Inhibitory Avoidance Training Research Articles

Postnatal Development of Synaptic Plasticity at Hippocampal CA1 Synapses: Correlation of Learning Performance with Pathway-Specific Plasticity.

To determine the critical timing for learning and the associated synaptic plasticity, we analyzed developmental changes in learning together with training-induced plasticity. Rats were subjected to an inhibitory avoidance (IA) task prior to weaning. While IA training did not alter latency at postnatal day (PN) 16, there was a significant increase in latency from PN 17, indicating a critical day for IA learning between PN 16 and 17. One hour after training, acute hippocampal slices were prepared for whole-cell patch clamp analysis following the retrieval test. In the presence of tetrodotoxin (0.5 µM), miniature excitatory postsynaptic currents (mEPSCs) and inhibitory postsynaptic currents (mIPSCs) were sequentially recorded from the same CA1 neuron. Although no changes in the amplitude of mEPSCs or mIPSCs were observed at PN 16 and 21, significant increases in both excitatory and inhibitory currents were observed at PN 23, suggesting a specific critical day for training-induced plasticity between PN 21 and 23. Training also increased the diversity of postsynaptic currents at PN 23 but not at PN 16 and 21, demonstrating a critical day for training-induced increase in the information entropy of CA1 neurons. Finally, we analyzed the plasticity at entorhinal cortex layer III (ECIII)-CA1 or CA3-CA1 synapses for each individual rat. At either ECIII-CA1 or CA3-CA1 synapses, a significant correlation between mean α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartic acid (AMPA/NMDA) ratio and learning outcomes emerged at PN 23 at both synapses, demonstrating a critical timing for the direct link between AMPA receptor-mediated synaptic plasticity and learning efficacy. Here, we identified multiple critical periods with respect to training-induced synaptic plasticity and delineated developmental trajectories of learning mechanisms at hippocampal CA1 synapses.

TrkB-BDNF Signalling and Arc/Arg3.1 Immediate Early Genes in the Anterior Cingulate Cortex and Hippocampus: Insights into Novel Memory Milestones Through Behavioural Tagging.

In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis-dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined "behavioural tag/PRP". Interfering with the expression of these molecules resulted in impaired LTM after 24h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a "behavioural tag/PRP" combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory.

Generalization and discrimination of inhibitory avoidance differentially engage anterior and posterior retrosplenial subregions.

In a variety of behavioral procedures animals will show selective fear responding in shock-associated contexts, but not in other contexts. However, several factors can lead to generalized fear behavior, where responding is no longer constrained to the conditioning context and will transfer to novel contexts. Here, we assessed memory generalization using an inhibitory avoidance paradigm to determine if generalized avoidance behavior engages the retrosplenial cortex (RSC). Male and female Long Evans rats received inhibitory avoidance training prior to testing in the same context or a shifted context in two distinct rooms; one room that had fluorescent lighting (Light) and one that had red LED lighting (Dark). We found that animals tested in a light context maintained context-specificity; animals tested in the same context as training showed longer latencies to cross and animals tested in the shifted context showed shorter latencies to cross. However, animals tested in the dark generalized their avoidance behavior; animals tested in the same context and animals tested in the shifted context showed similarly-high latencies to cross. We next examined expression of the immediate early gene zif268 and perineuronal nets (PNNs) following testing and found that while activity in the basolateral amygdala corresponded with overall levels of avoidance behaviors, anterior RSC (aRSC) activity corresponded with learned avoidance generally, but posterior RSC (pRSC) activity seemed to correspond with generalized memory. PNN reduction in the RSC was associated with memory formation and retrieval, suggesting a role for PNNs in synaptic plasticity. Further, PNNs did not reduce in the RSC in animals who showed a generalized avoidance behavior, in line with their hypothesized role in memory consolidation. These findings suggest that there is differential engagement of retrosplenial subregions along the rostrocaudal axis to generalization and discrimination.

