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The endocannabinoid system is involved in the fine-tuning of local synaptic plasticity in the hippocampus during the initial steps of memory formation/transformation. In spite of extensive studies, endocannabinoid modulation of these processes is still poorly understood. Here we studied the effects of intra-CA1 infused AM404, an anandamide (AEA) transport/metabolism inhibitor, upon an aversive memory consolidation with or without prior systemic administration of metyrapone, as well the concomitant intra-CA1 administration of AM404 plus AM251 (CB1 receptor inverse-agonist), capsazepine (TRPV1 receptor antagonist) or tropicamide (M4 receptor antagonist). We also investigated the effect of AM404 on memory retrieval and Long-Term Potentiation induction. Adult male Wistar rats were trained in the Contextual Fear Conditioning task and tested 48 h later. AM404 disrupted both memory consolidation and retrieval, and abolished LTP induction. The post-training effect, however, was reverted by metyrapone - which was amnestic by itself - corroborating the known co-dependency between glucocorticoids and endocannabinoids, and suggesting that some level of aversiveness is necessary for an adequate consolidation. In the coadministration experiments, while AM251 and tropicamide were able to revert the AM404 amnestic effect, capsazepine had no effect. This confirms that CB1 actually mediate the amnestic effect caused by the augmented AEA pool, but TRPV1 does not. The tropicamide result suggests an interesting comodulatory interaction between the endocannabinoid and the cholinergic systems. We propose a steady-state model centered in the idea of an optimal, stable extracellular concentration of anandamide as a necessary condition to ensure the consolidation of a stable memory trace in the CA1 area., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Exposure to stressors in early postnatal life induces long-lasting modifications in brain function. This plasticity, an essential characteristic of the brain that enables adaptation to the environment, may also induce impairments in some psychophysiological functions, including learning and memory. Early life stress (ELS) has long-term effects on the hypothalamic-pituitary-adrenal axis response to stressors, and has been reported to lead to neuroinflammation, altered levels of neurotrophic factors, modifications in neurogenesis and synaptic plasticity, with changes in neurotransmitter systems and network functioning. In this review, we focus on early postnatal stress in animal models and their effects on learning and memory. Many studies have reported ELS-induced impairments in different types of memories, including spatial memory, fear memory, recognition (both for objects and social) memory, working memory and reversal learning. Studies are not always in agreement, however, no effects, or sometimes facilitation, being reported, depending on the nature and intensity of the early intervention, as well as the age when the outcome was evaluated and the sex of the animals. When considering processes occurring after consolidation, related with memory maintenance/persistence or transformation, there are a very reduced number of reports. Future studies addressing the mechanisms underlying memory changes for ELS should shed some light on the understanding of the different effects induced by stressors of different types and intensities on cognitive functions., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Generalization is an adaptive process that allows animals to deal with threatening circumstances similar to prior experiences. Systems consolidation is a time-dependent process in which memory loses it precision concomitantly with reorganizational changes in the brain structures that support memory retrieval. In this, memory becomes progressively independent from the hippocampus and more reliant on cortical structures. Generalization, however, may take place much faster in adult animals depending on the presence of sex hormones. Notwithstanding its relevance, there are few studies on sex differences in memory modulation. Here, a contextual fear discrimination task was used to investigate the onset of memory generalization and hippocampus-independence in adolescent male and female rats (P42-49). Subjects were tested 2, 7, 14, 21, or 28 days after training, with females showing memory generalization from day 21 on, whereas males surprisingly unable to discriminate contexts at any time. Ovariectomized (OVX) females, however, displayed an early onset of generalization. Consistently, pretest pharmacological blocking of dorsal hippocampus was able to impair memory retrieval in females, but not in males, which indicate that precise memory is dependent on the hippocampus. To our notice, this is the first report of a memory systems consolidation process-expressed in its two dimensions, neuroanatomical and qualitative-in adolescent female rats, and one that can also be accelerated by the reduction of sex hormones through ovariectomy. It is also unprecedented that despite adolescent male rats being able to remember fear learning, they did not discriminate contexts with any precision. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4 years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4 years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Survival depends on the ability of animals to avoid threats and approach rewards. Traditionally, these two opposing motivational systems have been studied separately. In nature, however, they regularly compete for the control of behavior. When threat- and reward-eliciting stimuli (learned or unlearned) occur simultaneously, a motivational conflict emerges that challenges individuals to weigh available options and execute a single behavioral response (avoid or approach). Most previous animal models using approach/avoidance conflicts have often focused on the ability to avoid threats by forgoing or delaying the opportunity to obtain rewards. In contrast, behavioral tasks designed to capitalize on the ability to actively choose to execute approach behaviors despite threats are scarce. Thus, we developed a behavioral test battery composed of three conflict tasks to directly study rats confronting threats to obtain rewards guided by innate and conditioned cues. One conflict task involves crossing a potentially electrified grid to obtain food on the opposite end of a straight alley, the second task is based on the step-down threat avoidance paradigm, and the third one is a modified version of the open field test. We used diazepam to pharmacologically validate conflict behaviors in our tasks. We found that, regardless of whether competing stimuli were conditioned or innate, a low diazepam dose decreased risk assessment and facilitated taking action to obtain rewards in the face of threats during conflict, without affecting choice behavior when there was no conflict involved. Using this pharmacologically validated test battery of ethologically designed innate/learned conflict tasks could help understand the fundamental brain mechanisms underlying the ability to confront threats to achieve goals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Illescas-Huerta, Ramirez-Lugo, Sierra, Quillfeldt and Sotres-Bayon.)

