Consolidation and reconsolidation of object recognition memory.

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Consolidation and reconsolidation of object recognition memory Israela Balderas, Carlos J. Rodriguez-Ortiz, Federico Bermudez-Rattoni ∗ División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Apartado Postal 70-253, 04510 México D.F., Mexico

h i g h l i g h t s • • • • •

PRH and IC are necessary to consolidate object, but not object-in-context recognition memory. HIPP is necessary to consolidate object-in-context, but not object recognition memory. D1 dopamine receptors activity in the PRH but not in the HIPP is needed for ORM consolidation. Muscarinic receptor activity is required for LTM in the PRH but not in the HIPP. Retrieval is not necessary to reconsolidate ORM in the PRH.

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Article history: Received 12 May 2014 Received in revised form 22 August 2014 Accepted 25 August 2014 Available online xxx Keywords: Object recognition Perirhinal cortex Hippocampus Retrieval Consolidation Reconsolidation

a b s t r a c t In the first part of this review, we will present evidence showing a functional double dissociation between different structures of the medial temporal lobe in the consolidation of object and object-in-context recognition memory. In addition, we will provide evidence to support this differential participation through protein synthesis inhibitors and neurotransmitters antagonists and agonists. This evidence points out that the perirhinal, prefrontal and insular cortices consolidate the information of individual stimuli, i.e., objects, while the hippocampus consolidates the contextual information where the objects were experimented. In the second part of this review, we will present evidence that shows that the perirhinal cortex is also necessary for reconsolidation of ORM; the destabilization/re-stabilization memory process upon its activation. In the final part of this review, we will present evidence that shows that ORM reconsolidation is an independent process from its retrieval in the perirhinal cortex. Altogether, this review depicts part of the mechanisms by which the medial temporal lobe processes the functional components of recognition memory, in both consolidation and reconsolidation. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Recognition memory has been described as the ability to know that something has been previously experienced (individual stimulus or a whole event) [1,2]. At least two components of the recognition process have been identified: one is the judgment of stimulus familiarity and the other is the recollection of contextual information (spatial and/or temporal); i.e., where and when items were experienced [1,3]. Recognition memory has been associated to a network of medial temporal lobe regions, including the perirhinal, parahippocampal, entorhinal and insular cortices, as well as

Abbreviations: PRH, perirhinal cortex; HIPP, hippocampus; IC, insular cortex; ORM, object recognition memory; STM, short-term memory; LTM, long-term memory. ∗ Corresponding author. Tel.: +52 55 5622 5626; fax: +52 5 556225607. E-mail addresses: [email protected], [email protected] (F. Bermudez-Rattoni).

the hippocampus [4–6]. In the first part of this review, we will present evidence for the contribution of different temporal-lobe regions in memory consolidation for object and object-in-context recognition tasks. These two tasks allow us to dissociate the two above-mentioned components of recognition memory, the identity of the object (a whole representation of the stimulus), and the spatial context where the object was found. Object recognition task is based on the discrimination between familiar and novel stimuli; the subject needs to remember “what” stimulus experimented previously [7]. Conversely, object-in-context task is based on the association of a specific stimulus with a spatial arrangement and for this, the subject needs to remember “where” the stimulus was experimented [8,9]. Recognition memory tasks have been utilized to demonstrate the role of the temporal lobe regions in memory formation [10,11]. Earlier demonstrations were done by ablations of the medial temporal lobe in monkeys. This study suggested that combined lesions of the hippocampus and amygdala accounted for a severe recognition memory impairment [10]. However, more recent findings

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Please cite this article in press as: Balderas I, et al. Consolidation and reconsolidation of object recognition memory. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.08.049

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showed that recognition impairment was not directly related to damage to those structures but, rather, to damage to the anterior and posterior portions of the perirhinal and entorhinal cortices induced by the aspiration of the amygdala and the hippocampus [11].

2. Dissociation between the hippocampus and rhinal cortices in stimulus familiarity and context The perirhinal cortex is a multimodal association region that is densely interconnected with sensory areas specific to different sensory modalities [1]. Several studies have shown that multiple sensory systems related to stimulus recognition activate the perirhinal cortex [1,12–17], supporting the idea that association of individual features that represent a stimulus as a whole (within-stimulus association of components) are represented in the perirhinal cortex. On the other hand, complex associations between stimuli and environment (context) may be represented in the hippocampal formation [1]. One of the first reports on this topic was done by Winters et al.; they found that hippocampus lesions impair spatial but not object recognition memory. Conversely, peripostrhinal cortex lesions disrupt object recognition but not spatial memory [18]. Similar results were found by Eacott et al., who demonstrated that lesions of the perirhinal cortex disrupt memory of a non-contextual object recognition task without affecting the object-in-context task [19]. Contrary, it has been reported that perirhinal lesions impair an object-in-place task, where animals have to recognize that a specific object has changed position with respect to another. However, detailed histological analysis revealed that both perirhinal and lateral entorhinal cortices were lesioned in these experiments [20]. In this regard, it has been reported that excitotoxic lesions of the lateral entorhinal cortex do not disrupt the recognition of either novel objects or novel places, but clearly impair the discrimination of familiar objects in familiar places, suggesting that memory for new associations between objects and places is processed in the lateral entorhinal cortex [21–23]. Studies using electrophysiological recordings in the anterior temporal lobe cortex showed that visual stimuli produce noticeable neuronal changes in the perirhinal cortex [24–26]. The authors observed that cellular responses were considerably decreased between the first and second exposure to the same visual item. In addition, they demonstrated that the decremented neuronal activity persisted for at least one day after stimulation and was specific to a particular item; accordingly, exposure to another novel item induced a normal response. Thus, they identified neurons whose response is shaped by the relative familiarity of discrete visual stimuli. Furthermore, the decrement in neuronal activity to a specific item persisted even if several other items were presented in-between [27–29]. These findings suggest that the reduced responsiveness in the perirhinal cortex reflects long-term memory [30–32]. Interestingly, no significant changes in neuronal responses were found in the hippocampus after exposure to visual stimuli [25]. Accordingly, studies using Fos activation have reported that more neurons are activated by novel stimuli than by familiar items in the perirhinal cortex but not in the hippocampus. By contrast, hippocampal, lateral entorhinal and postrhinal, but not perirhinal cortices activity was enhanced when a new spatial arrangement of familiar objects was presented to rats [21,33–35]. In agreement with these results, considerable evidence have shown that neuronal responses in the hippocampus were related to spatial components, such as self-position in space or information concerning stimuli in particular places [36,37]. Although particular attention has been paid to the perirhinal cortex in object recognition, it is clear that other cortical regions are also important in recognition memory processing. In this regard,

we have reported that the insular cortex (IC) is required for both object and taste recognition memory consolidation [38–40]. The IC is located in the lateral temporal lobe deep within the Sylvian fissure in primates and humans. In rodents (Krieg’s areas 13 and 14) the IC is located along the confluence of the rhinal sulcus and the medial cerebral artery [41]. Due to reciprocal connectivity with several limbic structures and sensory areas of the cortex, the IC is involved in several cognitive functions, including memory formation for several appetitive and aversively motivated learning tasks [38,41]. Therefore, the temporal cortical structures located along the rhinal sulcus are critical for recognition memory storage. In the next section, we will describe experiments that by inhibiting protein synthesis, activating or blocking different neurotransmission systems, strongly support a double dissociation between the rhinal cortices and the hippocampus in object and object-in-context recognition memory consolidation.

