ORIGINAL INVESTIGATION

New automated procedure to assess context recognitionmemory in mice

David Reiss & Ondine Walter & Lucie Bourgoin &Brigitte L. Kieffer & Abdel-Mouttalib Ouagazzal

Received: 18 October 2013 /Accepted: 6 April 2014 /Published online: 27 April 2014# Springer-Verlag Berlin Heidelberg 2014

AbstractRationale and objectives Recognition memory is an impor-tant aspect of human declarative memory and is one of theroutine memory abilities altered in patients with amnesticsyndrome and Alzheimers disease. In rodents, recognitionmemory has been most widely assessed using the novel objectpreference paradigm, which exploits the spontaneous prefer-ence that animals display for novel objects. Here, we usednose-poke units instead of objects to design a simple automat-ed method for assessing context recognition memory in mice.Methods In the acquisition trial, mice are exposed for the firsttime to an operant chamber with one blinking nose-poke unit.In the choice session, a novel nonblinking nose-poke unit isinserted into an empty spatial location and the number of nose

poking dedicated to each set of nose-poke unit is used as anindex of recognition memory.Results We report that recognition performance varies as afunction of the length of the acquisition period and the reten-tion delay and is sensitive to conventional amnestic treat-ments. By manipulating the features of the operant chamberduring a brief retrieval episode (3-min long), we further dem-onstrate that reconsolidation of the original contextual mem-ory depends on the magnitude and the type of environmentalchanges introduced into the familiar spatial environment.Conclusions These results show that the nose-poke recogni-tion task provides a rapid and reliable way for assessingcontext recognition memory in mice and offers new possibil-ities for the deciphering of the brain mechanisms governingthe reconsolidation process.

Keywords Recognitionmemory . Nose-poke units . Spatialcontext . Consolidation . Reconsolidation .Mice

Introduction

Recognition memory is the ability to judge that a currentlypresent object, person, place, or event has previously beenencountered or experienced. Recognition memory is an im-portant aspect of human declarative memory and is one of theroutine memory abilities altered in patients with amnesticsyndrome and Alzheimers disease (Hildebrandt et al. 2013;Peters et al. 2013; Squire et al. 2007). One of the mostcommon tasks for assessing recognition memory in rodentsis the novel object preference (NOP) paradigm, which resem-bles the visual paired comparison (VPC) task given to humansubjects (Ennaceur 2010). Unlike other recognition memorytasks, delayed matching to sample and delayed nonmatchingto sample that involve an initial phase of rule learning, theNOP paradigm capitalizes on the animals innate preference

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D. Reiss :O. Walter : L. Bourgoin :B. L. Kieffer :A.

for novelty. The standard procedure consists of prehabituationto spatial context alone followed by an acquisition sessionduring which rats or mice are familiarized with two identicalobjects. In the testing trial, a novel object is presented togetherwith one of the previously encountered sample objects andrecognitionmemory is reflected by a greater exploration of thenovel object than the familiar one. Variants of the procedurehave also been developed to assess spatial-, temporal-, andepisodic-like memory (Balderas et al. 2008; Barker andWarburton 2011; Dere et al. 2007; Dix and Aggleton 1999;Eacott and Norman 2004; Wilson et al. 2013a). For instance,the object-in-context procedure has been used to assess a formof associative recognition memory that is considered as ananalog of human episodic memory (Balderas et al. 2008;Langston and Wood 2010; Wilson et al. 2013b). The proce-dure consists of two successive acquisition trials in which theanimals are exposed to two different pairs of identical objectslocated within two distinct contexts. In the testing trial, bothtypes of objects are presented in one of these familiar contexts.Normal rats or mice tend to explore more the objects presentedin an incongruent familiar context indicating that they haveremembered the previously encountered object-context asso-ciation. Since its introduction, the NOP task has rapidlygained popularity as a recognition memory test for rodents.The relative simplicity of this paradigm has allowed for wide-spread use across disciplines to evaluate the cognitive alter-ations associated with aging, genetic manipulations, and phar-macological interventions in rodents (Aggleton et al. 2012;Antunes and Biala 2012; Bertaina-Anglade et al. 2006; Dereet al. 2007; Ennaceur 2010; Lyon et al. 2012; Winters et al.2010). However, the manual scoring of the test is both timeand labor intensive, which limits its utilization for high-throughput behavioral phenotyping and pharmacologicalscreening. To overcome these limitations, automated versionsof the task have been successfully developed by severalgroups using video-tracking systems (Benice and Raber2008; Chambon et al. 2011; Rutten et al. 2008).

