Involvement of kinases in memory consolidation of inhibitory avoidance training.

The inhibitory avoidance (IA) task is a paradigm widely used to investigate the molecular and cellular mechanisms involved in the formation of long-term memory of aversive experiences. In this review, we discuss studies on different brain structures in rats associated with memory consolidation, such as the hippocampus, striatum, and amygdala, as well as some cortical areas, including the insular, cingulate, entorhinal, parietal and prefrontal cortex. These studies have shown that IA training triggers the release of neurotransmitters, hormones, growth factors, etc.

Intense training prevents the amnestic effect of inactivation of dorsomedial striatum and induces high resistance to extinction.

A large body of evidence has shown that treatments that interfere with memory consolidation become ineffective when animals are subjected to an intense learning experience; this effect has been observed after systemic and local administration of amnestic drugs into several brain areas, including the striatum. However, the effects of amnestic treatments on the process of extinction after intense training have not been studied. Previous research demonstrated increased spinogenesis in the dorsomedial striatum, but not in the dorsolateral striatum after intense training, indicating that the dorsomedial striatum is involved in the protective effect of intense training.

Inhibition of corticosterone synthesis impairs cued water maze consolidation, but it does not affect the expression of BDNF, CK2 and SGK1 genes in dorsal striatum.

Corticosterone (CORT) release during learning experiences is associated with strong memories and activity of the glucocorticoid receptor. It has been shown that lesions of the dorsal striatum (DS) of rats trained in the cued version of the Morris water maze impair memory, and that local injection of CORT improves its performance, suggesting that DS activity is involved in procedural memory which may be modulated by CORT. We trained rats in cued Morris water maze and analyzed the effect of CORT synthesis inhibition on performance, CORT levels, expression of plasticity-involved genes, such as the brain derived neurotrophic factor (BDNF), casein kinase 2 (CK2), and the serum/glucocorticoid regulated kinase 1 (SGK1), as well as the presence of phosphorylated nuclear glucocorticoid receptor in serine 232 (pGR-S232) in the DS.

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.

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.

Corticosterone in the dorsolateral striatum facilitates the extinction of stimulus-response memory.

Glucocorticoid hormones are crucially involved in modulating mnemonic processing of stressful or emotionally arousing experiences. They are known to enhance the consolidation of new memories, including those that extinguish older memories. In this study, we investigated whether glucocorticoids facilitate the extinction of a striatum-dependent, and behaviorally more rigid, stimulus-response memory.

Imbalance in cerebral protein homeostasis: Effects on memory consolidation.

The long-standing hypothesis that memory consolidation is dependent upon de novo protein synthesis is based primarily on the amnestic effects of systemic administration of protein synthesis inhibitors (PSIs). Early experiments on mice showed that PSIs produced interference with memory consolidation that was dependent on the doses of PSIs, on the interval between drug injection and training, and, importantly, on the degree and duration of protein synthesis inhibition in the brain. Surprisingly, there is a conspicuous lack of information regarding the relationship between the duration of protein synthesis inhibition produced by PSIs and memory consolidation in the rat, one of the species most widely used to study memory processes.

Differential Phosphorylation of the Glucocorticoid Receptor in Hippocampal Subregions Induced by Contextual Fear Conditioning Training.

Aversive events induce the release of glucocorticoid stress hormones that facilitate long-term memory consolidation, an effect that depends on the activation of glucocorticoid receptors (GRs). GRs are distributed widely in the hippocampus. The dorsal region of the hippocampus has been related to cognitive functions and the ventral region to stress and emotion.

Morris water maze overtraining increases the density of thorny excrescences in the basal dendrites of CA3 pyramidal neurons.

The hippocampus plays a fundamental role in spatial learning and memory. Dentate gyrus (DG) granular neurons project mainly to proximal apical dendrites of neurons in the CA3 stratum lucidum and also, to some extent, to the basal dendrites of CA3 pyramidal cells in the stratum oriens. The terminal specializations of DG neurons are the mossy fibers (MF), and these huge axon terminals show expansion in the CA3 stratum oriens after the animals undergo overtraining in the Morris Water Maze task (MWM).

Inhibition of transcription and translation in dorsal hippocampus does not interfere with consolidation of memory of intense training.

Findings of several experiments indicate that many treatments that typically interfere with memory consolidation are ineffective in preventing or attenuating memory induced by intense training. As extensive evidence suggests that the consolidation of newly acquired memories requires gene expression and de novo protein synthesis the present study investigated whether intense training prevents consolidation impairment induced by blockers of mRNA and protein synthesis. Rats were given a single inhibitory training trial using a moderate (1.

Effects of anisomycin infusions into the dorsal striatum on memory consolidation of intense training and neurotransmitter activity.