3. The role of the rhinal cortices and hippocampus in recognition memory consolidation As mentioned, pharmacological manipulations have provided evidence suggesting that the perirhinal and insular cortices store recognition memory for different sensory modalities [14,38,42,43]. In a previous study, we investigated the contribution of different temporal-lobe regions to recognition memory consolidation of objects and objects in context. In the ORM protocol after habituation to the context, rats were allowed to freely explore two identical objects (A1 and A2 ). Memory was tested 90 min (short-term memory) or 24 h later (long-term memory). In the memory test, rats were allowed to explore freely one copy of the previously presented object (A3 ) together with a new one (B) (see Fig. 1a). In our object-in-context protocol the objects and contexts were familiar in the test phase, but the relation between them was novel [39] (see Fig. 1c). In this protocol after habituation to two different contexts (1 and 2), rats were placed in the context 1 and were allowed to explore two different objects (A1 and B1 ). Sample phase 2 was conducted 24 h later and rats were placed in context 2 together with two identical objects [copies of one of the previously presented objects, (A2 and A3 )]. Therefore, object A was familiar in both contexts but object B was only presented in context 1. Memory was tested 90 min (shortterm memory) or 24 h (long-term memory) later. In the test, rats were reintroduced to context 2 and were allowed to explore one copy of each of the objects presented before (A4 and B2 ). Thus, the combination object B in context 2 is novel and allows evaluation of the context component of recognition memory. Together, these behavioral protocols were employed to separately assess the two components of recognition memory in the short and long term [39] (see Fig. 1a and c). In a series of experiments using these protocols, we demonstrated that object but not object-in-context recognition memory consolidation was impaired when the protein synthesis blocker anisomycin was infused into the perirhinal or insular cortices after the sample phase (see Fig. 1b). Conversely, administration of anisomycin into the dorsal hippocampus blocked the consolidation of object-in-context, but not object recognition memory (see Fig. 1d). It is important to highlight that anisomycin infusions in the hippocampus, perirhinal or insular cortices did not disrupt memory when tested 90 min after sample phase (see Ref. [39]), suggesting this is a suitable time point to evaluate memories in the shortterm for object and object-in-context [39]. Our findings provide additional information concerning the participation of distinct structures of the temporal lobe required for recognition memory processing, and make it clear that the hippocampus and the cortex have specific and different roles in long-lasting recognition



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Fig. 1. Perirhinal and insular cortices are required for consolidation of objects; while the hippocampus is necessary for consolidation of contextual information. (a) Protocol used to assess object recognition memory. After a habituation phase to the context, animals were allowed to freely explore to identical objects (A1 and A2 ). The pharmacological manipulation was done immediately after the sample phase in order to disrupt consolidation of objects. After a delay of 24 h to test LTM, animals were exposed to different objects, a copy of one previously presented (A3 ) and a new one (B1 ). With this protocol, changes in the relative position of the objects during the sample phase are avoided. (b) Anisomycin (ANI) infused into perirhinal (PRH) or insular cortices (IC) blocked object recognition memory consolidation. Infusions into the hippocampus (HIP) did not impair object recognition memory. (c) Protocol to test object-in-context memory. After a habituation phase to the two contexts (1 and 2), animals were allowed to freely explore two different objects (A1 and B1 ) in context 1. Twenty-four hours later, animals were exposed to two copies of a previously experimented object (A2 and A3 ) in context 2. After this phase, both contexts and objects are familiar. The pharmacological manipulation was done immediately after this phase in order to disrupt the consolidation of the novel relation between context 2 and object “B”. In the memory test (24 h later), animals were allowed to freely explore a copy of the object previously presented in both contexts (A4 ) and a copy of the familiar object (B2 ) presented for the first time in context 2. With this protocol, it is possible to test specifically the novel relation between an object in a particular context (depicted in the dash circle) (for more detail see Ref. [39]). (d) Anisomycin infusions into the hippocampus blocked object-in-context recognition memory consolidation; whereas infusions administered into the perirhinal or insular cortices did not affect object-in-context recognition memory. These results indicate that distinct regions of the temporal lobe are differentially involved in consolidation of object and object-in-context recognition memory. Recognition index: exploration time for novel object/total exploration time for both objects **p < 0.01 between groups. Source: Modified from Ref. [39].

memory storage. However, our results contrast with some papers reporting that protein synthesis in the hippocampus [44] through mTOR signaling is necessary for consolidation of object recognition memory [45,46]. It should be pointed out that these authors used protocols with two different objects in the sample phase. In this regard, a recent study reported that both the perirhinal cortex and hippocampus are necessary for ORM if two different objects are used in the sample phase [47]. Consistently, Mumby et al. reported that lesions of the hippocampus disrupt recognition memory only when the relative positions of the objects were changed [9]. On the other hand, a study by Jobim et al. used short periods of habituation to the arena (2 min in one day); it is important to know whether short periods of habituation are enough to consolidate the context. In this regard, a non-consolidated context could produce ambiguity for discrimination of novelty of the context and objects. The above-mentioned results support the hypothesis that the hippocampus is specifically involved in recollection, while familiarization depends in the rhinal cortices [1,48]. However, it should be noted that an opposing view maintains that both the hippocampus and the perirhinal cortex are involved in recollection and familiarity [49]. As mentioned earlier, it has been demonstrated that post-trial protein synthesis inhibition in the perirhinal and insular cortices but not in the hippocampus impaired LTM (at 24 h)

of object familiarization, whereas STM (90 min) remained unaffected. However, when the task is based on contextual information, protein synthesis inhibition in the hippocampus but not in the perirhinal and insular cortices impaired LTM while STM was spared [39]. An epigenetic approach to the study of the neurobiology of memory has appeared recently to explain the putative modulatory mechanisms of memory consolidation. This line of research tries to understand how modifications in chromatin could affect the activation of transcriptional factors involved in memory formation [41,50]. Thus, it has been demonstrated notable long-term ORM improvements when the inhibitor of histone deacetylases (HDACs) sodium butyrate was injected [51]. In addition, it has been demonstrated that post-trial infusions of sodium butyrate in the IC increase long-term memory of object recognition, while the infusion in the hippocampus does not affect ORM. Moreover, when post-trial infusions were done in an object location memory protocol, it was the hippocampal group that showed increased long-term memory while the IC group did not [50]. Importantly, in this study Roozendaal et al. showed that these memory consolidation enhancements occur by the regulation of chromatin structure through membrane-associated glucocorticoid receptors in the IC and hippocampus for object recognition and object location, respectively. These series of experiments clearly suggest