In the present study, we introduce a new automated methodfor assessing associative recognition memory that adopts thebasic concept behind the NOP and VPC paradigms. Theprocedure is conducted in an operant chamber and involvesdiscrimination of novel from familiar nose-poke units (NPUs)that are distinguishable by their visual features and spatiallocation. During the acquisition session, mice are familiarizedwith the spatial context in the presence of blinking NPU, andduring the choice session, a novel nonblinking NPU isinserted into an empty spatial location. Recognition memoryis assessed by comparing the amount of exploration (numberof nose poking) dedicated to each set of NPU. A series ofcontrol studies were conducted to establish that mice reliablydiscriminate novel from familiar NPU. We first examinedwhether discrimination between novel and familiar NPUvaries as a function of the length of the acquisition period

and the retention delay. The effects of amnestic drugs onrecognition memory were also assessed using systemic ad-ministration of scopolamine, an antagonist of the muscariniccholinergic receptors, and MK-801, an antagonist of the glu-tamatergic NMDA receptors.

To demonstrate another important potential use of the nose-poke recognition task, we studied the reconsolidation phe-nomenon. Compelling evidence now indicates that well-established memories can return to a labile state when re-trieved and again need to be restabilized in order to persist(Finnie and Nader 2012; Sara 2000). One hypothesized func-tion of the destabilization-restabilization (or reconsolidation)process is to mediate the updating of a memory to maintain itspredictive relevance (Finnie and Nader 2012; Kroes andFernandez 2012; Lee 2009). The destabilization of neuraltrace is thought to enable incorporation of new relevant infor-mation present during retrieval into preexisting memory rep-resentation, but this hypothesis is not unanimously accepted.While some studies have demonstrated that memoryreconsolidation occurs only under retrieval circumstances thatfavor novel information encoding (Jones et al. 2012; Morriset al. 2006; Pedreira et al. 2004; Rossato et al. 2007; Winterset al. 2009, 2011), others reported that the association of newinformation to retrieved memory requires a consolidation-likemechanism (Alberini 2011; Suarez et al. 2010; Tronel et al.2005). More recently, new computational and theoreticalmodels have been proposed to explain how in hippocampal-dependent tasks the availability of novel information duringrecall may trigger memory updating (reconsolidation process)or new learning (consolidation process) as a function of thedegree of similarity/dissimilarity that exists between the eventpresent at memory recall and the previously memorized expe-rience (Besnard et al. 2012; Osan et al. 2011). Here, wemanipulated the components of the operant chamber duringa brief reactivation trial interposed between the acquisitionand choice sessions to explore whether the engagement ofmemory reconsolidation depends on the magnitude and/or thetype of the transformation introduced into the familiar spatialcontext.

Materials and methods

Subjects

Eight-week-old C57BL/6 N (BL6N) and C57/BL6J (BL6J)male were purchased from the Charles River Laboratory(France). Mice were housed four per cage and maintained ona 12:12 h light/dark cycle with free access to food and waterand allowed to acclimatize to housing conditions until testing,at the age of 10 to 13 weeks. All experimental procedureswere conducted with the approval of the local ethics commit-tee (CREMEAS) based on adherence to European Union

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guidelines (European Community Guidelines on the Care andUse of Laboratory Animals 86/609/EEC).