Experience-Induced Remodeling of the Hippocampal Post-synaptic Proteome and Phosphoproteome

The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is a key node in the regulation of synaptic plasticity. To gain new mechanistic insight into experience-induced changes in the PSD, we examined the global dynamics of the hippocampal PSD proteome and phosphoproteome in mice following four different types ofexperience. Mice were trained using an inhibitory avoidance (IA) task and hippocampal PSD fractions were isolated from individual mice to investigate molecular mechanisms underlying experience-dependent remodeling of synapses. We developed a new strategy to identify and quantify the relatively low level of site-specific phosphorylation of PSD proteome from the hippocampus, by using a modified iTRAQ-based TiSH protocol. In the PSD, we identified 3938 proteins and 2761 phosphoproteins in the sequential strategy covering a total of 4968 unique protein groups (at least two peptides including a unique peptide). On the phosphoproteins, we identified a total of 6188 unambiguous phosphosites (75%<site-localization probability). Strikingly, of the significantly IA-regulated phosphoproteins, a large fraction of these displayed an overall decrease in phosphorylation level. Bioinformatic analysis of proteins and phosphoproteins that were regulated by IA were annotated for involvement in the regulation of glutamate receptor functionality, RHO GTPase cycle, and synaptic plasticity. We also identified synaptic kinases, phosphatases, and their respective phosphosites regulated by IA training or immediate shock. Furthermore, we found that AMPA receptor surface expression was regulated by Mg2+/Mn2+ dependent protein phosphatase 1H (Ppm1h). Together, these results unravel the dynamic remodeling ofthe PSD upon IA learning or immediate shock and serve asa resource for elucidating the synaptic proteome dynamics induced by experience-dependent plasticity.

Intense inhibitory avoidance training increases nuclear-phosphorylated glucocorticoid receptors in neurons of CA1 of hippocampus and ventral caudate putamen

Corticosterone (CORT), the principal glucocorticoid in rodents, is released after stressful experiences such as training with high foot-shock intensities in the inhibitory avoidance task (IA). CORT reaches the glucocorticoid receptor (GR) located in almost all brain cells; the GR is subsequently phosphorylated at serine 232 (pGRser232). This has been reported as an indicator of ligand-dependent activation of the GR, as well as a requirement for its translocation into the nucleus for its transcription factor activity. The GR is present in the hippocampus with a high concentration in CA1 and dentate gyrus (DG), and a smaller proportion in CA3, and sparsely present in the caudate putamen (CPu); both structures are involved in memory consolidation of IA. To study the participation of CORT in IA, we quantified the ratio of pGR-positive neurons in both dorsal hippocampus (CA1, CA3 and DG) and dorsal and ventral regions of CPu of rats trained in IA, using different foot-shock intensities. Brains were dissected 60 min after training for immunodetection of pGRser232 positive cells. The results show that the groups trained with 1.0 and 2.0 mA had higher retention latencies than the 0.0 mA or 0.5 mA groups. An increase in the ratio of pGR-positive neurons was found in CA1 and ventral region of CPu only for the 2.0 mA trained group. These findings suggest that activation of GRs in CA1 and ventral CPu is involved in the consolidation of a stronger memory of IA, possibly through the modulation of gene expression.

Computational analysis of memory consolidation following inhibitory avoidance (IA) training in adult and infant rats: Critical roles of CaMKIIα and MeCP2.

Key features of long-term memory (LTM), such as its stability and persistence, are acquired during processes collectively referred to as consolidation. The dynamics of biological changes during consolidation are complex. In adult rodents, consolidation exhibits distinct periods during which the engram is more or less resistant to disruption. Moreover, the ability to consolidate memories differs during developmental periods. Although the molecular mechanisms underlying consolidation are poorly understood, the initial stages rely on interacting signaling pathways that regulate gene expression, including brain-derived neurotrophic factor (BDNF) and Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) dependent feedback loops. We investigated the ways in which these pathways may contribute to developmental and dynamical features of consolidation. A computational model of molecular processes underlying consolidation following inhibitory avoidance (IA) training in rats was developed. Differential equations described the actions of CaMKIIα, multiple feedback loops regulating BDNF expression, and several transcription factors including methyl-CpG binding protein 2 (MeCP2), histone deacetylase 2 (HDAC2), and SIN3 transcription regulator family member A (Sin3a). This model provides novel explanations for the (apparent) rapid forgetting of infantile memory and the temporal progression of memory consolidation in adults. Simulations predict that dual effects of MeCP2 on the expression of bdnf, and interaction between MeCP2 and CaMKIIα, play critical roles in the rapid forgetting of infantile memory and the progress of memory resistance to disruptions. These insights suggest new potential targets of therapy for memory impairment.