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Fig. 2. Differential involvement of cholinergic and dopaminergic activity in the perirhinal cortex and the hippocampus in the consolidation of object recognition memory. (a) In the sample phase, rats were exposed to two identical objects (A1 and A2 ), and immediately after received a bilateral infusion into the perirhinal cortex (PRH) or hippocampus (HIP) of vehicle solution (VEH) or the muscarinic receptor antagonist scopolamine (SCOP). Memory test was conducted 90 min or 24 h after the end of the sample phase, in which a copy of the familiar object (A3 ) and a new one (B1 ) were presented. Results showed that scopolamine impaired short-term memory (STM) when infused in either the perirhinal cortex (c) or hippocampus (d). However, scopolamine disrupted long-term memory (LTM) when administrated in the perirhinal cortex (e) but not when applied in the hippocampus (f); (modified from Ref. [52]). (b) The involvement of D1 receptors activity in ORM consolidation was assessed by infusing the D1 receptor antagonist SCH23390 (SCH) 15 min before the sample phase in the perirhinal cortex or the hippocampus. SCH23390 impaired LTM when infused in the perirhinal cortex (i) but not when infused in the hippocampus (j). Importantly, SCH23390 infusions spared STM when infused in the perirhinal cortex (g) or hippocampus (h). Recognition index: exploration time for novel object/total exploration time for both objects. *p < 0.05, **p < 0.01 versus vehicle group. Source: Modified from Ref. [64].

a double dissociation between the perirhinal and insular cortices versus the hippocampus in the consolidation of object recognition and object-in-context recognition memories by inhibiting the synthesis of proteins or by activating gene expression. Studies at the neurochemical level have shed light on the upstream events to protein synthesis involved in recognition memory. In this regard, it has been demonstrated that acetylcholine receptor activity differentially processes object recognition memory. We were able to show that cholinergic activity in both the perirhinal cortex and hippocampus is essential for STM formation of object recognition by using post-trial infusions of the muscarinic receptor antagonist scopolamine (see Fig. 2a and b). However, only scopolamine infusions in the perirhinal cortex but not in the hippocampus impaired object recognition consolidation (see Fig. 2c and d) [52]. LTM was spared when scopolamine was administrated in the perirhinal cortex or hippocampus before retrieval or 160 min after the sample phase (see Ref. [52]). These results suggest that muscarinic receptor activity in both the hippocampus and perirhinal cortex plays a role in the maintenance of information for short periods following encoding. Perirhinal cortex muscarinic receptor involvement in object recognition memory at short delays has consistently been observed in a wide variety of experimental models and designs [53–55]. However, these studies used pre-sample

microinfusions making hard to dissociate effects on acquisition and memory consolidation. With regard to the role of cholinergic activity in the hippocampus, it has been demonstrated that scopolamine infusions into the CA3 region disrupt STM (3 min) of non-spatial as well as spatial versions of the object recognition task [56]. Moreover, significant increases in acetylcholine efflux have been observed in the hippocampus by in vivo microdialysis when rats actively explore a novel object [57]. Recently, it was reported that acetylcholine measured by in vivo microdialysis significantly increased from baseline when a novel object was presented 90 min after the sample phase [58]. All in all, these results suggest that acetylcholine neurotransmission is necessary during encoding and retention of a recently acquired object. Accordingly, we showed that interfering with acetylcholine signalization with post-sample scopolamine infusions in the hippocampus also affects object recognition STM. Our results show that LTM requires muscarinic activity in the perirhinal cortex but not in the hippocampus (see Fig. 2), suggesting that some of the newly synthesized proteins in the perirhinal cortex are a downstream signaling product of the muscarinic system. Similarly to the perirhinal cortex, scopolamine infusions in the insular cortex impaired object recognition LTM [38]. In addition, it was shown that attenuation of neophobia, a recognition




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Fig. 3. Protein synthesis inhibition disrupted reconsolidation only when new related information was presented. (a) Anisomycin spared reconsolidation when infused in the perirhinal cortex after presentation of two copies of a familiar object A3 and A4 . (b) Similarly, anisomycin had no effect on reconsolidation when infused in the perirhinal cortex after exploration of two copies of a novel object (B1 and B2 ). (c) However, anisomycin disrupted reconsolidation when infused in the perirhinal cortex after a novel and a familiar object were presented together (A3 and B1 ). Novel objects are depicted as dotted-line squares representing the unstable memory trace of these stimuli. Stable memory traces of familiar objects are symbolized as continued-line squares. Source: Modified from Ref. [72].

memory task for the taste modality, is affected by post-trial scopolamine infusions in either the perirhinal or insular cortices [14]. These results point toward a central role of cortical acetylcholine in the familiarity component of recognition memory. Although the role of dopamine in ORM formation has been scarcely investigated, there is abundant literature on the modulatory effects of dopamine activity on neural plasticity and the mechanisms whereby long-term memory is stored [59–61]. In this regard, there is evidence that the D1 dopamine receptor agonist SKF38393 at 5 mg/kg enhances object recognition memory when tested 24 and 72 h after the sample phase [62]. Conversely, D2 dopamine receptors do not participate in ORM, since systemic injections of the D2 agonist quinpirole at two different doses did not affect memory. Accordingly, other studies have shown that D1 /D5 (but not D2 ) receptor activity is involved in the late phase of longterm potentiation (LTP), suggesting that D1 /D5 receptor activity may be involved in the protein synthesis-dependent component of LTP [61]. Previously, we have reported a significant increase in the release of dopamine in rodents’ insular cortex during the

discrimination of novel stimuli (i.e., objects, or tastes); while the release of dopamine remained unchanged in the hippocampus [63], suggesting a dissociative involvement of dopaminergic transmission in cortical familiarity-based recognition. In a recent study, we addressed the role of perirhinal and hippocampus D1 receptors activity in consolidation of ORM. Since it has been described that release of dopamine increased significantly during the presentation of novel objects [63], we infused an agonist (SKF38393) or an antagonist (SCH23390) of D1 receptors 15 min before the presentation of novel stimuli in order to manipulate the receptors during the dopamine release. In these series of experiments, we found that SCH23390 impaired long-term memory (24 h) when infused in the perirhinal cortex but not when infused in the hippocampus (see Fig. 2g and h). Importantly, short-term memory (90 min) was spared when SCH23390 was infused in the perirhinal cortex or dorsal hippocampus suggesting that acquisition was unaffected (see Fig. 2e and f). Conversely, when the D1 receptor agonist SKF38393 was infused 10 min before the sample phase in the perirhinal cortex, long-term memory was enhanced, however, this was not