Drugs

Scopolamine hydrobromide (Sigma, France) and MK-801(Sigma, St Quentin Fallavier, France) were dissolved in phys-iological saline (0.9%NaCl). Drugs were injected at a volumeof 10 ml/kg either subcutaneously (scopolamine) or intraper-itoneally (MK-801). A 30-min pretreatment time was used inall experiments. The dose of scopolamine and MK-801 wasselected based on our previous studies (Goeldner et al. 2008,2009; Reiss et al. 2012).

Apparatus

Testing was carried out in four five-choice operant chambers(Coulbourn Instruments, Allentown, USA) dimly lit with apermanent house light. The front of the operant chamber wascurved and composed of five bays filled with metal wallpanels interchangeable with nose-poke modules (ModelH21-10 M). Each nose-poke hole is equipped with a con-trolled yellow LED cue light at the end and infrared photobeam across the opening that detects the number of nosepokes. The back wall was composed of a single bay fittedwith metal panels, and the plexiglass side walls werecompletely covered by cardboard with distinguishable geo-metrical motifs. The metal stainless-steel rod floor (the gridshock floor provided by the manufacturer) was covered by agrey vinyl-coated paper that was used as the standard flooringthroughout the study. An infrared activity monitor (ModelH24-61MC) placed on the ceiling was used for measuringthe animal locomotor activity.

Experimental procedures

The standard nose-poke recognition protocol comprised anacquisition session followed by a 10-min choice session. Theacquisition session consisted of the familiarization with thespatial context in the presence of a blinking nose-poke unit(NPU: two adjacent nose-pokemodules spaced 4 cm apart andturned on with a blinking cue light) presented either in theright or the left corner of the front wall. The spatial location ofNPUwas counterbalanced between mice for each condition orpharmacological treatment. In the choice session, the familiarNPU was presented in the same corner as in the acquisition,and a novel nonblinking NPU (turned on with constant cuelight) was introduced in the opposite corner (8 cm apart fromfamiliar NPU). The present experimental design was adoptedbased on a series of preliminary experiments showing that thevisual features of the familiar NPU do not impact noveltydiscrimination (supplementary Fig. 1A). The number of nosepokes made in each set of NPU was monitored during 10 min.

The recognition index (RI) was expressed by the ratio (100total number of exploration of novel NPU) / (total number ofexploration of all NPU). An RI of 50 % corresponds to achance level whereas a higher RI reflects a good recognition.

The reactivation protocol comprised a trial of 3-min durationinterposed between the acquisition and the choice sessions. A1-day intertrial delay was used in all experiments. Duringreactivation, familiar NPU and chamber floor were either ma-nipulated separately or conjointly. The manipulation of familiarNPU consists of removing the entire modules and replacing itbymetal wall panels.Manipulation of chamber floor consists ofremoving the grey vinyl-coated paper and keeping the metalstainless-steel grids as new flooring. For all experiments, priorto reactivation, mice were assigned into testing groups that hadboth an equivalent number of nose pokes and levels of loco-motor activity during acquisition session.

Statistical analysis

All data are expressed as mean group valuestandard error ofthe mean (SEM) and analyzed using Students t test, one-way,or two-way ANOVA as appropriate.When relevant, data weresubmitted to post hoc Fishers protected least significant dif-ference (PLSD) test analysis. One-sample Students t test wasused to compare recognition index values to chance level(50 %). The criterion for statistical significance was p0.05, Students ttest), demonstrating the lack of unconditioned preference forone set of these cues. Alternately, preference for the novelNPU (nonblinking one) increased as a function of the acqui-sition session. Mice exposed for 5 min to the context failed todistinguish the novel from the familiar NPU, whereas thoseexposed for longer durations, 10 or 20 min, displayed a clearpreference for the novel NPU (Table 1). One-way ANOVAperformed on discrimination scores (Fig. 1a) revealed a sig-nificant main effect of duration ((F3, 24)=3.12, p

post hoc analysis confirmed that the 20-min group had a betterrecognition performance compared with the control group(p

kg) or MK-801 (0.1 mg/kg) prior to the acquisition and testedthe following day. Control groups received systemic injectionsof the corresponding vehicles. As expected, scopolamine pro-duced dose-dependent memory impairment (Fig. 3a). One-way ANOVA revealed a significant effect of the treatment((F2, 21)=3.62, p

4 and 5 show that novelty encoding during retrieval wasnecessary for the engagement of memory reconsolidation.