Ubiquitination is involved in synaptic plasticity and memory, but the involvement of HECT E3 ligases in these processes has not yet been established. Here, we bilaterally infused heclin, a specific inhibitor of some of these ligases, into the dorsal hippocampus of male Wistar rats that were trained in a contextual fear conditioning. Heclin improved short-term memory, consolidation, retrieval, and reconsolidation when administered immediately post training, prior to testing, or after memory reactivation, respectively. In addition, it impaired memory extinction when administered prior to a long reactivation session. Heclin infusion was also tested for locomotor activity and anxiety-like behavior in a circular arena, but no effect was seen. Taken together, these results indicate that HECT E3 ligases are involved in the modulation of fear memory., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Early life experiences program lifelong responses to stress. In agreement, resilience and vulnerability to psychopathologies, such as posttraumatic stress disorder (PTSD), have been suggested to depend on the early background. New therapies have targeted memory reconsolidation as a strategy to modify the emotional valence of traumatic memories. Here, we used animal models to study the molecular mechanism through which early experiences may later affect aversive memory reconsolidation. Handling (H)-separation of pups from dams for 10 min-or maternal separation (MS) - 3-h separation-were performed from PDN1-10, using non-handled (NH) litters as controls. Adult males were trained in a contextual fear conditioning (CFC) task; 24 h later, a short reactivation session was conducted in the conditioned or in a novel context, followed by administration of midazolam 3 mg/kg i.p. (mdz), known to disturb reconsolidation, or vehicle; a test session was performed 24 h after. The immunocontent of relevant proteins was studied 15 and 60 min after memory reactivation in the dorsal hippocampus (dHc) and basolateral amygdala complex (BLA). Mdz-treated controls (NH) showed decreased freezing to the conditioned context, consistent with reconsolidation impairment, but H and MS were resistant to labilization. Additionally, MS males showed increased freezing to the novel context, suggesting fear generalization; H rats showed lower freezing than the other groups, in accordance with previous suggestions of reduced emotionality facing adversities. Increased levels of Zif268, GluN2B, β-actin and polyubiquitination found in the BLA of all groups suggest that memory reconsolidation was triggered. In the dHc, only NH showed increased Zif268 levels after memory retrieval; also, a delay in ERK1/2 activation was found in H and MS animals. We showed here that reconsolidation of a contextual fear memory is insensitive to interference by a GABAergic drug in adult male rats exposed to different neonatal experiences; surprisingly, we found no differences in the reconsolidation process in the BLA, but the dHc appears to suffer temporal desynchronization in the engagement of reconsolidation. Our results support a hippocampal-dependent mechanism for reconsolidation resistance in models of early experiences, which aligns with current hypotheses for the etiology of PTSD.

The ability to adapt to new situations involves behavioral changes expressed either from an innate repertoire, or by acquiring experience through memory consolidation mechanisms, by far a much richer and flexible source of adaptation. Memory formation consists of two interrelated processes that take place at different spatial and temporal scales, Synaptic Consolidation , local plastic changes in the recruited neurons, and Systems Consolidation, a process of gradual reorganization of the explicit/declarative memory trace between hippocampus and the neocortex. In this review, we summarize some converging experimental results from our lab that support a normal temporal framework of memory systems consolidation as measured both from the anatomical and the psychological points of view, and propose a hypothetical model that explains these findings while predicting other phenomena. Then, the same experimental design was repeated interposing additional tasks between the training and the remote test to verify for any interference: we found that (a) when the animals were subject to a succession of new learnings, systems consolidation was accelerated, with the disengagement of the hippocampus taking place before the natural time point of this functional switch, but (b) when a few reactivation sessions reexposed the animal to the training context without the shock, systems consolidation was delayed, with the hippocampus prolonging its involvement in retrieval. We hypothesize that new learning recruits from a fixed number of plastic synapses in the CA1 area to store the engram index, while reconsolidation lead to a different outcome, in which additional synapses are made available. The first situation implies the need of a reset mechanism in order to free synapses needed for further learning, and explains the acceleration observed under intense learning activity, while the delay might be explained by a different process, able to generate extra free synapses: depending on the cognitive demands, it deals either with a fixed or a variable pool of available synapses. The Synaptic Occupancy/Reset Theory (SORT) emerged as an explanation for the temporal flexibility of systems consolidation, to encompass the two different dynamics of explicit memories, as well as to bridge both synaptic and systems consolidation in one single mechanism.

Prior learning can modify the plasticity mechanisms that are used to encode new information. For example, NMDA receptor (NMDAR) activation is typically required for new spatial and contextual learning in the hippocampus. However, once animals have acquired this information, they can learn new tasks even if NMDARs are blocked. This finding suggests that behavioral training alters cellular plasticity mechanisms such that NMDARs are not required for subsequent learning. The mechanisms that mediate this change are currently unknown. To address this issue, we tested the idea that changes in intrinsic excitability (induced by learning) facilitate the encoding of new memories via metabotropic glutamate receptor (mGluR) activation. Consistent with this hypothesis, hippocampal neurons exhibited increases in intrinsic excitability after learning that lasted for several days. This increase was selective and only observed in neurons that were activated by the learning event. When animals were trained on a new task during this period, excitable neurons were reactivated and memory formation required the activation of mGluRs instead of NMDARs. These data suggest that increases in intrinsic excitability may serve as a metaplastic mechanism for memory formation.