The most influential hypothesis about the neurobiological basis of memory consolidation posits that this process is dependent upon de novo protein synthesis. Strong support for this proposition has been provided by a multitude of experiments showing that protein synthesis inhibitors (PSIs) interfere with consolidation. However, this hypothesis has been challenged by the results of studies showing that PSIs also produce a host of side effects that, by themselves, could account for their amnestic effects.

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.

Retrieval of Inhibitory Avoidance Memory Induces Differential Transcription of arc in Striatum, Hippocampus, and Amygdala.

Similar to the hippocampus and amygdala, the dorsal striatum is involved in memory retrieval of inhibitory avoidance, a task commonly used to study memory processes. It has been reported that memory retrieval of fear conditioning regulates gene expression of arc and zif268 in the amygdala and the hippocampus, and it is surprising that only limited effort has been made to study the molecular events caused by retrieval in the striatum. To further explore the involvement of immediate early genes in retrieval, we used real-time PCR to analyze arc and zif268 transcription in dorsal striatum, dorsal hippocampus, and amygdala at different time intervals after retrieval of step-through inhibitory avoidance memory.

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.

Glucocorticoid administration into the dorsolateral but not dorsomedial striatum accelerates the shift from a spatial toward procedural memory.

Glucocorticoid stress hormones are known to enhance the consolidation of hippocampus-dependent spatial and contextual memory. Recent findings indicate that glucocorticoids also enhance the consolidation of procedural memory that relies on the dorsal striatum. The dorsal striatum can be functionally subdivided into the dorsolateral striatum (DLS), which is primarily implicated in shaping procedural memories, and the dorsomedial striatum (DMS), which is engaged in spatial memory.

Subclinical Doses of ATP-Sensitive Potassium Channel Modulators Prevent Alterations in Memory and Synaptic Plasticity Induced by Amyloid-β.

In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer's disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity.

Differential Arc protein expression in dorsal and ventral striatum after moderate and intense inhibitory avoidance training.

Intense training refers to training mediated by emotionally arousing experiences, such as aversive conditioning motivated by relatively high intensities of foot-shock, which produces a strong memory that is highly resistant to extinction. Intense training protects memory consolidation against the amnestic effects of a wide variety of treatments, administered systemically or directly into brain structures. The mechanisms of this protective effect are unknown.

Inhibition of transcription and translation in the striatum after memory reactivation: Lack of evidence of reconsolidation.

It has been found that interference with neural activity after a consolidated memory is retrieved produces an amnestic state; this has been taken has indicative of destabilization of the memory trace that would have been produced by a process of reconsolidation (allowing for maintenance of the original trace). However, a growing body of evidence shows that this is not a reliable effect, and that it is dependent upon some experimental conditions, such as the age of the memory, memory reactivation procedures, the predictability of the reactivation stimulus, and strength of training. In some instances, where post-retrieval treatments induce a retention deficit (which would be suggestive of interference with reconsolidation), memory is rescued by simple passing of time or by repeated retention tests.

Mushroom spine dynamics in medium spiny neurons of dorsal striatum associated with memory of moderate and intense training.

A growing body of evidence indicates that treatments that typically impair memory consolidation become ineffective when animals are given intense training. This effect has been obtained by treatments interfering with the neural activity of several brain structures, including the dorsal striatum. The mechanisms that mediate this phenomenon are unknown.

Amyloid β Enhances Typical Rodent Behavior While It Impairs Contextual Memory Consolidation.

Alzheimer's disease (AD) is associated with an early hippocampal dysfunction, which is likely induced by an increase in soluble amyloid beta peptide (Aβ). This hippocampal failure contributes to the initial memory deficits observed both in patients and in AD animal models and possibly to the deterioration in activities of daily living (ADL). One typical rodent behavior that has been proposed as a hippocampus-dependent assessment model of ADL in mice and rats is burrowing.

Protein synthesis is not required for acquisition, consolidation, and extinction of high foot-shock active avoidance training.

Long-term memory of active avoidance in mice is not disturbed by administration of protein synthesis inhibitors (PSIs) when relatively high levels of training are used, whereas a detrimental effect is produced with lower levels of training. PSIs also disrupt extinction of avoidance behaviors in rodents, but it is not clear whether PSIs also affect this form of learning when the behavior to be extinguished was produced by a high level of training. Experiment 1 demonstrated that rats treated with the PSI cycloheximide (CXM) 30 min before training developed normal acquisition after training with either high or low foot-shock stimulation, but that memory consolidation was hindered only after low foot-shock training.

Intense aversive training protects memory from the amnestic effects of hippocampal inactivation.

There is extensive evidence that amnestic treatments are less effective, or ineffective when administered to subjects that have been overtrained or subjected to high foot-shock intensities in aversively motivated learning. This protective effect has been found with a variety of learning tasks and with treatments that disrupt activity in several regions of the brain, including the hippocampus, amygdala, striatum, and substantia nigra. Such findings have been interpreted as suggesting that the brain regions disrupted are not critical sites for the memory processes induced by these types of training.