Experiment 6 In subsequent studies, we examined whethermanipulation of the chamber flooring could promote thereconsolidation phenomenon. To this end, the smooth vinyl-coated paper used as the standard flooring was replaced bystainless-steel grid flooring (see Materials and methodssection). Mice were submitted to 20-min familiarization inthe standard context and treated the following day with sco-polamine (1 mg/kg) or MK-801 (0.1 mg/kg) prior to reactiva-tion with the new flooring. Memory retention was assessed24 h later (48 h post-acquisition) in the original learningcontext. Figure 5a shows that none of the antagonists impaireddiscrimination performance compared with the correspondingvehicle treatments (p>0.05, Students t test), suggesting that

original memory trace remained intact upon retrieval. A seriesof experiments were then conducted to investigate whetherencoding of novel changes was mediated by a consolidation-like mechanism. We first verified whether in the presence ofthe new flooring mice still displayed preference for the novelNPU. To achieve this, animals were familiarized during20 min with the standard context and tested the followingday in the presence of the new flooring. As observed, trainedmice behave like nave animals (p>0.05 vs chance level, one-sample Students t test, Fig. 5b). This shows that in thepresence of new flooring, trained mice treated the familiarNPU as a novel cue. We then examined whether the briefreactivation with the new chamber flooring was sufficient formice to acquire a long-term recognition memory. Figure 5bshows that control mice familiarized with the standard contextand tested 48 h later in the presence of the new flooringperformed at chance level (p>0.05, one-sample t test), repli-cating previous results. By contrast, those submitted to thereactivation trial had a good recognition performance com-pared with the control group (p

the modified spatial context and tested the following day inthe standard context. Nonreactivated mice tested directly inthe original spatial context performed significantly abovechance (p

associative recognition memory (the association of the familiarNPU with the old chamber configuration). All together, theseobservations suggest that the nose-poke recognition task assessescontextual recognitionmemory and not only recognitionmemoryfor individual item.

As mentioned earlier, a challenge to the memory-updatinghypothesis of reconsolidation comes from a set of studiesshowing that novel information encoding during retrieval doesnot systematically engage destabilization of reactivated mem-ory (Alberini 2011; Pedreira and Maldonado 2003; Suarez

24 h24 h20 min

a

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tion

Inde

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MK-801Scopolamine

20 min24 h24 h

24-48 h

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Fig. 5 Manipulation of chamber flooring alone did not trigger memoryreconsolidation. a Twenty-four hours after acquisition (20 min) in thestandard context, mice were treated with scopolamine (1 mg/kg, n=12,black bar), MK-801 (1 mg/kg, n=7, black bar), or corresponding vehicle(white bars, n=11 and 7, respectively) prior to reactivation with newflooring. Testing was carried the following day (48 h post-acquisition) inthe standard context. b Reactivation with new flooring promotes memorychanges. Dashed bar, nave mice tested directly in the modified context.White bars, mice familiarized with standard context and tested 24 (n=6) or48 h (n=10) later in the modified context. Grey bar, mice reactivated with

the new floor and tested the following day in the modified context (n=6). cMice submitted to a 20-min learning session in the standard context andtreated with scopolamine (1 mg/kg, black bar, n=7), MK-801 (0.1 mg/kg,black bar, n=7), or corresponding vehicles (white bars, n=8 and 6, respec-tively) prior to reactivation in themodified context. Testingwas carried 24 hlater (48 h post-acquisition) in the same modified context. Values are meanof %RI SEM. The horizontal arrows denote the passage of time. Thevertical arrows stand for drug injections. The dashed line shows a chancelevel of 50 %. *p