It has been proposed that long-lasting changes in dendritic spines provide a physical correlate for memory formation and maintenance. Spine size and shape are highly plastic, controlled by actin polymerization/depolymerization cycles. This actin dynamics are regulated by proteins such as calpain, a calcium-dependent cysteine protease that cleaves the structural cytoskeleton proteins and other targets involved in synaptic plasticity. Here, we tested whether the pharmacological inhibition of calpain in the dorsal hippocampus affects memory consolidation, retrieval and reconsolidation in rats trained in contextual fear conditioning. We first found that post-training infusion of the calpain inhibitor PD150606 impaired long-term memory consolidation, but not short-term memory. Next, we showed that pre-test infusion of the calpain inhibitor hindered memory retrieval. Finally, blocking calpain activity after memory reactivation disrupted reconsolidation. Taken together, our results show that calpain play an essential role in the hippocampus by enabling memory formation, expression and reconsolidation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The requirement of NMDA receptor (NMDAR) activity for memory formation is well described. However, the plasticity mechanisms for memory can be modified by experience, such that a future similar learning becomes independent of NMDARs. This effect has often been reported in learning events conducted with a few days interval. In this work, we asked whether the NMDAR-independency is permanent or the brain regions and plasticity mechanisms of experience-dependent learning may change over time. Considering that contextual memories undergo a gradual reorganization over time, becoming progressively independent from the hippocampus and dependent upon cortical regions, we investigated the brain regions mediating a new related learning conducted at a remote time-point, when the first memory was already cortically established. First, we demonstrated that anterior cingulate cortex was not able to support a learning subsequent to a previous systems-level consolidated memory; it did require at least one functional subregion of the hippocampus (ventral or dorsal). Moreover, after replicating findings showing that a few days interval between trainings induces a NMDAR-independent learning, we managed to show that a learning following a longer interval once again becomes dependent on NMDARs in the hippocampus. These findings suggest that while the previous memory grows independent from the hippocampus over time, an experience-dependent learning following a systems-consolidated memory once again engages the hippocampus and a NMDAR-dependent plasticity mechanism., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Memories are not instantly created in the brain, requiring a gradual stabilization process called consolidation to be stored and persist in a long-lasting manner. However, little is known whether this time-dependent process is dynamic or static, and the factors that might modulate it. Here, we hypothesized that the time-course of consolidation could be affected by specific learning parameters, changing the time window where memory is susceptible to retroactive interference. In the rodent contextual fear conditioning paradigm, we compared weak and strong training protocols and found that in the latter memory is susceptible to post-training hippocampal inactivation for a shorter period of time. The accelerated consolidation process triggered by the strong training was mediated by glucocorticoids, since this effect was blocked by pre-training administration of metyrapone. In addition, we found that pre-exposure to the training context also accelerates fear memory consolidation. Hence, our results demonstrate that the time window in which memory is susceptible to post-training interferences varies depending on fear conditioning intensity and contextual familiarity. We propose that the time-course of memory consolidation is dynamic, being directly affected by attributes of the learning experiences., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Heat shock proteins of the 70-kDa (HSP70) family are cytoprotective molecular chaperones that are present in neuronal cells and can be induced by a variety of homeostatically stressful situations (not only proteostatic insults), but also by synaptic activity, including learning tasks. Physiological stimuli that induce long-term memory formation are also capable of stimulating the synthesis of HSP70 through the activation of heat shock transcription factor-1 (HSF1). In this study, we investigated the influence of HSP70 on fear memory consolidation and MAPK activity. Male rats were trained in contextual fear conditioning task and HSP70 content was analyzed by western blot in the hippocampus at different time points. We observed rapid and transient elevations in HSP70 60 min following training. Double immunofluorescence with GFAP and HSP72 revealed that astrocytes were not the site for HSP72 induction by CFC training. HSP72 distribution markedly surrounded synapses between Shaffer collateral and CA1 pyramidal cells. Infusion of recombinant HSP70 (hspa1a) into the dorsal hippocampus immediately after training facilitated memory consolidation and enhanced ERK activity while decreasing the activated forms of JNK and p38 in the hippocampus. Blocking endogenous extracellular HSP70 through the administration of specific antibody did not produce any further effect on memory consolidation when applied immediately after training, suggesting that it is indeed acting intracellularly. Induction of HSP70 after fear conditioning is fast and can act as a signaling molecule, modulating MAPK downstream signaling during memory consolidation in the hippocampus, which is crucial for fear memory formation., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Long-lasting changes in dendritic spines provide a physical correlate for memory formation and persistence. LIM kinase (LIMK) plays a critical role in orchestrating dendritic actin dynamics during memory processing, since it is the convergent downstream target of both the Rac1/PAK and RhoA/ROCK pathways that in turn induce cofilin phosphorylation and prevent depolymerization of actin filaments. Here, using a potent LIMK inhibitor (BMS-5), we investigated the role of LIMK activity in the dorsal hippocampus during contextual fear memory in rats. We first found that post-training administration of BMS-5 impaired memory consolidation in a dose-dependent manner. Inhibiting LIMK before training also disrupted memory acquisition. We then demonstrated that hippocampal LIMK activity seems to be critical for memory retrieval and reconsolidation, since both processes were impaired by BMS-5 treatment. Contextual fear memory extinction, however, was not sensitive to the same treatment. In conclusion, our findings demonstrate that hippocampal LIMK activity plays an important role in memory acquisition, consolidation, retrieval, and reconsolidation during contextual fear conditioning.

Extinction is a process that involves new learning that inhibits the expression of previously acquired memories. Although temporarily effective, extinction does not erase an original fear association. Since the extinction trace tends to fade over time, the original memory can resurge. On the other hand, strengthening effects have been described in several reconsolidation studies using different behavioral and pharmacological manipulations. In order to know whether an extinction memory can be strengthened by reactivation-based interventions in the contextual fear conditioning task, we began by replicating the classic phenomenon of spontaneous recovery to show that brief reexposure sessions can prevent the decay of the extinction trace over time in a long-lasting way. This fear attenuation was shown to depend both on L-type calcium channels and protein synthesis, which suggests a reconsolidation process behind the reactivation-induced strengthening effect. The extinction trace was also susceptible to enhancement by a post-reactivation infusion of a memory-enhancing drug (NaB), which was also able to prevent rapid fear reacquisition (savings). These findings point to new reactivation-based approaches able to strengthen an extinction memory to promote its persistence. The constructive interactions between extinction and reconsolidation may represent a promising novel approach in the realm of fear-related disorder treatments.

Systems consolidation has been described as a time-dependent reorganization process involving the neocortical and hippocampal networks underlying memory storage and retrieval. Previous studies of our lab were able to demonstrate that systems consolidation is a dynamic process, rather than a merely passive, time-dependent phenomenon. Here, we studied the influence of sequential learning in contextual fear conditioning (CFC) with different training intensities in the time-course of hippocampal dependency and contextual specificity. We found that sequential learning with high-intensity shocks during CFC induces generalization of the first learning (context A) and maintains contextual specificity of the second learning (context B) 15 days after acquisition. Moreover, subsequent experiences reorganize brain structures involved in retrieval, accelerating the involvement of cortical structures and diminishing the hippocampal participation. Exposure to original context before novelty seems to only induce context specificity in hippocampal-dependent memories. We propose that systems consolidation could be considered a potential biological mechanism for reducing possible interferences between similar memory traces. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Systems consolidation is a time-dependent reorganization process involving neocortical and hippocampal networks underlying memory storage and retrieval. The involvement of the hippocampus during acquisition is well described; however we know much less about the concomitant contribution of cortical activity levels to the formation of stable remote memories. Here, after a reversible pharmacological inhibition of the anterior cingulate cortex (ACC) during the acquisition of a contextual fear conditioning, retrieval of both recent and remote memories were impaired, an effect that was reverted by a single memory reactivation session 48 h after training, through a destabilization-dependent mechanism interpreted as reconsolidation, that restored the normal course of systems consolidation in order to rescue a remote memory. Next we have shown that the integrity of both the anterior cingulate cortex and the thalamic nucleus reuniens (RE) were required for this reactivation-induced memory rescue. Because lidocaine infused into the RE inhibited LTP induction in the CA1-anterior cingulate cortex pathways, it seems that RE is a necessary component of the circuit underlying systems consolidation, mediating communication between dorsal hippocampus and cortical areas. To our notice, this is the first demonstration of the rescue of remote memories disrupted by ACC inhibition during acquisition, via a reconsolidation-driven mechanism. We have also shown the importance of RE to ensure the interconnection among brain areas that collectively seem to control the natural course of systems consolidation and allow the persistence of relevant emotional engrams. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

After initial encoding memories may undergo a time-dependent reorganization, becoming progressively independent from the hippocampus (HPC) and dependent on cortical regions such as the anterior cingulate cortex (ACC). Although the mechanisms underlying systems consolidation are somewhat known, the factors determining its temporal dynamics are still poorly understood. Here, we studied the influence of novel learning occurring between training and test sessions on the time-course of HPC- and ACC-dependency of contextual fear conditioning (CFC) memory expression. We found that muscimol was disruptive when infused into the HPC up to 35 days after training, while the ACC is vulnerable only after 45 days. However, when animals were subjected to a series of additional, distinct tasks to be learned within the first 3 weeks, muscimol became effective sooner. Muscimol had no effect in the HPC at 20 days after training, exactly when the ACC becomes responsive to this treatment. Thus, our data indicates that the encoding of new information generates a tight interplay between distinct memories, accelerating the reorganization of previously stored long term memories between the hippocampal and cortical areas. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