Intrahippocampal Adeno-Associated Virus-Mediated Overexpression of Nerve Growth Factor Reverses 192IgG-Saporin-Induced Impairments of Hippocampal Plasticity and Behavior.

One of the aspects of Alzheimer disease is loss of cholinergic neurons in the basal forebrain, which leads to development of cognitive impairment. Here, we used a model of cholinergic deficit caused by immunotoxin 192IgG-saporin to study possible beneficial effects of adeno-associated virus (AAV)–mediated overexpression of nerve growth factor (NGF) in the hippocampus of rats with cholinergic deficit. Suspension of recombinant AAV carrying control cassette or cassette with NGF was injected into both hippocampi of control rats or rats with cholinergic deficit induced by intraseptal injection of 192IgG-saporin. Analysis of choline acetyltransferase (ChAT) immunostaining showed that NGF overexpression in the hippocampus did not prevent strong loss of ChAT-positive neurons in the septal area caused by the immunotoxin. Induction of cholinergic deficit in the hippocampus led to impairments in Y-maze and beam-walking test but did not affect behavioral indices in the T-maze, open field test, and inhibitory avoidance training. NGF overexpression in the rats with cholinergic deficit restored normal animal behavior in Y-maze and beam-walking test. Recording of field excitatory postsynaptic potentials in vivo in the hippocampal CA1 area showed that induction of cholinergic deficit decreased magnitude of long-term potentiation (LTP) and prevented a decrease in paired-pulse ratio after LTP induction, and NGF overexpression reversed these negative changes in hippocampal synaptic characteristics. The beneficial effect of NGF was not associated with compensatory changes in the number of cells that express NGF receptors TrkA and NGFR in the hippocampus and medial septal area. NGF overexpression also did not prevent a 192IgG-saporin–induced decrease in the activity of acetylcholine esterase in the hippocampus. We conclude that NGF overexpression in the hippocampus under conditions of cholinergic deficit induces beneficial effects which are not related to maintenance of cholinergic function.

Dynamics of Dendritic Spines in Dorsal Striatum after Retrieval of Moderate and Strong Inhibitory Avoidance Learning

In marked contrast to the ample literature showing that the dorsal striatum is engaged in memory consolidation, little is known about its involvement in memory retrieval. Recent findings demonstrated significant increments in dendritic spine density and mushroom spine counts in dorsal striatum after memory consolidation of moderate inhibitory avoidance (IA) training; further increments were found after strong training. Here, we provide evidence that in this region spine counts were also increased as a consequence of retrieval of moderate IA training, and even higher mushroom spine counts after retrieval of strong training; by contrast, there were fewer thin spines after retrieval. Similar changes in mushroom and thin spine populations were found in the ventral striatum (nucleus accumbens), but they were related to the aversive stimulation and not to memory retrieval. These results suggest that memory retrieval is a dynamic process which produces neuronal structural plasticity that might be necessary for maintaining or strengthening assemblies that encode stored information.

Behavioral tagging as a mechanism for aversive-memory formation under acute stress.

The behavioral tagging (BT) hypothesis postulates that a weak learning experience, which only induces short-term memory, may benefit from another event that provides plasticity-related proteins (PRPs) to establish a long-lasting memory. According to BT, the weak experience sets a transient learning tag at specific activated sites, and its temporal and spatial convergence with the PRPs allows the long-term memory (LTM) formation. In this work, rats were subjected to a weak inhibitory avoidance (IAw) training and we observed that acute stress (elevated platform, EP) experienced 1hr before IAw promoted IA-LTM formation. This effect was dependent on glucocorticoid-receptor activity as well as protein synthesis in the dorsal hippocampus. However, the same stress has negative effects on IA-LTM formation when training is strong, probably by competing for necessary PRPs.Furthermore, our experiments showed that EP immediately after training did not impair the setting of the learning tag and even facilitated IA-LTM formation. These findings reveal different impacts of a given acute stressful experience on the formation of an aversive memory that could be explained by BT processes.