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observed when the D1 agonist was infused in the hippocampus [64]. These results suggest that dopaminergic transmission in the perirhinal cortex and hippocampus have a differential involvement in object recognition memory consolidation, supporting the hypothesis that familiarity information is processed in the PRH. In a recent study by Rossato et al., it was demonstrated that infusions of SCH23390 in the prefrontal cortex or the amygdala, but not in the hippocampus, disrupt ORM consolidation. Importantly the D2 receptor antagonist quinpirole had no effect. Conversely, coinfusions of SKF38393 in the prefrontal cortex and the amygdala, but not in a combination with the hippocampus, reverse the ORM deficit induced by the inactivation of the ventral tegmental area with muscimol [65]. All these results give us a panoramic view of the participation of neurotransmitter systems in discrimination of objects; and importantly, these results suggest a differential involvement of medial temporal lobe structures in recognition memory. Perirhinal, insular and prefrontal cortices process the information of objects, while the entorhinal cortex and the hippocampus process the contextual information where objects were experimented. Further studies will be designed to reveal the interaction between the different structures involved in recognition memory, as well to clarify more the role of the medial temporal lobe structures in the processing of the different components of recognition memory.

4. Reconsolidation of object recognition memory In the previous section, we reviewed object recognition longterm memory requirement for protein synthesis in the rhinal cortices, and that activation of intracellular cascades leading to transcriptional factors is initiated by acetylcholine and dopamine receptors. In this section, we will review selected literature on object recognition memory reconsolidation and discuss the idea that reconsolidation is the mechanism by means of which longterm memory is updated. After consolidation, memories can undergo destabilization– restabilization processes referred to as reconsolidation. Reconsolidation is heavily supported by a plethora of experiments showing that memories are susceptible to disruption by the same treatments that disrupt memory during consolidation. Therefore, it comes that stored memories can turn unstable under some conditions. To remain in the long term, unstable memories must be fixed again [66,67]. Kelly et al. [68] published the first study on object recognition memory reconsolidation in 2003. They infused the MAP kinase inhibitor UO126 into the brain ventricles and observed effects on consolidation and reconsolidation but not on short-term memory. Later the same year, Bozon et al. reported object recognition consolidation and reconsolidation deficits on mice bearing a mutant form of the transcription factor zif268 [69], and as with consolidation, considerable evidence supports that object recognition reconsolidation is dependent on protein synthesis [44,70–73]. Our group explored reconsolidation dependence on protein synthesis specifically in the perirhinal cortex. In these experiments, rats were exposed to two copies of the same object in the sample phase (A1 and A2 ). The next day, three different protocols were assessed in independent groups followed by bilateral infusion in the perirhinal cortex of the translation inhibitor anisomycin (see Fig. 3). One group was exposed to two copies of the object presented the day before (A3 and A4 , see Fig. 3a). A second cohort of animals was exposed to two copies of a novel object (B1 and B2 , see Fig. 3b) and, the last group was presented with a copy of the familiar object and a copy of the novel object (A3 and B1 , see Fig. 3c). Memory was tested 24 h later in all groups by presenting one copy of the object showed in the sample phase together with a third novel object (A5 and C1 ).

We observed that only rats exposed to novel and familiar objects together are susceptible to protein synthesis inhibition. This group showed similar exploration times for novel and familiar objects in the test (see Fig. 3). These results indicate that information stored in the perirhinal cortex undergoes reconsolidation only when relevant new information was presented, in this case, information of a second object (see Ref. [72]). These findings are consistent with the idea that reconsolidation is intended to update memory [74]. This study opposes a previous report where anisomycin in the perirhinal cortex effectively disrupted reconsolidation whether new stimuli were presented or not [73]. However, the protocol used in that report has been shown to produce relatively weak object memories [75], and evidence indicates that weak memories can be strengthened through reconsolidation (reviewed in Ref. [76]). Our findings are consistent with other studies that have analyzed whether object recognition reconsolidation is initiated by conjoint exposure to familiar and new information. Intraperitoneal injection of the NMDA antagonist MK801 was proven to disrupt reconsolidation of well-established object memories only when new contextual information was presented [75]. In another report, it was found that intrahippocampal infusions of anisomycin impaired object recognition reconsolidation when administered after animals were exposed to novel and familiar objects together but not when presented with familiar stimuli, like exposure to the context alone or to previously presented objects [44]. Although this latter report showed the importance of a new stimulus to trigger object recognition reconsolidation, it was surprising that effects were observed upon anisomycin intrahippocampal infusions. As noted in the previous section, this may be related to the fact that different objects were presented together during all the sessions and their relative positions were interchanged providing relevant contextual information that would be incorporated to memory. In this regard, it was reported that protein synthesis inhibition in the hippocampus disrupted reconsolidation only when new contextual information was presented [73]. Furthermore, it has been shown that reconsolidation supports updating of recognition memory in humans [77]. In these experiments subjects memorized a list of objects. On the next day, participants learned a second list of objects. Before presentation of the second list, some individuals were asked to describe the previous training session (reminder group). When tested for the first list of words, only the reminder group showed a high number of intrusions from the second list, i.e., when asked to recall words from list 1 these subjects intermixed both list of objects, suggesting that information from the second list was integrated to the memory of the first list [77]. Evidence to propose that reconsolidation is aimed to integrate updated information into long-term memory not only comes from reports evaluating recognition memory but from a growing number of studies evaluating several different kinds of memory [40,78–84]. From this body of research the proposal has emerged that reconsolidation is not only an opportunity to update memory but that updated information triggers memory reconsolidation [74]. Under this hypothesis, incoming information would be compared with already stored memory and would produce destabilization of relevant stored memory. Later, both destabilized memory and incoming information would be re-stabilized in an updated longterm memory. In a simple scenario, two types of information can modify stored memory, reinforcing (strengthening) information and divergent information [74]. Based on the assumption that neuronal ensembles underlie memories, reinforcing information would modify existing memories by two means: by making the synaptic weights of the already existing ensemble stronger or by adding cellular entities to the existing ensemble. In both cases, modifications of the synaptic weights involved in the ensemble are required. Furthermore, when




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Fig. 4. Schematic representation showing evidence that the retrieval and reconsolidation of ORM are independent processes. Novel objects are depicted as dotted-line squares representing the unstable memory trace of these stimuli. Stable memory traces of familiar objects are symbolized as continued-line squares. In the sample phase, new objects (“A”) have an unstable memory trace. Object “A” becomes familiar through consolidation. In the reactivation phase, behavioral outputs are impaired by infusion of muscimol (MUSC) or CNQX in the perirhinal cortex; since rats did not show preference for any object. However, the effects of MUSC or CNQX were transient since animals showed preference for the new object (“C”) in the test phase, indicating that reconsolidation of object “A” was not impaired by MUSC or CNQX. Conversely, anisomycin (ANI) or APV infusions disrupted reconsolidation of object “A”, even in conditions where retrieval was blocked (for more details of experimental data see Refs. [72,89]).