et al. 2010). A number of explanations have been promulgatedover the past years to reconcile the disparate evidence (Finnieand Nader 2012; Lee 2009; McKenzie and Eichenbaum 2011;Nadel et al. 2012; Pedreira et al. 2004; Rodriguez-Ortiz andBermudez-Rattoni 2007). More recently, Besnard et al. (2012)have proposed a theoretical model that explains why inhippocampal-dependent tasks the availability of novel infor-mation during recall may lead to memory updating or newlearning (see also (Osan et al. 2011). They posit that a highdegree of similarity will trigger the reconsolidation processthat mediates the updating of old-memory representation,while a low degree of similarity will engage the consolidationprocess that supports formation of new-memory representa-tion. The present study provides empirical evidence in supportof this prediction by showing that the engagement ofreconsolidation depends on the magnitude of context changesintroduced during retrieval. Specifically, a substantial trans-formation of the spatial context, such as removal of the NPUand replacement of the chamber flooring, led to the formationof a new competing memory (Fig. 6a), as indicated by theprotective effect of scopolamine (Fig. 6b). By contrast, aminor context transformation, the removal of the NPU, trig-gered memory reconsolidation (Fig. 4a and supplementaryFig. 1B). Indeed, the fact that reexposure to the standardcontext without the familiar NPU rendered recognition mem-ory susceptible to the amnestic treatments suggests that theoriginal memory trace underwent a destabilization process. Asa consequence, the blockade of muscarinic or NMDA recep-tors prior to the reactivation prevented not only the encodingof the novel information but also the restabilization of theoriginal memory trace, thereby resulting in amnesia. It mightbe argued that these antagonists may have simply speeded upmemory loss upon reactivation. However, the set of studiesconducted with the manipulation of chamber floor either alone(Fig. 5a) or conjointly with the NPU (Fig. 6b) argues againstthis possibility. It should be also stressed that neither scopol-amine nor MK-801 impaired recognition memory when ad-ministered in the home cage (Fig. 4b) or prior to reactivationin the presence of the familiar NPU (Fig. 4c and supplemen-tary Fig. 1C) suggesting that the engagement ofreconsolidation only occurs when the retrieved memory needsto be updated with new relevant information in the environ-ment. Overall, our findings corroborate previous studiesshowing that a dual encoding retrieval state is necessaryto trigger destabilization of the memory trace and pro-vide new behavioral evidence supporting the memory-updating hypothesis of reconsolidation.

An interesting finding was that the engagement of memoryreconsolidation was also dependent on the type of contextchanges introduced during retrieval. Unlike removal of theNPU (Fig. 4a and supplementary Fig. 1B), replacement of thechamber flooring did not trigger destabilization of the originalmemory (Fig. 5a). These results may be explained by the fact

that mice have a greater contact with the chamber floor andthat the sensory experiences (e.g., visual, tactile, propriocep-tive, etc.) elicited by the new (stainless-steel grids) and the old(smooth vinyl-coated paper) floorings are radically distinct.As such, upon reexposure to the chamber, the novel sensoryexperience is encoded as a distinct episodic memory fromolder one. Consistent with this idea, when familiarized micewere directly tested in the presence of new flooring, theybehave like nave animals and engaged in active sampling ofall sets of NPU (Fig. 5b), more likely to form a new memoryrepresentation. This result extends those reported in the fearconditioning paradigm showing that mice treated the condi-tioning context as a novel environment when the floor texturewas modified, a phenomenon illustrating a form of behavioralpattern separation (McHugh et al. 2007). Further evidence thatanimals use sensory information supplied by the floor todiscriminate between similar environments comes from elec-trophysiological studies in rats showing that modifying thefloor color alone resulted in activation of completely differentassemblies of hippocampal place cells (global remapping orpattern separation process) like changing the entire recordingchamber, thus reflecting the creation of a new hippocampalrepresentation or spatial map for the modified environment(Jeffery 2007; Jeffery and Anderson 2003). Interestingly, thebrief re-reactivation episode with the new flooring was suffi-cient for the familiarized mice to acquire a long-term recog-nition memory (Fig. 5b and c), while a longer duration(>5 min) was necessary for naive mice (Fig. 1a). Furtherstudies are required to clarify whether the learning improve-ment displayed by reactivated mice reflects formation of newindependent memory or a form of memory updating (orintegrative encoding), which consists of linking together noveland retrieved context information by a consolidation-likemechanism (Alberini 2011).