Epinephrine modulates memory of latent learning in an inhibitory avoidance task

The present study examined the memory modulatory effect of epinephrine on latent learning of an inhibitory avoidance task. Male Sprague-Dawley rats on the first day were subjected to one of three conditions (no, short or long) in pre-exposure to the task apparatus. One day or several days later, they received the typical inhibitory avoidance training with a 0.5 mA/0.5 s foot shock. Memory of the inhibitory avoidance response was tested one day after the foot-shock training. The long pre-exposure group showed better memory than the no or short pre-exposure group, and this latent memory could last for 6 days: Retention scores of the long pre-exposure group were significantly better than those of the no pre-exposure group if the shock training was given 3 or 6 days, but not 12 or 21 days, after the pre-exposure. Epinephrine injected after the pre-exposure training modulated the latent memory in a dose- and time-dependent manner: 0.01 mg/kg given shortly after the short pre-exposure enhanced the memory, but 0.5 mg/kg given shortly after the long pre-exposure impaired it. Epinephrine injected 4 h after the pre-exposure had no effect, neither did that given to rats pre-exposed to a different context. Epinephrine (0.01 mg/kg) also made the latent memory lasting longer as the rats treated with it showed significant avoidance behavior when they had the shock training at 12 or 21 days after the pre-exposure. These findings suggest that epinephrine could modulate memory formed in the latent learning.

Recruitment of neurons in basolateral amygdala after intense training produces a stronger memory trace

Typical amnestic treatments are ineffective when administered to subjects trained in aversively-motivated tasks using relatively high foot-shock intensities. This effect has been found when treatments that disrupt neuronal activity are administered to different regions of the brain, including the amygdala. However, the molecular mechanisms induced by this intense training are unknown. We made a detailed mapping of c-Fos-expressing neurons in four regions of the amygdala after moderate and intense one-trial inhibitory avoidance training. Rats were sacrificed 90 min after training or after appropriate control procedures, and their brains were prepared for immunohistochemical c-Fos protein detection in the central, lateral, and in the anterior and posterior parts of the basolateral amygdaloid nucleus. We found a high percentage of neurons expressing c-Fos in the anterior part of the basolateral nucleus after moderate training, and this percentage increased further after intense training. Moderate and intense training did not induce changes in c-Fos expression in the other explored amygdaloid regions. These results show that inhibitory avoidance training produces a localized expression of c-Fos in the basolateral anterior nucleus of the amygdala, which is dependent upon the intensity of training, and indicate that synaptic plastic changes in this region may be required for the formation of memory of moderate and intense aversive learning.