there is no more relevant information to be learned, memory is no longer prone to reconsolidation. Other possible kind of information that could lead to reconsolidation would be information that produces a shift of previous learning (referred also as mismatch [85,86]). In this case divergent information would be integrated into memory by either modification of the already existing ensemble or, a different but overlapping trace would be created for this divergent information, in which case modifications in the synaptic weights involved in the first ensemble would take place as well. Overlapping between the ensembles is supposed because they represent divergent associations between overlapping stimuli. In all cases, the result of these processes will be stable overlapping traces. The relationship between these converging (trace reinforcement) and diverging (trace shift) overlapping traces would determine behavior (trace competition under Dudai’s view [87]). 5. Reconsolidation of object recognition in the absence of retrieval Upon reconsolidation, memories can be erased or modified [74,87], making manipulation of reconsolidation a plausible therapeutic tool for treating people with anxiety disorders, like post-traumatic stress disorder and phobias. However, the physiological conditions that trigger reconsolidation are not fully understood and are subject to intense research [67,87]. Above, we explored the possibility of reconsolidation as a process to update memory with relevant information. Now, we will review literature on the relationship between reconsolidation and another important parameter, retrieval. It is implicit and even granted that retrieval is an essential condition to initiate reconsolidation. This assumption makes sense when

we consider that specificity is a hallmark feature of reconsolidation. Only relevant cues would induce reconsolidation. For example, reconsolidation of a context footshock conditioning would be triggered by the same context used in training but a different context would be an ineffective cue to initiate reconsolidation for that particular conditioning. Another important consideration is the theoretical process that occurs when incoming information is presented. Incoming information must be compared with stored information. Consequently, stored memories must somehow be accessed for comparison with incoming information and retrieval seems the logical mechanism to accomplish such a goal [88]. However, recent reports showed that pharmacological inhibition of retrieval does not interfere with reconsolidation, indicating that retrieval is a dispensable condition to undergo reconsolidation. In our laboratory we studied reconsolidation independence from retrieval on object recognition [72]. First, rats were familiarized to two copies of the same object. On the next day, memory was updated by presenting together the familiar and a new object. As described in the previous section, this protocol induces reconsolidation as anisomycin-infused rats showed similar exploration times for novel and familiar objects when tested on the next day. In another group, the GABA receptor agonist muscimol was infused and memory disruption was observed on that session but rats were able to discriminate objects the next day, indicating retrieval deficits. One last group of rats was given muscimol before and anisomycin after exposition to the familiar and new objects. Animals under this treatment exhibited similar exploration times for the novel and familiar objects on the infusion and test trials. These results indicated that reconsolidation was impaired by anisomycin on conditions where retrieval was suppressed [72] (see Fig. 4).



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A follow-up study revealed that CNQX disrupts retrieval; while APV impairs reconsolidation of object recognition memory when apply to the perirhinal cortex [89]. More important, double infusions showed that APV impeded reconsolidation even when CNQX blocked retrieval. It is well established that treatments that disrupt reconsolidation, as it occurs with consolidation, spare short-term memory [90]. Therefore, to strengthen the view that the observed effects were specific to reconsolidation, rats were conjointly infused with CNQX and APV but tested for short-term memory. As expected, CNQX blocked retrieval but APV spared memory [89] (see also Refs. [91,92]. This report sums to a large body of work that indicates that AMPA and NMDA receptors play consistent roles on memory retrieval and reconsolidation, respectively [42,70,89,91,93–96] (see Fig. 4). Experiments showing that inhibition of retrieval do not impede memory to undergo reconsolidation have been reported for fear conditioning [91,95], taste aversion [94,96] and contextual memory in crabs [92]. The major conclusion from this body of work is that memory destabilization, uncovered by reconsolidation impairments, can occur despite pharmacological inhibition of retrieval, inferred from the animals’ inability to execute the task. The different reports indicate that this is true for different kinds of memories, using different drugs and applied in different brain regions. The implication from this research is that mechanisms required to retrieve memory are different from mechanisms needed to destabilize memory, and suggest that retrieval and reconsolidation are independent and dissociable processes. However, experiments that conclude impairments in retrieval are based on the observation that there is no behavioral outcome after infusion of the drug and there is, at least, another possible interpretation to these results. Animals under the effects of the drug may retrieve the memory, but may not express it in behavior, i.e., animals are unable to perform the task because the drug inhibits some mechanism required for behavioral output (see Fig. 4). We argue that these studies indicate that retrieval is not a unitary process but has, at least, two distinct components. One component access stored memory to produce some sort of outcome, namely expression. In the case of behavioral expression, neural mechanisms involved in expression presumably coordinate with motor cognitive operations to display behavior. The other component must also gain access to stored information but in this case, the consequence is destabilization of consolidated memory. The rationale to propose that retrieval has two components is that these components can be experimentally dissociated. Expression can be attained without destabilization and destabilization can be achieved without expression. Almost since the resurgence of reconsolidation in the year 2000, it was noticed that memory does not undergoes reconsolidation every time it is expressed [97,98] (reviewed in Ref. [99]). These findings indicate that expression is not sufficient condition to destabilize memory. On the other hand, the experiments described above reveal that destabilization can be obtained in the absence of expression. For example, two studies that conjointly manipulated AMPA and NMDA receptors showed that, in the case of object recognition and taste aversion, reconsolidation relies on NMDA activity that is independent from AMPA activity that leads to expression [89,96], suggesting the occurrence of memory destabilization without expression

6. Conclusion As we have seen in this review, increasingly evidence suggests a dissociative role of different structures in the formation of recognition memory. The evidence from lesion and pharmacological manipulations studies point out that perirhinal, insular