In the past decades, the cellular and molecular mechanisms underlying memory consolidation, reconsolidation, and extinction have been well characterized. However, the neurobiological underpinnings of forgetting processes remain to be elucidated. Here we used behavioral, pharmacological and electrophysiological approaches to explore mechanisms controlling forgetting. We found that post-acquisition chronic inhibition of the N-methyl-D-aspartate receptor (NMDAR), L-type voltage-dependent Ca(2+) channel (LVDCC), and protein phosphatase calcineurin (CaN), maintains long-term object location memory that otherwise would have been forgotten. We further show that NMDAR activation is necessary to induce forgetting of object recognition memory. Studying the role of NMDAR activation in the decay of the early phase of long-term potentiation (E-LTP) in the hippocampus, we found that ifenprodil infused 30 min after LTP induction in vivo blocks the decay of CA1-evoked postsynaptic plasticity, suggesting that GluN2B-containing NMDARs activation are critical to promote LTP decay. Taken together, these findings indicate that a well-regulated forgetting process, initiated by Ca(2+) influx through LVDCCs and GluN2B-NMDARs followed by CaN activation, controls the maintenance of hippocampal LTP and long-term memories over time.

Memory fades over time, becoming more schematic or abstract. The loss of contextual detail in memory may reflect a time-dependent change in the brain structures supporting memory. It has been well established that contextual fear memory relies on the hippocampus for expression shortly after learning, but it becomes hippocampus-independent at a later time point, a process called systems consolidation. This time-dependent process correlates with the loss of memory precision. Here, we investigated whether training intensity predicts the gradual decay of hippocampal dependency to retrieve memory, and the quality of the contextual memory representation over time. We have found that training intensity modulates the progressive decay of hippocampal dependency and memory precision. Strong training intensity accelerates systems consolidation and memory generalization in a remarkable timeframe match. The mechanisms underpinning such process are triggered by glucocorticoid and noradrenaline released during training. These results suggest that the stress levels during emotional learning act as a switch, determining the fate of memory quality. Moderate stress will create a detailed memory, whereas a highly stressful training will develop a generic gist-like memory., (© 2015 Wiley Periodicals, Inc.)

The dynamic processes related to mnemonic plasticity have been extensively researched in the last decades. More recently, studies have attracted attention because they show an unusual plasticity mechanism that is independent of the receptor most usually related to first-time learning--that is, memory acquisition-the NMDA receptor. An interesting feature of this type of learning is that a previous experience may cause modifications in the plasticity mechanism of a subsequent learning, suggesting that prior experience in a very similar task triggers a memory acquisition process that does not depend on NMDARs. The intracellular molecular cascades necessary to assist the learning process seem to depend on the activation of hippocampal CP-AMPARs. Moreover, most of these studies were performed on hippocampus-dependent tasks, even though other brain areas, such as the basolateral amygdala, also display NMDAR-independent learning., ((c) 2016 APA, all rights reserved).)

The endocannabinoid system (ECS) has a pivotal role in different cognitive functions such as learning and memory. Recent evidence confirm the involvement of the hippocampal CB1 receptors in the modulation of both memory extinction and reconsolidation processes in different brain areas, but few studies focused on the infralimbic cortex, another important cognitive area. Here, we infused the cannabinoid agonist CP55,940 either into the infralimbic cortex (IL) or the CA1 area of the dorsal hippocampus (HPC) of adult male Wistar rats immediately after a short (3min) reactivation session, known to labilize a previously consolidated memory trace in order to allow its reconsolidation with some modification. In both structures, the treatment was able to disrupt reconsolidation in a relatively long lasting way, reducing the freezing response. To our notice, this is the first demonstration of ECS involvement in reconsolidation in the Infralimbic Cortex. Despite poorly discriminative between CB1 and CB2 receptors, CP55,940 is a potent agent, and these results suggest that a similar CB1-dependent circuitry is at work both in HPC and in the IL during memory reconsolidation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Despite the fact that the cannabinoid receptor type 1 (CB1R) plays a pivotal role in emotional memory processing in different regions of the brain, its function in the retrosplenial cortex (RSC) remains unknown. Here, using contextual fear conditioning in rats, we showed that a post-training intra-RSC infusion of the CB1R antagonist AM251 impaired, and the agonist CP55940 improved, long-term memory consolidation. Additionally, a post-reactivation infusion of AM251 enhanced memory reconsolidation, while CP55940 had the opposite effect. Finally, AM251 blocked extinction, whereas CP55940 facilitated it and maintained memory extinguished over time. Altogether, our data strongly suggest that the cannabinoid system of the RSC modulates emotional memory., (© 2015 Sachser et al.; Published by Cold Spring Harbor Laboratory Press.)

Memories can be destabilized by the reexposure to the training context, and may reconsolidate into a modified engram. Reconsolidation relies on some particular molecular mechanisms involving LVGCCs and GluN2B-containing NMDARs. In this study we investigate the interference caused by the presence of a distractor - a brief, unanticipated stimulus that impair a fear memory expression - during the reactivation session, and tested the hypothesis that this disruptive effect relies on a reconsolidation process. Rats previously trained in the contextual fear conditioning (CFC) were reactivated in the presence or absence of a distractor stimulus. In the test, groups reactivated in the original context with distractor displayed a reduction of the freezing response lasting up to 20 days. To check for the involvement of destabilization / reconsolidation mechanisms, we studied the effect of systemic nimodipine (a L-VGCC blocker) or intra-CA1 ifenprodil (a selective GluN2B/NMDAR antagonist) infused right before the reactivation session. Both treatments were able to prevent the disruptive effect of distraction. Ifenprodil results also bolstered the case for hippocampus as the putative brain structure hosting this phenomenon. Our results provide some evidence in support of a behavioral, non-invasive procedure that was able to disrupt an aversive memory in a long-lasting way.

The capacity to adapt to new situations is one of the most important features of memory. When retrieved, memories may undergo a labile state that is sensitive to modification. This process, called reconsolidation, can lead to memory updating through the integration of new information into a previously consolidated memory background. Thus reconsolidation provides the opportunity to modify an undesired fear memory by updating its emotional valence to a less aversive level. Here we evaluated whether a fear memory can be reinterpreted by the concomitant presentation of an appetitive stimulus during its reactivation, hindering fear expression. We found that memory reactivation in the presence of appetitive stimuli resulted in the suppression of a fear response. In addition, fear expression was not amenable to reinstatement, spontaneous recovery, or rapid reacquisition. Such effect was prevented by either systemic injection of nimodipine or intra-hippocampal infusion of ifenprodil, indicating that memory updating was mediated by a reconsolidation mechanism relying on hippocampal neuronal plasticity. Taken together, this study shows that reconsolidation allows for a 're-signification' of unwanted fear memories through the incorporation of appetitive information. It brings a new promising cognitive approach to treat fear-related disorders.