Novelty Exposition Facilitates Memory Extinction By Dopaminergic Mechanisms

Memory extinction has been considered an interesting strategy for attenuating responsiveness to the original fear memory, and has been widely used on clinic to treat fear‐related disorders. However, exposure therapy tend to require a long and slow process of treatment and generally produce transient fear reduction that is often bound to the context in which the therapy was administered. Here we investigate the effects of novelty exposure on memory extinction. 50 male Wistar rats were divided in five groups: (i) control; (ii) novelty exposure; (iii) familiar context exposure; (iv) dopamine; and, (v) dopamine + familiar. All animals were trained in Inhibitory Avoidance (IA) and 24h after submitted to extinction training carried out in three sessions 90 min apart. 24 hours after the last extinction session, the animals were submitted to the retention test, which also made 3, 7, 14 and 21 days after the extinction sessions. Thirty minutes before the first extinction training session, rats from the group (ii) were exposed for 5 min to a novelty (a novel environment). Additional control groups were exposed to a familiar environment. The animals from dopamine groups received an intrahippocampal infusion of dopamine (1 μg/μL, 1 μL per side). During the IA training, all the animals presented similar step‐down latency when compared to each other (P &gt; 0.05). In the 24h retention test the step‐down latency of the group (ii) was significantly lower than the one of control group (i) (P&lt;0.01), indicating that novelty promoted memory extinction. On the other hand, the group (iii) (Familiar OF) present similar step‐down latency than group (i) (P&gt;0.05) and differences from group (ii) (P&lt;0.01), indicating that the exposure to a familiar environment does not promote memory extinction. The group (iv) presented significantly lower latencies than control (i) and familiar (iii) groups (P&lt;0.01), indicating that dopamine promoted memory extinction. On the other hand, the group (iv) present similar step‐down latency than group (ii) (novelty) (P&gt;0.05), indicating that the dopamine mimics novelty effects on memory extinction. Regarding the memory persistence, we observed that the group (ii) presented step‐down latencies significantly lower than control group (i) throughout the 21 days (P&lt;0.01 in all tests). The group (iv) also presented step‐down latencies significantly lower than control group (i) throughout the 21 days (P&lt;0.05 in all tests). Therefore, the exposure to a novelty, as well as, the infusion of dopamine on CA1 region of the hippocampus, promoted persistent memory extinction. In the present work we confirmed that novelty exposure can facilitated the aversive memory extinction and demonstrated that the novelty effects can persist along the time. Finally, we show that the novelty effects on extinction are mimicked by dopamine infusion on CA1 region of hippocampus, reinforcing the importance of hippocampal dopamine on novelty effects.Support or Funding InformationThis work was supported by research grants and fellowships from Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS), CAPES, Federal University of Pampa, and the National Council of Research of Brazil (CNPq).A. Training, extinctions, and 24h test step‐down latencies on IA. B. Training, extinctions, and 3, 7, 14 and 21 days test step‐down latencies on IA. In each session, different letters represent significant differences between the groups (P &lt; 0.05; Kruskall‐Wallis followed by Dunn’s post‐hoc). * P &lt; 0.05 in comparison to training (Wilcoxon test, training vs. test).Figure 1

Bed nuclei of the stria terminalis modulate memory consolidation via glucocorticoid-dependent and -independent circuits

There is extensive evidence that glucocorticoid hormones enhance memory consolidation, helping to ensure that emotionally significant events are well remembered. Prior findings suggest that the anteroventral region of bed nuclei of the stria terminalis (avBST) regulates glucocorticoid release, suggesting the potential for avBST activity to influence memory consolidation following an emotionally arousing learning event. To investigate this issue, male Sprague-Dawley rats underwent inhibitory avoidance training and repeated measurement of stress hormones, immediately followed by optogenetic manipulations of either the avBST or its projections to downstream regions, and 48 h later were tested for retention. The results indicate that avBST inhibition augmented posttraining pituitary-adrenal output and enhanced the memory for inhibitory avoidance training. Pretreatment with a glucocorticoid synthesis inhibitor blocked the memory enhancement as well as the potentiated corticosterone response, indicating the dependence of the memory enhancement on glucocorticoid release during the immediate posttraining period. In contrast, posttraining avBST stimulation decreased retention yet had no effect on stress hormonal output. Subsequent experiments revealed that inhibition of avBST input to the paraventricular hypothalamus enhanced stress hormonal output and subsequent retention, whereas stimulation did not affect either. Conversely, stimulation-but not inhibition-of avBST input to the ventrolateral periaqueductal gray impaired consolidation, whereas neither manipulation affected glucocorticoid secretion. These findings indicate that divergent pathways from the avBST are responsible for the mnemonic effects of avBST inhibition versus stimulation and do so via glucocorticoid-dependent and -independent mechanisms, respectively.

A Single Dose of Methylprednisolone Improves Aversive Memory Consolidation and Extinction in Rats.