and prefrontal cortices consolidate the information of individual stimuli, i.e., an object, while the hippocampus consolidate the contextual information where stimuli were encounter. Although some studies have shown several neurotransmitter systems involved on ORM consolidation, further studies will determine the role of the neurotransmitter systems in object-in-context recognition task. Since the perirhinal cortex has an important role in ORM consolidation, most studies exploring reconsolidation of ORM have focused in this region. Moreover, it has been demonstrated that object recognition memory reconsolidation can be disrupted despite retrieval blockage by different pharmacological manipulations in the perirhinal cortex, suggesting that memory reconsolidation is independent of its retrieval. Acknowledgments This paper was supported by CONACYT, grant number: 155242 and DGAPA-UNAM, grant number: IN209413. We thank Perla Moreno-Castilla and Francisco Pérez Eugenio for technical support. References [1] Brown MW, Aggleton JP. Recognition memory: what are the roles of the perirhinal cortex and hippocampus. Nat Rev Neurosci 2001;2:51–61. [2] Mandler G. The judgment of previous occurrence. Psychol Rev 1980;87:252–71. [3] Yonelinas AP, Kroll NE, Quamme JR, Lazzara MM, Sauve MJ, Widaman KF, et al. Effects of extensive temporal lobe damage or mild hypoxia on recollection and familiarity. Nat Neurosci 2002;5:1236–41. [4] Aggleton JP, Brown MW. Episodic memory, amnesia, and the hippocampalanterior thalamic axis. Behav Brain Sci 1999;22:425–44 [discussion 44–89]. [5] Malkova L, Mishkin M. One-trial memory for object-place associations after separate lesions of hippocampus and posterior parahippocampal region in the monkey. J Neurosci 2003;23:1956–65. [6] Reed CL, Shoham S, Halgren E. Neural substrates of tactile object recognition: an fMRI study. Hum Brain Mapp 2004;21:236–46. [7] Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1. Behavioral data. Behav Brain Res 1988;31:47–59. [8] Dix SL, Aggleton JP. Extending the spontaneous preference test of recognition: evidence of object-location and object-context recognition. Behav Brain Res 1999;99:191–200. [9] Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H. Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts. Learn Mem 2002;9:49–57. [10] Mishkin M. Memory in monkeys severely impaired by combined but not by separate removal of amygdala and hippocampus. Nature 1978;273:297–8. [11] Murray EA, Mishkin M. Object recognition and location memory in monkeys with excitotoxic lesions of the amygdala and hippocampus. J Neurosci 1998;18:6568–82. [12] Burwell RD, Witter MP, Amaral DG. Perirhinal and postrhinal cortices of the rat: a review of the neuroanatomical literature and comparison with findings from the monkey brain. Hippocampus 1995;5:390–408. [13] Buffalo EA, Ramus SJ, Clark RE, Teng E, Squire LR, Zola SM. Dissociation between the effects of damage to perirhinal cortex and area TE. Learn Mem 1999;6:572–99. [14] Gutierrez R, De la Cruz V, Rodriguez-Ortiz CJ, Bermudez-Rattoni F. Perirhinal cortex muscarinic receptor blockade impairs taste recognition memory formation. Learn Mem 2004;11:95–101. [15] Murray EA, Richmond BJ. Role of perirhinal cortex in object perception, memory, and associations. Curr Opin Neurobiol 2001;11:188–93. [16] Otto T, Eichenbaum H. Complementary roles of the orbital prefrontal cortex and the perirhinal–entorhinal cortices in an odor-guided delayed-nonmatching-tosample task. Behav Neurosci 1992;106:762–75. [17] Suzuki WA, Zola-Morgan S, Squire LR, Amaral DG. Lesions of the perirhinal and parahippocampal cortices in the monkey produce long-lasting memory impairment in the visual and tactual modalities. J Neurosci 1993;13:2430–51. [18] Winters BD, Forwood SE, Cowell RA, Saksida LM, Bussey TJ. Double dissociation between the effects of peri-postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: heterogeneity of function within the temporal lobe. J Neurosci 2004;24:5901–8. [19] Norman G, Eacott MJ. Impaired object recognition with increasing levels of feature ambiguity in rats with perirhinal cortex lesions. Behav Brain Res 2004;148:79–91. [20] Barker GR, Bird F, Alexander V, Warburton EC. Recognition memory for objects, place, and temporal order: a disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex. J Neurosci 2007;27:2948–57. [21] Wilson DI, Langston RF, Schlesiger MI, Wagner M, Watanabe S, Ainge JA. Lateral entorhinal cortex is critical for novel object-context recognition. Hippocampus 2013;23:352–66.




[22] Wilson DI, Watanabe S, Milner H, Ainge JA. Lateral entorhinal cortex is necessary for associative but not nonassociative recognition memory. Hippocampus 2013;23:1280–90. [23] Van Cauter T, Camon J, Alvernhe A, Elduayen C, Sargolini F, Save E. Distinct roles of medial and lateral entorhinal cortex in spatial cognition. Cereb Cortex 2013;23:451–9. [24] Baylis GC, Rolls ET. Responses of neurons in the inferior temporal cortex in short term and serial recognition memory tasks. Exp Brain Res 1987;65:614–22. [25] Brown MW, Wilson FA, Riches IP. Neuronal evidence that inferomedial temporal cortex is more important than hippocampus in certain processes underlying recognition memory. Brain Res 1987;409:158–62. [26] Miller EK, Li L, Desimone R. A neural mechanism for working and recognition memory in inferior temporal cortex. Science 1991;254:1377–9. [27] Riches IP, Wilson FA, Brown MW. The effects of visual stimulation and memory on neurons of the hippocampal formation and the neighboring parahippocampal gyrus and inferior temporal cortex of the primate. J Neurosci 1991;11:1763–79. [28] Fahy FL, Riches IP, Brown MW. Neuronal activity related to visual recognition memory: long-term memory and the encoding of recency and familiarity information in the primate anterior and medial inferior temporal and rhinal cortex. Exp Brain Res 1993;96:457–72. [29] Xiang JZ, Brown MW. Differential neuronal encoding of novelty, familiarity and recency in regions of the anterior temporal lobe. Neuropharmacology 1998;37:657–76. [30] Brown MW, Xiang JZ. Recognition memory: neuronal substrates of the judgement of prior occurrence. Prog Neurobiol 1998;55:149–89. [31] Rainer G, Miller EK. Effects of visual experience on the representation of objects in the prefrontal cortex. Neuron 2000;27:179–89. [32] Ranganath C, Rainer G. Neural mechanisms for detecting and remembering novel events. Nat Rev Neurosci 2003;4:193–202. [33] Zhu XO, Brown MW, McCabe BJ, Aggleton JP. Effects of the novelty or familiarity of visual stimuli on the expression of the immediate early gene c-fos in rat brain. Neuroscience 1995;69:821–9. [34] Zhu XO, McCabe BJ, Aggleton JP, Brown MW. Mapping visual recognition memory through expression of the immediate early gene c-fos. Neuroreport 1996;7:1871–5. [35] Zhu XO, McCabe BJ, Aggleton JP, Brown MW. Differential activation of the rat hippocampus and perirhinal cortex by novel visual stimuli and a novel environment. Neurosci Lett 1997;229:141–3. [36] Gaffan D, Parker A. Interaction of perirhinal cortex with the fornix-fimbria: memory for objects and object-in-place memory. J Neurosci 1996;16: 5864–9. [37] Muller R. A quarter of a century of place cells. Neuron 1996;17:813–22. [38] Bermudez-Rattoni F, Okuda S, Roozendaal B, McGaugh JL. Insular cortex is involved in consolidation of object recognition memory. Learn Mem 2005;12:447–9. [39] Balderas I, Rodriguez-Ortiz CJ, Salgado-Tonda P, Chavez-Hurtado J, McGaugh JL, Bermudez-Rattoni F. The consolidation of object and context recognition memory involve different regions of the temporal lobe. Learn Mem 2008;15:618–24. [40] Rodriguez-Ortiz CJ, De la Cruz V, Gutierrez R, Bermudez-Rattoni F. Protein synthesis underlies post-retrieval memory consolidation to a restricted degree only when updated information is obtained. Learn Mem 2005;12:533–7. [41] Bermudez-Rattoni F. The forgotten insular cortex: its role on recognition memory formation. Neurobiol Learn Mem 2014;109:207–16. [42] Winters BD, Bussey TJ. Glutamate receptors in perirhinal cortex mediate encoding, retrieval, and consolidation of object recognition memory. J Neurosci 2005;25:4243–51. [43] Winters BD, Bussey TJ. Removal of cholinergic input to perirhinal cortex disrupts object recognition but not spatial working memory in the rat. Eur J Neurosci 2005;21:2263–70. [44] Rossato JI, Bevilaqua LR, Myskiw JC, Medina JH, Izquierdo I, Cammarota M. On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory. Learn Mem 2007;14:36–46. [45] Myskiw JC, Rossato JI, Bevilaqua LR, Medina JH, Izquierdo I, Cammarota M. On the participation of mTOR in recognition memory. Neurobiol Learn Mem 2008;89:338–51. [46] Jobim PF, Pedroso TR, Werenicz A, Christoff RR, Maurmann N, Reolon GK, et al. Impairment of object recognition memory by rapamycin inhibition of mTOR in the amygdala or hippocampus around the time of learning or reactivation. Behav Brain Res 2012;228:151–8. [47] Warburton EC, Barker GR, Brown MW. Investigations into the involvement of NMDA mechanisms in recognition memory. Neuropharmacology 2013;74:41–7. [48] Eichenbaum H, Yonelinas AP, Ranganath C. The medial temporal lobe and recognition memory. Annu Rev Neurosci 2007;30:123–52. [49] Squire LR, Wixted JT, Clark RE. Recognition memory and the medial temporal lobe: a new perspective. Nat Rev Neurosci 2007;8:872–83. [50] Roozendaal B, Hernandez A, Cabrera SM, Hagewoud R, Malvaez M, Stefanko DP, et al. Membrane-associated glucocorticoid activity is necessary for modulation of long-term memory via chromatin modification. J Neurosci 2010;30:5037–46. [51] Stefanko DP, Barrett RM, Ly AR, Reolon GK, Wood MA. Modulation of long-term memory for object recognition via HDAC inhibition. Proc Natl Acad Sci U S A 2009;106:9447–52. [52] Balderas I, Morin JP, Rodriguez-Ortiz CJ, Bermudez-Rattoni F. Muscarinic receptors activity in the perirhinal cortex and hippocampus has differential