The muscarinic cholinergic receptor (MAChR) blockade with scopolamine either extended or restricted to the hippocampus, before or after training in inhibitory avoidance (IA) caused anterograde or retrograde amnesia, respectively, in the rat, because there was no long-term memory (LTM) expression. Adult Wistar rats previously exposed to one or two open-field (OF) sessions of 3 min each (habituated), behaved as control animals after a weak though over-threshold training in IA. However, after OF exposure, IA LTM was formed and expressed in spite of an extensive or restricted to the hippocampus MAChR blockade. It was reported that during and after OF exposure and reexposure there was an increase in both hippocampal and cortical ACh release that would contribute to "prime the substrate," e.g., by lowering the synaptic threshold for plasticity, leading to LTM consolidation. In the frame of the "synaptic tagging and capture" hypothesis, plasticity-related proteins synthesized during/after the previous OF could facilitate synaptic plasticity for IA in the same structure. However, IA anterograde amnesia by hippocampal protein synthesis inhibition with anisomycin was also prevented by two OF exposures, strongly suggesting that there would be alternative interpretations for the role of protein synthesis in memory formation and that another structure could also be involved in this "OF effect.", (© 2014 Colettis et al.; Published by Cold Spring Harbor Laboratory Press.)

Motivated by the synaptic tagging and capture (STC) hypothesis, it was recently shown that a weak learning, only able to produce short-term memory (STM), can succeed in establishing long-term memory (LTM) with a concomitant, stronger experience. This is consistent with the capture, by the first-tagged event, of the so-called plasticity-related proteins (PRPs) provided by the second one. Here, we describe how a concomitant session of reactivation/reconsolidation of a stronger, contextual fear conditioning (CFC) memory, allowed LTM to result from a weak spatial object recognition (wSOR) training. Consistent with an STC process, the effect was observed only during a critical time window and was dependent on the CFC reconsolidation-related protein synthesis. Retrieval by itself (without reconsolidation) did not have the same promoting effect. We also found that the inactivation of the NMDA receptor by AP5 prevented wSOR training to receive this support of CFC reconsolidation (supposedly through the production of PRPs), which may be the equivalent of blocking the setting of a learning tag in the dorsal CA1 region for that task. Furthermore, either a Water Maze reconsolidation, or a CFC extinction session, allowed the formation of wSOR-LTM. These results suggest for the first time that a reconsolidation session can promote the consolidation of a concomitant weak learning through a probable STC mechanism. These findings allow new insights concerning the influence of reconsolidation in the acquisition of memories of otherwise unrelated events during daily life situations., (Copyright © 2013 Wiley Periodicals, Inc.)

Although much has been learned regarding the molecular and cellular mechanisms of memory reconsolidation, its actual biological function remains unclear. In this work we investigate the possibility that three different mnemonic processes - updating, precision-keeping and trace strengthening - are mediated by reconsolidation in contextual fear conditioning. Reconsolidation involves the activation of calcium channels for the destabilization during the reactivation. Our results show that when memory is reactivated in a situation that does not match the original information, content is modified, i.e., "updated". However, when the contextual condition matches the original one, memory reactivation contributes either to its strengthening or to the maintenance of its precision content over time. Since the L-type voltage-gated calcium channel antagonist nimodipine blocked these effects, we suggest that reconsolidation is the mechanism supporting these processes., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Some memories enter into a labile state after retrieval, requiring reconsolidation in order to persist. One functional role of memory reconsolidation is the updating of existing memories. There are reports suggesting that reconsolidation can be modulated by a particular endogenous process taking place concomitantly to its natural course, such as water or sleep deprivation. Here, we investigated whether an endogenous process activated during a natural/physiological experience, or a pharmacological intervention, can also contribute to memory content updating. Using the contextual fear conditioning paradigm in rats, we found that the endogenous content of an aversive memory can be updated during its reconsolidation incorporating consequences of natural events such as water deprivation, transforming a previously stored memory into a state-dependent one. This updating seems to be mediated by the activation of angiotensin AT1 receptors in the dorsal hippocampus and local infusion of human angiotensin II (ANGII) was shown to mimic the water deprivation effects on memory reconsolidation. Systemic morphine injection was also able to turn a previously acquired experience into a state-dependent memory, reproducing the very same effects obtained by water deprivation or local angiotensin II infusion, and suggesting that other state-dependent-inducing protocols would also be able to contribute to memory updating. These findings trigger new insights about the influence of ordinary daily life events upon memory in its continuing reconstruction, adding the realm of reconsolidation to the classical view of endogenous modulation of consolidation.

Despite the fact that TRPV1 receptors are widely expressed in brain structures such as the hippocampus, its functions remain largely unknown. In the present study, we have investigated the possible modulatory role of the hippocampal endovanilloid system upon memory consolidation of two different behavioral tasks in rats. Post-training infusion of the TRPV1 antagonist capsazepine disrupted memory consolidation with a strong training protocol, but not with a weak one in the contextual fear conditioning or in the step-down inhibitory avoidance task. These results provide evidence that the modulation of the hippocampal memory consolidation through TRPV1 receptors takes place only in presence of a strong emotional experience, suggesting that a certain aversiveness level is required in order to recruit endovanilloids to exert this function. A possible synergic role of hippocampal endovanilloid and endocannabinoid system on memory consolidation is discussed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Hippocampus is hypothesized to play a temporary role in the retrieval of context memories. Similarly, previous studies have reported that the expression of context memories becomes more generalized as memory ages. We report, first, that contextual fear memory expression changes from being sensitive to dorsal hippocampus inactivation by muscimol at 2 days post-conditioning, to insensitive at 28 days, and second, that over the same period rats lose their ability to discriminate between a novel and conditioned context. Furthermore, we show that repeated brief memory reactivation sessions prevent memory from becoming both hippocampus-independent and generalized., (Copyright © 2011 Wiley Periodicals, Inc.)

Adverse early life events, such as periodic maternal separation, may alter the normal pattern of brain development and subsequently the vulnerability to a variety of mental disorders in adulthood. Patients with a history of early adversities show higher frequency of post-traumatic stress disorder (PTSD). This study was undertaken to verify if repeated long-term separation of pups from dams would affect memory and oxidative stress parameters after exposure to an animal model of PTSD. Nests of Wistar rats were divided into intact and subjected to maternal separation (incubator at 32°C, 3 h/day) during post-natal days 1-10. When adults, the animals were subdivided into exposed or not to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. One month after exposure to the shock, the animals were exposed to a memory task (Morris water maze) and another month later animals were sacrificed and DNA breaks and antioxidant enzymes activities were measured in the hippocampus. Rats exposed to shock or maternal separation plus shock showed long-lasting effects on spatial memory, spending more time in the opposite quadrant of the water maze. This effect was higher in animals subjected to both maternal separation and shock. Both shock and maternal separation induced a higher score of DNA breaks in the hippocampus. No differences were observed on antioxidant enzymes activities. In conclusion, periodic maternal separation may increase the susceptibility to the effects of a stressor applied in adulthood on performance in the water maze. Increased DNA breaks in hippocampus was induced by both, maternal separation and exposure to shock.