Aversive memory is essential for survival, but in some situations its exacerbation can be potentially dangerous. There are several ways to modulate memory, among them, through stress-related hormones physiological release or administration of exogenous substances analogous to them. Recently, our group shown that a chronic treatment with a low dose of methylprednisolone (MP) is able to promote memory persistence in rats. Herein, we evaluate if a single intraperitoneal (IP) dose of MP (5 mg/kg) is able to modulate aversive memory consolidation and promote memory persistence and extinction in rats. For this, two experiments were carried out. In the first one, we demonstrated that a single IP MP administration in specific times after inhibitory avoidance (IA) training improved memory consolidation and persistence. In the second experiment, we verified that a single IP MP administration 2 h after IA extinction training promoted memory extinction. This results suggest a possible new clinical applicability for MP on the aversive memory disorders, as post-traumatic stress.

Prenatal Exposure to Cadmium During Organogenesis Impairs Memory in Young Rats.

Pregnant rats were treated with 0.3 and 0.6 mg cadmium (CdCl2)/kg injected subcutaneously on a daily basis from gestational day 7 to day 15 (organogenesis period). One control group was not injected and other received saline. The 45-day-old offspring were tested in a step-down inhibitory avoidance to evaluate short-term and long-term memory and in a radial maze for the study of spatial memory. These studies showed that gestational exposure to 0.6 mg Cd/kg produced in the male offspring a significant impairment in the retention of long-term memory evaluated 24 hours after training in the step-down inhibitory avoidance. The radial maze also demonstrated that the male offspring prenatally exposed to 0.6 mg Cd presented a significant deficit in the retention of spatial memory evaluated 42 days after training. These results demonstrate that the exposure to Cd during organogenesis may affect the retention of some types of memory.

Prefrontal-amygdala plasticity enabled by observational fear.

Observing fear in others (OF) is a form of social stress. In mice, it enhances inhibitory avoidance learning and causes the formation of silent synapses in the prefrontal-amygdala pathway. Here, we report that OF made that pathway prone to facilitation both ex vivo and in vivo. Ex vivo, OF enabled induction of long-term potentiation (LTP), expressed mostly postsynaptically and occluded by inhibitory avoidance training. In vivo, OF enabled facilitation of the dmPFC-BLA pathway by inhibitory avoidance training. The facilitation persisted during the first 4 h after the training when the prefrontal cortex and amygdala are involved in memory consolidation. Thus, the OF-generated silent synapses likely enable plasticity that may enhance the consolidation of inhibitory avoidance memories.

Glucocorticoid interactions with the dorsal striatal endocannabinoid system in regulating inhibitory avoidance memory

The endocannabinoid (eCB) system is highly stress sensitive and known to modulate memory formation of emotionally arousing experiences across different corticolimbic structures. eCB signaling within these circuits is also essentially involved in regulating non-genomically mediated glucocorticoid hormone effects on memory. It has long been thought that the dorsal striatum, which plays a major role in procedural memory and habit formation, is considerably less impacted by stressful experiences; however, recent findings indicate that stress and glucocorticoids also affect striatal-dependent memory processes. Yet, to what extent eCB signaling within the dorsal striatum may mediate such glucocorticoid effects on memory consolidation is currently unknown. Here we show, in male Wistar rats, that the cannabinoid agonist WIN55,212-2 administered into the dorsal striatum immediately after an inhibitory avoidance training experience dose-dependently enhanced 48-h retention performance. Conversely, the cannabinoid type 1 receptor (CB1R) antagonist AM251 impaired retention when administered into the dorsal striatum after inhibitory avoidance training. Most importantly, antagonism of striatal CB1R activity with AM251 completely abolished the effect of corticosterone or of the membrane-impermeable ligand corticosterone:BSA administered posttraining into the dorsal striatum or injected systemically on enhancement of inhibitory avoidance memory. Further, suppression of glucocorticoid signaling by systemic injection of the corticosterone-synthesis inhibitor metyrapone also impaired the memory-enhancing effect of intra-striatal WIN55, 212-2 administration. These findings indicate that the eCB system, in close interaction with glucocorticoid signaling, is involved in modulating plasticity changes underlying memory consolidation not only in corticolimbic structures but also within the dorsal striatum.