In conclusion, the above findings demonstrate that our newautomated method using the NPU permits a rapid and reliableway for assessing recognition memory in rodents. Eventhough the procedure described here can be used in its currentversion for characterizing the effects of various pharmacolog-ical and genetic manipulations on recognition memory, furtheroptimization of the procedure might be necessary dependingupon the experimental conditions (e.g., mouse strains, types ofoperant chambers, etc) and the questions addressed. Oneshortcoming of the current experimental design lies in the factthat animals can only be tested once, but this may be over-come by implementing few modifications to make it suitablefor repeated testing, for instance, by shortening the initialacquisition session (e.g., 10 min) to prevent an over-habituation of the animals to the chamber and by performingthe testing in the presence of a novel NPU configuration (e.g.,blinking or nonblinking NPU displaced to a novel spatiallocation or a third NPU unit introduced in an empty location).For routine screening of new drugs and behavioral

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phenotyping of new mouse lines, counterbalancing for theidentity of the NPU as well the spatial location is also recom-mended to control for a potential nonspecific changes innovelty discrimination. Overall, the development of thenose-poke recognition task should provide a valuable com-plement to existing rodent learning paradigms by offering newpossibilities for assessing contextual memory and decipheringthe neural and genetic mechanisms underpinning thereconsolidation process.

Acknowledgments This work was supported by grants from the CentreNational de la Recherche Scientifique (CNRS), the Institut National de laSant et de la Recherche Mdicale (INSERM), the Universit de Stras-bourg (UDS). The authors thank Dr. Steve Brooks for the Englishcorrections.

References

Aggleton JP, BrownMW, Albasser MM (2012) Contrasting brain activitypatterns for item recognition memory and associative recognitionmemory: insights from immediate-early gene functional imaging.Neuropsychologia 50:31413155

Alberini CM (2011) The role of reconsolidation and the dynamic process oflong-termmemory formation and storage. Front Behav Neurosci 5:12

Antunes M, Biala G (2012) The novel object recognition memory:neurobiology, test procedure, and its modifications. Cogn Process13:93110

Balderas I, Rodriguez-Ortiz CJ, Salgado-Tonda P, Chavez-Hurtado J,McGaugh JL, Bermudez-Rattoni F (2008) The consolidation ofobject and context recognition memory involve different regionsof the temporal lobe. Learn Mem 15:618624

Barker GR, Warburton EC (2011) When is the hippocampus involved inrecognition memory? J Neurosci 31:1072110731

Benice TS, Raber J (2008) Object recognition analysis in mice usingnose-point digital video tracking. J Neurosci Methods 168:422430

Bertaina-Anglade V, Enjuanes E, Morillon D, Drieu la Rochelle C (2006)The object recognition task in rats and mice: a simple and rapidmodel in safety pharmacology to detect amnesic properties of a newchemical entity. J Pharmacol Toxicol Methods 54:99105

Besnard A, Caboche J, Laroche S (2012) Reconsolidation of memory: adecade of debate. Prog Neurobiol 99:6180

Boccia MM, Baratti CM (1999) Effects of oxytocin and an oxytocinreceptor antagonist on retention of a nose-poke habituation responsein mice. Acta Physiol Pharmacol Ther Latinoam 49:155160