[53] [54]

[55]

[56]

[57] [58] [59] [60]

[61]

[62]

[63]

[64]

[65]

[66] [67] [68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76] [77]

[78]

[79] [80] [81]

9

involvement in the formation of recognition memory. Neurobiol Learn Mem 2012;97:418–24. Tang Y, Mishkin M, Aigner TG. Effects of muscarinic blockade in perirhinal cortex during visual recognition. Proc Natl Acad Sci U S A 1997;94:12667–9. Warburton EC, Koder T, Cho K, Massey PV, Duguid G, Barker GR, et al. Cholinergic neurotransmission is essential for perirhinal cortical plasticity and recognition memory. Neuron 2003;38:987–96. Tinsley CJ, Fontaine-Palmer NS, Vincent M, Endean EP, Aggleton JP, Brown MW, et al. Differing time dependencies of object recognition memory impairments produced by nicotinic and muscarinic cholinergic antagonism in perirhinal cortex. Learn Mem 2011;18:484–92. Hunsaker MR, Rogers JL, Kesner RP. Behavioral characterization of a transection of dorsal CA3 subcortical efferents: comparison with scopolamine and physostigmine infusions into dorsal CA3. Neurobiol Learn Mem 2007;88:127–36. Degroot A, Wolff MC, Nomikos GG. Acute exposure to a novel object during consolidation enhances cognition. Neuroreport 2005;16:63–7. Stanley EM, Wilson MA, Fadel JR. Hippocampal neurotransmitter efflux during one-trial novel object recognition in rats. Neurosci Lett 2012;511:38–42. Lisman J, Grace AA, Duzel E. A neoHebbian framework for episodic memory; role of dopamine-dependent late LTP. Trends Neurosci 2011;34:536–47. Morikawa H, Paladini CA. Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms. Neuroscience 2011;198:95–111. Huang YY, Kandel ER. D1/D5 receptor agonists induce a protein synthesisdependent late potentiation in the CA1 region of the hippocampus. Proc Natl Acad Sci U S A 1995;92:2446–50. de Lima MN, Presti-Torres J, Dornelles A, Scalco FS, Roesler R, Garcia VA, et al. Modulatory influence of dopamine receptors on consolidation of object recognition memory. Neurobiol Learn Mem 2011;95:305–10. Guzman-Ramos K, Moreno-Castilla P, Castro-Cruz M, McGaugh JL, MartinezCoria H, LaFerla FM, et al. Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer’s disease. Learn Mem 2012;19:453–60. Balderas I, Moreno-Castilla P, Bermudez-Rattoni F. Dopamine D1 receptor activity modulates object recognition memory consolidation in the perirhinal cortex but not in the hippocampus. Hippocampus 2013;23:873–8. Rossato JI, Radiske A, Kohler CA, Gonzalez C, Bevilaqua LR, Medina JH, et al. Consolidation of object recognition memory requires simultaneous activation of dopamine D1/D5 receptors in the amygdala and medial prefrontal cortex but not in the hippocampus. Neurobiol Learn Mem 2013;106:66–70. Sara SJ. Retrieval and reconsolidation: toward a neurobiology of remembering. Learn Mem 2000;7:73–84. Nader K, Einarsson EO. Memory reconsolidation: an update. Ann N Y Acad Sci 2010;1191:27–41. Kelly A, Laroche S, Davis S. Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase in hippocampal circuitry is required for consolidation and reconsolidation of recognition memory. J Neurosci 2003;23:5354–60. Bozon B, Davis S, Laroche S. A requirement for the immediate early gene zif268 in reconsolidation of recognition memory after retrieval. Neuron 2003;40:695–701. Akirav I, Maroun M. Ventromedial prefrontal cortex is obligatory for consolidation and reconsolidation of object recognition memory. Cereb Cortex 2006;16:1759–65. Romero-Granados R, Fontan-Lozano A, Delgado-Garcia JM, Carrion AM. From learning to forgetting: behavioral, circuitry, and molecular properties define the different functional states of the recognition memory trace. Hippocampus 2010;20:584–95. Balderas I, Rodriguez-Ortiz CJ, Bermudez-Rattoni F. Retrieval and reconsolidation of object recognition memory are independent processes in the perirhinal cortex. Neuroscience 2013;253:398–405. Winters BD, Tucci MC, Jacklin DL, Reid JM, Newsome J. On the dynamic nature of the engram: evidence for circuit-level reorganization of object memory traces following reactivation. J Neurosci 2011;31:17719–28. Rodriguez-Ortiz CJ, Bermudez-Rattoni F. Memory reconsolidation or updating consolidation? In: Federico B-R, editor. Neural plasticity and memory: from genes to brain imaging. Boca Raton, FL: CRC Press; 2007. Winters BD, Tucci MC, DaCosta-Furtado M. Older and stronger object memories are selectively destabilized by reactivation in the presence of new information. Learn Mem 2009;16:545–53. Tronson NC, Taylor JR. Molecular mechanisms of memory reconsolidation. Nat Rev Neurosci 2007;8:262–75. Hupbach A, Gomez R, Hardt O, Nadel L. Reconsolidation of episodic memories: a subtle reminder triggers integration of new information. Learn Mem 2007;14:47–53. Morris RG, Inglis J, Ainge JA, Olverman HJ, Tulloch J, Dudai Y, et al. Memory reconsolidation: sensitivity of spatial memory to inhibition of protein synthesis in dorsal hippocampus during encoding and retrieval. Neuron 2006;50:479–89. Forcato C, Burgos VL, Argibay PF, Molina VA, Pedreira ME, Maldonado H. Reconsolidation of declarative memory in humans. Learn Mem 2007;14:295–303. Lee JL. Memory reconsolidation mediates the strengthening of memories by additional learning. Nat Neurosci 2008;11:1264–6. Lee JL, Everitt BJ. Appetitive memory reconsolidation depends upon NMDA receptor-mediated neurotransmission. Neurobiol Learn Mem 2008;90:147–54.



