Biomedical subjects

Lia R M Bevilaqua

Publications and source records attributed to Lia R M Bevilaqua.

At least 19 recordsLinked to original sources

PubMed2007

Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus.

Persistence is the most characteristic attribute of long-term memory (LTM). To understand LTM, we must understand how memory traces persist over time despite the short-lived nature and rapid turnover of their molecular substrates. It is widely accepted that LTM formation is dependent upon hippocampal de novo protein synthesis and Brain-Derived Neurotrophic Factor (BDNF) signaling during or early after acquisition. Here we show that 12 hr after acquisition of a one-trial associative learning task, there is a novel protein synthesis and BDNF-dependent phase in the rat hippocampus that is critical for the persistence of LTM storage. Our findings indicate that a delayed stabilization phase is specifically required for maintenance, but not formation, of the memory trace. We propose that memory formation and memory persistence share some of the same molecular mechanisms and that recurrent rounds of consolidation-like events take place in the hippocampus for maintenance of the memory trace.

Animals↗

PubMed2006

Anxiolytic-, antidepressant- and anticonvulsant-like effects of the alkaloid montanine isolated from Hippeastrum vittatum.

Compounds isolated from different members of the Amaryllidaceae family are becoming relevant options for the treatment of neurological disorders and neurodegenerative diseases. In particular, species of the Hippeastrum genus are important source of alkaloids with a wide profile of putative therapeutical applications. Here, we report on the behavioral and pharmaco-toxicological characterization of montanine, an isoquinoline alkaloid isolated from Hippeastrum vittatum, an ornamental plant found throughout the world. In mice, montanine showed a LD(50) of 64.7 mg/kg and 67.6 mg/kg for male and female, respectively. When given i.p., montanine dose-dependently decreased sodium pentobarbital-induced sleep, protected against pentylenetetrazole-provoked convulsions, increased the number of entries and the time spent in the open arms of an elevated plus maze and augmented the time spent struggling during a forced swimming test. When given immediately after inhibitory avoidance training, montanine did not affect avoidance memory retention in rats. Our results suggest that montanine, as other alkaloids isolated from Amaryllidaceae species, has psychopharmacological activities including anxiolytic, antidepressive and anticonvulsive effects.

Animals↗

PubMed2006

Different molecular cascades in different sites of the brain control memory consolidation.

To understand cognition, it is important to understand how a learned response becomes a long-lasting memory. This process of memory consolidation has been modeled extensively using one-trial avoidance learning, in which animals (or humans) establish a conditioned response by learning to avoid danger in just one trial. This relies on molecular events in the CA1 region of the hippocampus that resemble those involved in CA1 long-term potentiation (LTP), and it also requires equivalent events to occur with different timings in the basolateral amygdala and the entorhinal, parietal and cingulate cortex. Many of these steps are modulated by monoaminergic pathways related to the perception of and reaction to emotion, which at least partly explains why strong and resistant consolidation is typical of emotion-laden memories. Thus memory consolidation involves a complex network of brain systems and serial and parallel molecular events, even for a task as deceptively simple as one-trial avoidance. We propose that these molecular events might also be involved in many other memory types in animals and humans.

Animals↗

PubMed2006

Retinol induces the ERK1/2-dependent phosphorylation of CREB through a pathway involving the generation of reactive oxygen species in cultured Sertoli cells.

The ability to regulate cell cycle progression and apoptosis through the activation of nuclear receptors and gene transcription has been generally accepted as a potential chemopreventive and therapeutic property of retinoids. However, recent studies suggest that retinol and related compounds can exert rapid and non-genomic effects, which may increase the production of reactive oxygen species (ROS) and lead to cell cycle disruption and malignant transformation. In this work, we report that, in Sertoli cells, retinol (7 microM) induces the Src-dependent activation of ERK1/2 MAPK and the ERK1/2-mediated phosphorylation of the transcription factor CREB. We found that these retinol-induced effects were completely blocked by the antioxidant Trolox 100 microM (a hydrophilic analogue of alpha-tocopherol), the hydroxyl radical scavenger mannitol (1 mM) and the addition of native superoxide dismutase (200 U/ml), and also that retinol increased the production of ROS and several other parameters indicative of oxidative stress during the same incubation periods in which ERK1/2 and CREB were phosphorylated. The activation of the ERK1/2-CREB pathway appears to be involved in the onset of some of the malignant effects caused by retinol in Sertoli cells since inhibition of ERK1/2 activation blocked the retinol-induced cell transformation and proliferation.

Animals↗

PubMed2006

Histamine enhances inhibitory avoidance memory consolidation through a H2 receptor-dependent mechanism.