Changes in the element concentration of the dorsal hippocampus CA1 region during memory consolidation and reconsolidation

The concentration and distribution of Mg, P, Cl, K, Cu and Zn in the dorsal hippocampus CA1 region of rat brains were studied during memory consolidation and reconsolidation processes stimulated with inhibitory avoidance (IA) tests. Experimental rats were divided into four groups: i) group not submitted to inhibitory avoidance task (IA-N); ii) group submitted to inhibitory avoidance training session (IA-Y); iii) group submitted to inhibitory avoidance reactivation session but did not step down from the platform (IAR-N); and iv) group submitted to avoidance reactivation session and stepped down from the platform (IAR-Y). Elemental concentration and distribution in the CA1 hippocampus region were obtained through the Particle-Induced X-ray Emission (PIXE) technique. The results indicate that the concentration of Mg, P, Cl, K and Cu increased during memory consolidation. During the memory reconsolidation process, the concentrations of Mg, P, Cl and K increased, while Cu and Zn had no significant changes with respect to their basal condition. These results show that the major part of these elements may be engaged in memory consolidation could be also participating in memory reconsolidation. For all elements, the general trend related to their concentration did not change during reconsolidation regardless the presence of a novelty event, i.e. stepping down from the platform.

Differential Effects of Inactivation of Discrete Regions of Medial Prefrontal Cortex on Memory Consolidation of Moderate and Intense Inhibitory Avoidance Training.

It has been found that the medial prefrontal cortex (mPFC) is involved in memory encoding of aversive events, such as inhibitory avoidance (IA) training. Dissociable roles have been described for different mPFC subregions regarding various memory processes, wherein the anterior cingulate cortex (ACC), prelimbic cortex (PL), and infralimbic cortex (IL) are involved in acquisition, retrieval, and extinction of aversive events, respectively. On the other hand, it has been demonstrated that intense training impedes the effects on memory of treatments that typically interfere with memory consolidation. The aim of this work was to determine if there are differential effects on memory induced by reversible inactivation of neural activity of ACC, PL, or IL produced by tetrodotoxin (TTX) in rats trained in IA using moderate (1.0 mA) and intense (3.0 mA) foot-shocks. We found that inactivation of ACC has no effects on memory consolidation, regardless of intensity of training. PL inactivation impairs memory consolidation in the 1.0 mA group, while no effect on consolidation was produced in the 3.0 mA group. In the case of IL, a remarkable amnestic effect in LTM was observed in both training conditions. However, state-dependency can explain the amnestic effect of TTX found in the 3.0 mA IL group. In order to circumvent this effect, TTX was injected into IL immediately after training (thus avoiding state-dependency). The behavioral results are equivalent to those found after PL inactivation. Therefore, these findings provide evidence that PL and IL, but not ACC, mediate LTM of IA only in moderate training.

Different doses of sevoflurane facilitate and impair learning and memory function through activation of the ERK pathway and synthesis of ARC protein in the rat hippocampus

BackgroundSevoflurane has been shown to stimulate or depress memory in adult rats; however, the cellular mechanism of this bidirectional effect has not been fully investigated. MethodsWe used an intra-hippocampal microinfusion of U0126 to suppress ERK activation. Male SD rats were randomly assigned to four groups: Sham, 0.11%SEV, 0.3%SEV and 0.3%+U0126. They received bilateral injections of U0126 or saline. Rats were anesthetized, and Inhibitory Avoidance (IA) training was performed immediately after anesthesia. The memory retention latency was observed 24 h later. In another experiment, the hippocampus was removed 45 min after IA training to assess ARC expression, the synapsin 1 protein levels and the phosphorylation level of ERK. ResultsTreatment with 0.11%SEV led to rapid phosphorylation of ERK, while 0.3%SEV inhibited phosphorylation; the latter change was reversed by the microinfusion of U0126 in the hippocampus. The memory latency result had similar tendencies. The local infusion of U0126 abolished the 0.3%SEV-induced memory impairment and ERK inhibition. Selective upregulations of ARC and synapsin 1 proteins were observed in the 0.3%SEV group compared with the 0.11%SEV group. ConclusionsThe results indicate that different doses of sevoflurane trigger synaptic plasticity-related cytoskeleton proteins through the ERK signaling pathway. This novel modulation by inhalational agents may help to reduce their side-effects on memory function.