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10


[82] Rodriguez-Ortiz CJ, Garcia-DeLaTorre P, Benavidez E, Ballesteros MA, Bermudez-Rattoni F. Intrahippocampal anisomycin infusions disrupt previously consolidated spatial memory only when memory is updated. Neurobiol Learn Mem 2008;89:352–9. [83] Garcia-DeLaTorre P, Rodriguez-Ortiz CJ, Arreguin-Martinez JL, Cruz-Castaneda P, Bermudez-Rattoni F. Simultaneous but not independent anisomycin infusions in insular cortex and amygdala hinder stabilization of taste memory when updated. Learn Mem 2009;16:514–9. [84] Sevenster D, Beckers T, Kindt M. Prediction error governs pharmacologically induced amnesia for learned fear. Science 2013;339:830–3. [85] Kesner R. A neural system analysis of memory storage and retrieval. Psychol Bull 1973;80:177–203. [86] Pedreira ME, Perez-Cuesta LM, Maldonado H. Mismatch between what is expected and what actually occurs triggers memory reconsolidation or extinction. Learn Mem 2004;11:579–85. [87] Dudai Y. The restless engram: consolidations never end. Annu Rev Neurosci 2012;35:227–47. [88] Lewis DJ. Psychobiology of active and inactive memory. Psychol Bull 1979;86:1054–83. [89] Santoyo-Zedillo M, Rodriguez-Ortiz CJ, Chavez-Marchetta G, Bermudez-Rattoni F, Balderas I. Retrieval is not necessary to trigger reconsolidation of object recognition memory in the perirhinal cortex. Learn Mem 2014;21:452–6. [90] Nader K, Schafe GE, LeDoux JE. The labile nature of consolidation theory. Nat Rev Neurosci 2000;1:216–9. [91] Ben Mamou C, Gamache K, Nader K. NMDA receptors are critical for unleashing consolidated auditory fear memories. Nat Neurosci 2006;9:1237–9.

[92] Barreiro KA, Suarez LD, Lynch VM, Molina VA, Delorenzi A. Memory expression is independent of memory labilization/reconsolidation. Neurobiol Learn Mem 2013;106:283–91. [93] Yasoshima Y, Yamamoto T, Kobayashi K. Amygdala-dependent mechanisms underlying memory retrieval of conditioned taste aversion. Chem Senses 2005;30(Suppl. 1):i158–9. [94] Rodriguez-Ortiz CJ, Balderas I, Garcia-DeLaTorre P, Bermudez-Rattoni F. Taste aversion memory reconsolidation is independent of its retrieval. Neurobiol Learn Mem 2012;98:215–9. [95] Milton AL, Merlo E, Ratano P, Gregory BL, Dumbreck JK, Everitt BJ. Double dissociation of the requirement for GluN2B- and GluN2A-containing NMDA receptors in the destabilization and restabilization of a reconsolidating memory. J Neurosci 2013;33:1109–15. [96] Garcia-Delatorre P, Perez-Sanchez C, Guzman-Ramos K, Bermudez-Rattoni F. Role of glutamate receptors of central and basolateral amygdala nuclei on retrieval and reconsolidation of taste aversive memory. Neurobiol Learn Mem 2014;111:35–40. [97] Vianna MR, Szapiro G, McGaugh JL, Medina JH, Izquierdo I. Retrieval of memory for fear-motivated training initiates extinction requiring protein synthesis in the rat hippocampus. Proc Natl Acad Sci U S A 2001;98:12251–4. [98] Berman DE, Dudai Y. Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex. Science 2001;291:2417–9. [99] Dudai Y. The neurobiology of consolidations, or, how stable is the engram. Annu Rev Psychol 2004;55:51–86.


Molecular Mechanisms of Memory Consolidation, Reconsolidation, and Persistence.

Nicotine enhances the reconsolidation of novel object recognition memory in rats.

Retrieval is not necessary to trigger reconsolidation of object recognition memory in the perirhinal cortex.

Neuropeptide S interacts with the basolateral amygdala noradrenergic system in facilitating object recognition memory consolidation.

Neuropharmacology of memory consolidation and reconsolidation: Insights on central cholinergic mechanisms.

HDAC inhibition promotes both initial consolidation and reconsolidation of spatial memory in mice.

The role of apelin-13 in novel object recognition memory.

The role of nitric oxide in the object recognition memory.

Characterization of spatial memory reconsolidation.

Epigenetic mechanisms of memory formation and reconsolidation.

Reconsolidation of a well-learned instrumental memory.

Reconsolidation of Long-Term Memory in Aplysia.

Dreaming and offline memory consolidation.

reconsolidation.

Understanding the boundary conditions of memory reconsolidation.

Stress enhances reconsolidation of declarative memory.

β-Arrestin-biased signaling mediates memory reconsolidation.

Memory consolidation for duration.

Two waves of proteasome-dependent protein degradation in the hippocampus are required for recognition memory consolidation.

Noradrenergic regulation of fear and drug-associated memory reconsolidation.

Reconsolidation and the regulation of plasticity: moving beyond memory.

Progestogens' effects and mechanisms for object recognition memory across the lifespan.

The relationship between protein synthesis and protein degradation in object recognition memory.

Constant Light Desynchronizes Olfactory versus Object and Visuospatial Recognition Memory Performance.