Bozon B, Davis S, Laroche S (2003) A requirement for the immediateearly gene zif268 in reconsolidation of recognition memory afterretrieval. Neuron 40:695701

Brodkin J (1999) Assessing memory in mice using habituation of nose-poke responding. Behav Pharmacol 10:445451

Chambon C,Wegener N, Gravius A, DanyszW (2011) A new automatedmethod to assess the rat recognition memory: validation of themethod. Behav Brain Res 222:151157

Dere E, Huston JP, De Souza Silva MA (2007) The pharmacology,neuroanatomy and neurogenetics of one-trial object recognition inrodents. Neurosci Biobehav Rev 31:673704

Dix SL, Aggleton JP (1999) Extending the spontaneous preference test ofrecognition: evidence of object-location and object-context recogni-tion. Behav Brain Res 99:191200

Dodart JC, Mathis C, Ungerer A (1997) Scopolamine-induceddeficits in a two-trial object recognition task in mice.Neuroreport 8:11731178

Eacott MJ, Norman G (2004) Integrated memory for object, place, andcontext in rats: a possible model of episodic-like memory? JNeurosci 24:19481953

Ennaceur A (2010) One-trial object recognition in rats and mice: meth-odological and theoretical issues. Behav Brain Res 215:244254

Finnie PS, Nader K (2012) The role of metaplasticity mechanisms inregulating memory destabilization and reconsolidation. NeurosciBiobehav Rev 36:16671707

Goeldner C, Reiss D, Wichmann J, Meziane H, Kieffer BL, OuagazzalAM (2008) Nociceptin receptor impairs recognition memory viainteraction with NMDA receptor-dependent mitogen-activated pro-tein kinase/extracellular signal-regulated kinase signaling in thehippocampus. J Neurosci 28:21902198

Goeldner C, Reiss D, Wichmann J, Kieffer BL, Ouagazzal AM (2009)Activation of nociceptin opioid peptide (NOP) receptor impairscontextual fear learning in mice through glutamatergic mechanisms.Neurobiol Learn Mem 91:393401

Hildebrandt H, Fink F, Kastrup A, Haupts M, Eling P (2013) Cognitiveprofiles of patients with mild cognitive impairment or dementia inAlzheimers or Parkinsons disease. Dement Geriatr Cogn Dis Extra3:102112

Jeffery KJ (2007) Integration of the sensory inputs to place cells: What,where, why, and how? Hippocampus 17:775785

Jeffery KJ, Anderson MI (2003) Dissociation of the geometric andcontextual influences on place cells. Hippocampus 13:868872

Jones B, Bukoski E, Nadel L, Fellous JM (2012) Remaking memories:reconsolidation updates positively motivated spatial memory in rats.Learn Mem 19:9198

KroesMC, Fernandez G (2012)Dynamic neural systems enable adaptive,flexible memories. Neurosci Biobehav Rev 36:16461666

Langston RF, Wood ER (2010) Associative recognition and the hippocam-pus: differential effects of hippocampal lesions on object-place, object-context and object-place-context memory. Hippocampus 20:11391153

Lee JLC (2009) Reconsolidation: maintaining memory relevance. TrendsNeurosci 32:413420

Lyon L, Saksida LM, Bussey TJ (2012) Spontaneous object recognitionand its relevance to schizophrenia: a review of findings from phar-macological, genetic, lesion and developmental rodent models.Psychopharmacology (Berl) 220:647672

McHugh TJ, Jones MW, Quinn JJ, Balthasar N, Coppari R, Elmquist JKet al (2007) Dentate gyrus NMDA receptors mediate rapid patternseparation in the hippocampal network. Science 317:9499

McKenzie S, Eichenbaum H (2011) Consolidation and reconsolidation:two lives of memories? Neuron 71:224233

Morris RG, Inglis J, Ainge JA, Olverman HJ, Tulloch J, Dudai Y et al(2006) Memory reconsolidation: sensitivity of spatial memory toinhibition of protein synthesis in dorsal hippocampus duringencoding and retrieval. Neuron 50:479489

