.Thisphenomenon
be explained by the arousal level of the animal during the is known for drug effects on memory consolidation and
training. forms the foundation of the inverted-U-shaped dose-
Our dissociation effect is in line with others suggesting response effect.
dissimilarities between consolidation and reconsolidation. Interestingly, in the habituated group, exposure to the
For example, protein synthesis and C/EBPb in the dorsal stressor increased the rats’ tendency to explore the old
hippocampus are crucial for consolidation, but not for object. One possible explanation is that exposure to
reconsolidation of inhibitory avoidance memory (Tauben- the stressor disrupted the consolidation and animals
feld et al, 2001). Similarly, a double dissociation between exhibited impaired retrieval as they did not remember the
consolidation and reconsolidation in the hippocampus was familiar object they have seen before. Yet another possible
found with brain-derived neurotrophic factor and zif268 explanation is that the animals have associated the
(Lee et al, 2004). aversivenessofthestressorwithwhatprecededitsexposure
Prop to the BLA or exposure to a stressor had the same to the stressor (ie, the arena). Once placed again in the
effect of enhancing consolidation of nonhabituated control arena for the test, rats explored the familiar object more
Neuropsychopharmacology
Stresseffectsonrecognitionmemory
MMarounandIAkirav
403
thanthenovelobjectbecausetheywantedtoavoidnovelty, Summary
and this was expressed in avoiding the novel object and
A major conclusion from this study is that although some
preferringthefamiliaronethatsignalssafety.Thisdoesnot
generalfeaturesunderlieconsolidationandreconsolidation,
necessarily suggest that theyhad an explicit memory of the
there is a possible dissimilarity between the two processes,
old object, but that the stressor somehow changed the
which is dependent on the emotional state of the animal
emotionalstateoftheratssuchthattheywillavoidnovelty.
during training. It has been proposed that reactivating
Thus, the explorationoftheoldobjectmaybemediatedby
traumatic memories under conditions that would prevent
familiarity and not by explicit memory.
reconsolidation may help in treating post-traumatic stress
disorder(PSTD)orotheranxiety-relatedconditions(Nader,
The Stressor Impairs the Reconsolidation of 2003). We present first evidence, as far as we know, for the
Recognition Memory deleteriouseffectsthatastressfulexperiencemighthaveon
the reconsolidation of a memory trace. Thus, this raises an
Both habituated and nonhabituated control rats performed
interesting possibility that the stress that is induced by
well in the task following reactivation of the memory trace.
recalling the traumatic episode might affect its own
Thus, it seems that the reactivation of the memory trace
reconsolidation or that part of the symptomatology in
contributed to stabilizing the original memory of the
PTSDmightresultfromthefactthatthetraumaimpairsthe
objects. We tend to rule out that this strengthening of
reconsolidationofanymemoriesthatareactiveatthetime.
the memory trace might result from the mere exposure
tothearena,asthenonhabituatedratsthatwereexposedto
the arena twice before the test (with one exposure to the
ACKNOWLEDGEMENTS
objects)(Figure5a,left),ormerelyexposedtothecontextof
the arena (Figure 5b) showed impaired performance. Supported by a grant from The National Institute for
Furthermore, exposing nonhabituated animals to differ- Psychobiology in Israel (no. 22-2004–5) to MM, by The
ent objects in the arena twice before the test (and thus EbelinandGerdBuceriusZEITFoundationtoMM,andbya
without a specific reactivation of the memory trace; postdoctoral fellowship from The National Institute for
Figure 5a, right) also resulted in poor performance in the Psychobiology inIsraeltoIA.Wethank LarisaPershinand
task. Hence, we suggest that nonhabituated animals are Noam Hikind for technical help.
still highly aroused after two exposures to the arena and
objects and that this arousal has an impairing effect on the
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