The modulation of memory processes is one of the several functions of the endocannabinoid system (ECS) in the brain, with CB1 receptors highly expressed in areas such as the dorsal hippocampus. Experimental evidence suggested an important role of the ECS in aversively motivated memories. Similarly, glucocorticoids released in response to stress exposure also modulates memory formation, and both stress and dexamethasone activate the ECS. Here, we investigate the interaction between the ECS and glucocorticoids in the hippocampus in the modulation of fear memory consolidation. Two protocols with different shock intensities were used in order to control the level of aversiveness. Local infusion of AM251 into the hippocampus immediately after training was amnestic in the strong, but not in the weak protocol. Moreover, AM251 was amnestic in animals stressed 0, but not 30-min prior to the weak protocol, reverting the stress-induced facilitatory effect. Finally, intrahippocampal AM251 infusion reduced memory in animals that received dexamethasone immediately, but not 30 min before training. These results are (1) consistent with the view that the dorsal hippocampus ECS is activated on demand, in a rapid and short-lived fashion in order to modulate the consolidation of an aversive memory, and (2) show that this recruitment seems to be mediated by glucocorticoids, either in the hippocampus or in other brain regions functionally associated with the hippocampus.

In our previous studies, we reported that neonatally handled rats have an increased ingestion of sweet food but are resistant to the damaging effects of a chronic exposure to a highly palatable diet. Accumbal serotonin (5-HT) is important for feeding behavior and plays a role in the vulnerability to diet-induced obesity. Therefore, our hypotheses were (1) 5-HT turnover in the nucleus accumbens is altered in neonatally handled animals and plays a role in their differential feeding behavior and (2) if this is so, a chronic pharmacological treatment affecting 5-HT reuptake (chronic imipramine) would be able to revert the behavioral findings. Litters were divided into nonhandled and handled (10 min/day, Days 1-10 after birth). In Experiment 1, we demonstrated that a decreased 5-HT metabolism in the nucleus accumbens was observed in adult handled animals. In Experiment 2, the two previous groups were subdivided and assigned to receive imipramine diluted in water or water alone. After 30 days of treatment, we evaluated their weight gain and feeding behavior. Handled rats weighed less than nonhandled rats, and all imipramine-treated rats showed a reduction in weight gain after 60 days of treatment. Imipramine reverted the increased sweet food consumption seen in neonatally handled rats. We conclude that serotonin is involved in the altered feeding behavior of neonatally handled rats, and this protocol is an important tool for studying the mechanisms by which early life events have a long-term impact on feeding preferences.

Neonatal handling in rats persistently alters behavioral parameters and responses to stress. Such animals eat more sweet food in adult life, without alterations in lab chow ingestion. Here, we show that neonatally handled rats display greater incentive salience to a sweet reward in a runway test; however they are less prone to conditioned place preference and show less positive hedonic reactions to sweet food. When injected with methylphenidate (a dopamine mimetic agent), non-handled rats increase their sweet food ingestion in the fasted state, while neonatally handled rats do not respond. We did not observe any differences regarding baseline general ambulatory activity between the groups. A lower dopamine metabolism in the nucleus accumbens was observed in handled animals, without differences in norepinephrine content. We suggest that early handling leads to a particular response to positive reinforcers such as palatable food, in a very peculiar fashion of higher ingestion but lower hedonic impact, as well as higher incentive salience, but diminished dopaminergic metabolism in the nucleus accumbens., (Copyright 2009 ISDN. Published by Elsevier Ltd. All rights reserved.)

The five muscarinic acetylcholine receptors (M(1)-M(5)) are differentially expressed in the brain. M(2) and M(4) are coupled to inhibition of stimulated adenylyl cyclase, while M(1), M(3) and M(5) are mainly coupled to the phosphoinositide pathway. We studied the muscarinic receptor regulation of adenylyl cyclase activity in the rat hippocampus, compared to the striatum and amygdala. Basal and forskolin-stimulated adenylyl cyclase activity was higher in the striatum but the muscarinic inhibition was much lower. Highly selective muscarinic toxins MT1 and MT2-affinity order M(1) > or = M(4) >> others-and MT3-highly selective M(4) antagonist-did not show significant effects on basal or forskolin-stimulated cyclic AMP production but, like scopolamine, counteracted oxotremorine inhibition. Since MTs have negligible affinity for M(2), M(4) would be the main subtype responsible for muscarinic inhibition of forskolin-stimulated enzyme. Dopamine stimulated a small fraction of the enzyme (3.1% in striatum, 1.3% in the hippocampus). Since MT3 fully blocked muscarinic inhibition of dopamine-stimulated enzyme, M(4) receptor would be responsible for this regulation.

Lesion of the nucleus basalis magnocellularis (nbm) is a suitable approach to study cognitive deficit and behavior alterations involving cholinergic dysfunction, which is associated with the major types of dementia. Cortical astrogliosis also has been described in this model, but it is not clear whether hippocampal astrocytes are activated. In this study, we investigated possible specific astrocyte alterations in the hippocampi of Wistar rats submitted to nbm damage with ibotenic acid, investigating the content and immunohistochemistry of glial fibrillary acidic protein (GFAP), as well as S100B protein content, glutamate uptake and glutamine synthetase activity on the 7th and 28th post-lesion days. Cognitive deficit was confirmed by the step-down inhibitory avoidance task. Interestingly, we found a decrease in GFAP content, S100B content and glutamate uptake activity in the hippocampus on the 28th day after nbm lesion. No alterations were observed in glutamine synthetase activity or in the cerebrospinal fluid S100B content. Although our data suggest caution in the use of nbm lesion with ibotenic acid as a dementia model, it is possible that these alterations could contribute to the cognitive deficit observed in these rats.