Nadel L, Hupbach A, Gomez R, Newman-Smith K (2012) Memoryformation, consolidation and transformation. Neurosci BiobehavRev 36:16401645

Osan R, Tort AB, Amaral OB (2011) A mismatch-based model formemory reconsolidation and extinction in attractor networks. PlosOne 6:e23113

Pedreira ME, Maldonado H (2003) Protein synthesis subservesreconsolidation or extinction depending on reminder duration.Neuron 38:863869

Pedreira ME, Perez-Cuesta LM,MaldonadoH (2004)Mismatch betweenwhat is expected and what actually occurs triggers memoryreconsolidation or extinction. Learn Mem 11:579585

Peters F, Villeneuve S, Belleville S (2013) Predicting progression todementia in elderly subjects with mild cognitive impairment usingboth cognitive and neuroimaging predictors. J Alzheimers Dis 38:307318

Reiss D, Prinssen EP, Wichmann J, Kieffer BL, Ouagazzal AM (2012)The nociceptin orphanin FQ peptide receptor agonist, Ro64-6198,

4346 Psychopharmacology (2014) 231:43374347

impairs recognition memory formation through interaction withglutamatergic but not cholinergic receptor antagonists. NeurobiolLearn Mem 98:254260

Rodriguez-Ortiz CJ, Bermudez-Rattoni F (2007) Memoryreconsolidation or updating consolidation?

Rossato JI, Bevilaqua LR, Myskiw JC, Medina JH, Izquierdo I,Cammarota M (2007) On the role of hippocampal protein synthesisin the consolidation and reconsolidation of object recognition mem-ory. Learn Mem 14:3646

Rutten K, Reneerkens OA, Hamers H, Sik A, McGregor IS, Prickaerts Jet al (2008) Automated scoring of novel object recognition in rats. JNeurosci Methods 171:7277

Sara SJ (2000) Retrieval and reconsolidation: toward a neurobiology ofremembering. Learn Mem 7:7384

Squire LR,Wixted JT, ClarkRE (2007)Recognitionmemory and themedialtemporal lobe: a new perspective. Nat Rev Neurosci 8:872883

Suarez LD, Smal L, Delorenzi A (2010) Updating contextual informationduring consolidation as result of a new memory trace. NeurobiolLearn Mem 93:561571

Tronel S, Milekic MH, Alberini CM (2005) Linking new information to areactivated memory requires consolidation and not reconsolidationmechanisms. PLoS Biol 3:e293

Wilson DI, Langston RF, Schlesiger MI, Wagner M, Watanabe S, AingeJA (2013a) Lateral entorhinal cortex is critical for novel object-context recognition. Hippocampus 23:352366

Wilson DI, Watanabe S, Milner H, Ainge JA (2013b) Lateral entorhinalcortex is necessary for associative but not nonassociative recogni-tion memory. Hippocampus

Winters BD, Tucci MC, DaCosta-Furtado M (2009) Older and strongerobject memories are selectively destabilized by reactivation in thepresence of new information. Learn Mem 16:545553

Winters BD, Saksida LM, Bussey TJ (2010) Implications of animalobject memory research for human amnesia. Neuropsychologia48:22512261

Winters BD, Tucci MC, Jacklin DL, Reid JM, Newsome J (2011) On thedynamic nature of the engram: evidence for circuit-level reorgani-zation of object memory traces following reactivation. J Neurosci31:1771917728

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New automated procedure to assess context recognition memory in miceAbstractAbstractAbstractAbstractAbstractIntroductionMaterials and methodsSubjectsDrugsApparatusExperimental proceduresStatistical analysis

ResultsNose-poke recognition memory as a function of the acquisition length and the retention delayRelationship between nose-poke recognition performance and exploratory behaviorEffect of amnestic treatments on nose-poke recognition memory formationEffect of spatial context transformations on recognition memory stability upon retrieval

DiscussionReferences