Retrieval of a consolidated memory triggers a number of processes which depend, among other factors, on the duration of the reactivation session: reconsolidation requires a brief reactivation session, and extinction, a prolonged one. The scope of this study is to explore the potential role of the hippocampal endocannabinoid system on reconsolidation and extinction processes. Bilateral infusion of the CB1 cannabinoid receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) into the CA1 region of the dorsal hippocampus of Wistar rats after memory reactivation facilitated the reconsolidation of the contextual fear conditioning memory. The inhibition of protein synthesis with DRB in the same brain region blocked memory reconsolidation. Both effects were persistent, lasting up to 7 days after the first retrieval experience. In contrast, the local infusion of anandamide blocked memory reconsolidation, an effect that was antagonized by the combined administration of anandamide with a subthreshold dose of a CB1 antagonist, supporting a CB1-mediated role of the hippocampal endocannabinoid system in the modulation of the memory reconsolidation. Local infusion of AM251 into CA1 blocked memory extinction whereas the administration of anandamide facilitated it; however, when combined with a subthreshold concentration of the CB1 antagonist, anandamide did not affect the extinction process. The clear-cut, opposite effects observed in each situation suggest a possible role of the hippocampal endocannabinoid system as a switching mechanism deciding which processes will take place, either maintaining the original memory (reconsolidation) or promoting a new learning (extinction).

CB1 cannabinoid receptors are abundantly expressed in the brain, with large concentrations present in the hippocampus, a brain structure essential for memory processing. In the present study, we have investigated the possible modulatory role of the endocannabinoid system in the dorsal hippocampus upon the different phases of memory processing of an aversive task. AM251, a selective antagonist of CB1 receptors, and anandamide, an endogenous agonist of cannabinoid receptors, were bilaterally infused into the dorsal hippocampus of male Wistar rats either before training, immediately after training, or before test in the step-down inhibitory avoidance (IA) task. Results showed that pre-training infusion of CB1 drugs did not influence the acquisition of the task. In contrast, post-training infusion of the CB1 antagonist disrupted while the antagonist facilitated memory consolidation of IA. The post-training results demonstrate that memory consolidation depends on the integrity of the endocannabinoid system in the CA1 region of the dorsal hippocampus. While we still have no direct proof of endocannabinoids released there after an aversive task such as IA, these results suggests that (a) AM251 acts blocking the binding of endogenously released cannabinoids and (b) exogenously supplemented anandamide may be adding its contribution to the action of the endogenously released pool. Considering our data and the higher density of CB1 receptors present in the GABAergic interneurons, we propose them as the putative target of the endocannabinoid modulation of memory, a hypothesis that needs to be proven. In addition, pre-test infusion of the CB1 receptor antagonist facilitated while infusion of the agonist did not affect memory retrieval of IA. The completely opposite action of the same drug upon memory at the post-training (consolidation) and pre-test (recall) contexts suggests that some durable change took place in the CA1 region during the consolidation process that modified the logical attributes of the pharmacological response, i.e., the drug response changed from memory disruption to memory facilitation. A similar phenomenon was previously described by us in the M4 cholinergic muscarinic subsystem in the hippocampus for the same task (Diehl, F., Fürstenau, L. O., Sanchez, G., Camboim, C., de Oliveira Alvares, L., Lanziotti, V. B., et al. (2007). Facilitatory effect of the intra-hippocampal pretest administration of MT3 in the inhibitory avoidance task. Behavioral Brain Research, 177(2), 227-231), but the biological nature of such change in the local neural circuitry remains to be investigated.

Purpose: This study investigated putative correlations among behavioral changes and: (1) neuronal loss, (2) hippocampal mossy fiber sprouting, and (3) reactive astrogliosis in adult rats submitted to early-life LiCl-pilocarpine-induced status epilepticus (SE)., Methods: Rats (P15) received LiCl (3 mEq/kg, i.p.) 12-18 h prior pilocarpine (60 mg/kg; s.c.). At adulthood, animals were submitted to behavioral tasks and after the completion of tasks biochemical and histological analysis were performed., Results: In SE group, it was observed an increased number of degenerating neurons in the CA1 subfield and in the hilus of animals 24 h after SE. At adulthood, SE group presented an aversive memory deficit in an inhibitory avoidance task and the animals that presented lower latency to the step down showed a higher score for mossy fiber sprouting. In the light-dark exploration task, SE rats returned less and spent less time in the light compartment and present an increased number of risk assessment behavior (RA). There was a negative correlation between the time spent in the light compartment and the score for mossy fiber sprouting and a positive correlation between score for mossy fiber sprouting and number of RA. LiCl-pilocarpine-treated animals showed higher levels of S100B immunocontent in the CSF as well as a positive correlation between the score for sprouting and the GFAP immunocontent in the CA1 subfield, suggesting an astrocytic response to neuronal injury., Conclusions: We showed that LiCl-pilocarpine-induced SE during development produced long-lasting behavioral abnormalities, which might be associated with mossy fiber sprouting and elevated CSF S100B levels at adulthood.

This study was undertaken to verify if repeated long-term separation from dams would affect the development of parameters related to post-traumatic stress disorder (PTSD) after animals are subjected to inescapable shock when adults. Wistar rats were subjected to repeated maternal separation during post-natal days 1-10. When adults, rats from both sexes were submitted to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. We observed long-lasting effects of both interventions. Exposure to shock increased fear conditioning. Anxiety-like behavior was increased and exploratory activity decreased by both treatments, and these effects were more robust in males. Additionally, basal corticosterone in plasma was decreased, paralleling effects observed in PTSD patients. Levels of S100B protein in serum and cerebrospinal fluid (CSF) were measured. Levels in serum correlated with the effects observed in anxiety-like behavior, increasing in males exposed to shock, and presenting no effect in females. S100B in CSF was increased in females submitted to maternal separation during the neonatal period. These results suggest that, in rats, an early stress experience such as maternal separation may aggravate some effects of exposure to a stressor during adult age, and that this effect is sex-specific. Additionally, data suggest that the increased S100B levels, observed in serum, have an extracerebral origin, possibly mediated by an increase in the noradrenergic tonus. Increased S100B in brain could be related to its neurotrophic actions.

The cholinergic system plays a crucial role in learning and memory. Modulatory mechanisms of this system in the acquisition and consolidation processes have been extensively studied, but their participation in the memory retrieval process is still poorly understood. Conventional pharmacological agents are not highly selective for particular muscarinic acetylcholine receptor subtypes. Muscarinic toxins (MTs) that are highly selective for muscarinic receptors were extracted from the venom of the mamba snake, like the toxin MT3, selective for the M4 receptor subtype. These toxins are useful tools in studies of the specific functions of the M4 mediated transmission. The M4 receptor selective antagonist MT3, given into the dorsal hippocampus before the test, have enhanced the memory retrieval of an inhibitory avoidance task in rats. MT3 had no effect in the habituation to a new environment, including basic motor parameters, meaning that the effect in he inhibitory avoidance is purely cognitive. Our results suggest an endogenous negative modulation of the cholinergic muscarinic system upon the retrieval of previously consolidated aversive memories, hereby shown by the facilitatory effect of MT3.

During the last decade, a considerable amount of evidence has accumulated to show that oxytocin (OT) is involved with functions other than its classical roles in reproduction-associated processes, such as social recognition, maternal behavior and neuroendocrine regulation of the stress response. It has been shown, for instance, that post-training systemic administration of oxytocin in mice produces an amnestic effect on the step-through inhibitory avoidance. Since it is still unclear how systemic levels of OT may affect CNS memory processes, our aim here was to investigate the hypothesis that systemic OT effects on memory retrieval might be mediated through an oxytocin-induced decrease in glucocorticoid release. In our first experiment, we have found an amnestic effect of i.p. pre-test 0.4 microg/kg of OT upon memory retrieval in the inhibitory avoidance task (IA); this OT dose was shown to (a) significantly decrease plasma corticosterone levels when compared to the saline group, and (b) not to cause any anxiety effects by itself in a plus-maze task. At last, an ineffective-by-itself dose of dexamethasone was able to reverse the amnestic effect of this OT dose. Our results suggest that the amnestic effect of systemically administered oxytocin upon memory retrieval in the inhibitory avoidance task was probably caused by an oxytocin-induced decrease in glucocorticoid release from the adrenal gland.

Long-term potentiation (LTP) has a long history as putative mechanism of memory formation, specially in the hippocampus, a structure essential for memory formation. Endocannabinoids are one of the endogenous systems that modulate this plasticity event: the activation of hippocampal CB1 receptors may inhibit local GABA release. Here, we have studied both (1) the role of the selective CB1 antagonist AM251 upon LTP induction in a hippocampal slice preparation, and (2) the effect of its intrahippocampal administration in the step-down inhibitory avoidance (IA) and the open field habituation tasks (OF). Standard extracellular electrophysiology techniques were used to record field excitatory postsynaptic potentials from the dendritic region of CA1 neurons in response to a high frequency stimulation of Schaffer's collaterals; a micropipette ejected 0.2 microM of AM251 (in DMSO/PBS) 2 min before the stimulus: LTP was induced and lasted more than 30 min in the control, but not in the AM251-treated group. Immediately after training, either in IA (footshock, 0.5 mA) or OF, animals received a bilateral infusion of 0.55 or 5.5 ng/side of AM251 or its vehicle in the CA1 region, and test was performed 24 h later. AM251 has caused a significative decrease in the test step-down latency when compared to the control group, but no differences were detected in the OF task, including the number of crossings, i.e., there were no motor effects. The LTP supression could be caused by AM251 acting over GABAergic interneurons that modulate the LTP-bearing glutamatergic neurons. Endocanabinoids would then be the natural dis-inhibitors of local plasticity in the dorsal hippocampus, and the amnestic action of AM251 would be due to a disruption of this endogenous modulatory system.

CB1 is the most abundant metabotropic receptor of the brain, being found in areas classically involved in learning and memory and present at higher density at presynaptic terminals. Different sets of evidence support the idea that endogenous ligands (endocannabinoids) to the CB1 receptors act as modulators of neurotransmission. In hippocampus, endocannabinoids seem to act as retrograde messengers mediating down-regulation of GABA release. Previous reports have described a cognitive impairment effect of cannabinoid agonists, or facilitation by antagonists. The scope of the present study is to investigate the effect of intrahippocampal administration of the CB1-selective antagonist, AM251, in two behavioral tasks. One hundred and twelve male Wistar rats with bilateral cannulae implanted in the CA1 region of the dorsal hippocampus were trained in a step-down inhibitory avoidance task (IA, footshock, 0.5 mA) or an open field habituation task (OF). Immediately, after training, animals received an infusion of 0.55, 5.5, and 55.5 ng/side of AM251 (Tocris), or its vehicle (DMSO/saline), via these cannulae. Our results show that AM251 disrupted memory consolidation of the IA task, but not the OF task, an effect that seems to be purely mnemonic since the drug showed no motor performance effects. Only the intermediate dose (5.5 ng/side) of AM251 was effective in IA and the absence of effect with the larger dose may be the consequence of non-specific binding. The fact that OF was not affected raises the possibility that this endogenous system requires some degree of aversiveness to be recruited. We propose that increased levels of endogenous cannabinoids in the hippocampus, following a training session, contribute to facilitate memory consolidation, a process that may have been disrupted with AM251.

Muscarinic receptors in the hippocampus are relevant to learning and memory, but the role of each subtype is poorly understood. Muscarinic toxins (MTs) from Dendroaspis snakes venom are selective for muscarinic receptor subtypes. MT2, a selective agonist for M(1) receptors, given into the hippocampus immediately after training, improved memory consolidation of an inhibitory avoidance task in rats, whereas the antagonist pirenzepine was amnestic, supporting a facilitatory role of M(1) receptors. Instead, MT3, a selective antagonist at M(4) receptors, caused amnesia. Neither M(1) nor M(4) receptor appeared involved in habituation to a new environment. Thus, our results suggest that memory consolidation of an inhibitory avoidance task in the rat involves the participation of both M(1) and M(4) hippocampal receptors, with a positive modulatory role.

It has previously been shown that Hebb learning in a single column in the trion model of cortical organization occurs by selection. Motivated by von Neumann's solution for obtaining reliability and by models of circulating cortical activity, we introduce Hebb intercolumnar couplings to achieve dramatic enhancements in reliability in the firing of connected columns. In order for these enhancements to occur, specific temporal phase differences must exist between the same inherent spatial-temporal memory patterns in connected columns. We then generalize the criteria of large enhancements in the global firing of the entire connected columnar network to investigate the case when different inherent memory patterns are in the columns. The spatial rotations as well as the temporal phases now are crucial. Only certain combinations of inherent memory patterns meet these criteria with the symmetry properties playing a major role. The columnar order of these memory patterns not in the same symmetry family can be extremely important. This yields the first higher-level architecture of a cortical language and grammar within the trion model. The implications of this result with regard to an innate human language and grammar are discussed.

Adult male Wistar rats were bilaterally implanted with indwelling cannulae in the hippocampus. Forty-eight hours after surgery, animals were habituated to an open-field box during 2 min, being tested 24 h later; next they were trained in a step-down inhibitory avoidance task (3.0 s, 0.4 mA foot-shock), being tested again 24 h later. Immediately after the training session of each task, animals received a 0.5-microl infusion of calcium-phosphate-buffered saline (PBS) and S100B (20, 200, 2000, or 20,000 nM). In the inhibitory avoidance task, animals infused with the two highest concentrations of S100B, 2 and 20 microM, obtained higher scores of retention relative to controls in the test session (p<0.05), and a trend toward an increase was observed in animals infused with 200 nM (p<0. 10). In both sessions of the habituation task, groups were not different regarding crossings, rearings, and time for leaving the first square (p>0.10). These results indicate that, in rats, post-training increased hippocampal levels of S100B right after training facilitate, in a dose-dependent way, long-term memory for an inhibitory avoidance task, but not for an open-field habituation.