Several evidences suggest that brain histamine is involved in memory consolidation but the actual contribution of the hippocampal histaminergic system to this process remains controversial. Here, we show that when infused into the CA1 region of the dorsal hippocampus immediately after training in an inhibitory avoidance task, but not later, histamine induced a dose-dependent promnesic effect without altering locomotor activity, exploratory behavior, anxiety state or retrieval of the avoidance response. The facilitatory effect of intra-CA1 histamine was mimicked by the histamine N-methyltransferase inhibitor SKF-91844 as well as by the H2 receptor agonist dimaprit and it was blocked completely by the H2 receptor antagonist ranitidine. Conversely, the promnesic action of histamine was unaffected by the H1 receptor antagonist pyrilamine, the H3 receptor antagonist, thioperamide, and the NMDAr polyamine-binding site antagonist ifenprodil. By themselves, ranitidine, pyrilamine, thioperamide, and ifenprodil did not affect IA memory consolidation. Our data indicate that, when given into CA1, histamine enhances memory consolidation through a mechanism that involves activation of H2 receptors; however, endogenous CA1 histamine does not seem to participate in the consolidation of IA memory at least at the post-training times analyzed.

Animals↗

PubMed2006

A link between the hippocampal and the striatal memory systems of the brain.

Two major memory systems have been recognized over the years (Squire 1987): the declarative memory system, which is under the control of the hippocampus and related temporal lobe structures, and the procedural or habit memory system, which is under the control of the striatum and its connections. Most if not all learning tasks studied in animals, however, involve either the performance or the suppression of movement; this, if learned well, may be viewed as having become a habit. It is agreed that memory rules change from their first association to those that take place when the task is mastered. Does this change of rules involve a switch from one memory system to another? Here we will comment on: 1) reversal learning in the Morris water maze (MWM), in which the declarative or spatial component of a task is changed but the procedural component (to swim to safety) persists and needs to be re-linked with a different set of spatial cues; and 2) a series of observations on an inhibitory avoidance task that indicate that the brain systems involved change with further learning.

Animals↗

PubMed2005

Gastrin-releasing peptide receptor antagonist effects on an animal model of sepsis.

RATIONALE: Several new therapeutic strategies have been described for the treatment of sepsis, but to date none are related to alterations in the bombesin/gastrin-releasing peptide (GRP) receptor pathways. OBJECTIVES: To determine the effects of a selective GRP receptor antagonist, RC-3095, on cytokine release from macrophages and its in vivo effects in the cecal ligation and puncture (CLP) model of sepsis and in acute lung injury induced by intratracheal instillation of LPS. METHODS: We determined the effects of RC-3095 in the CLP model of sepsis and in acute lung injury induced by intratracheal instillation of LPS. In addition, we determined the effects of RC-3095 on tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-10, and nitric oxide release from activated macrophages. MEASUREMENTS AND MAIN RESULTS: The GRP antagonist attenuated LPS- or CLP-induced TNF-alpha, IL-1beta, and nitric oxide release in cultured macrophages and decreased the mRNA levels of inducible nitric oxide synthase. The administration of RC-3095 (0.3 mg/kg) 6 h after sepsis induction improved survival in the CLP model, and diminished lung damage after intratracheal instillation of LPS. These effects were associated with attenuation on the circulating TNF-alpha and IL-1beta levels and decreased myeloperoxidase activity in several organs. CONCLUSIONS: We report that a selective GRP receptor antagonist attenuates the release of proinflammatory cytokines in vitro and in vivo and improves survival in "established" sepsis. These are consistent with the involvement of a new inflammatory pathway relevant to the development of sepsis.

Animals↗

PubMed2005

Extinction and reacquisition of a fear-motivated memory require activity of the Src family of tyrosine kinases in the CA1 region of the hippocampus.

Evidences indicate that extinction represents a NMDA receptor (NMDAr)-dependent learning rather than erasure of previously stored information. Several members of the Src family of tyrosine kinases are activated by stimulation of the NMDAr and are involved in both induction of hippocampal long-term potentiation and consolidation of hippocampal-dependent, NMDAr-sensitive, memories. Here we analyzed the role of the Src family within the CA1 region of the hippocampus in extinction and reacquisition of the memory for step-down, inhibitory avoidance learning task (IA). Rats trained in IA were submitted to 5 daily extinction sessions during which the avoidance response was elicited in the absence of the unconditioned stimulus. Immediately or 180 min after each extinction session animals received intra-CA1 infusions of either 0.1% DMSO, the Src-family inhibitor PP2 or its inactive analog, PP3. PP2 blocked extinction of the IA response which was otherwise evident in DMSO and PP3-treated animals. After being submitted to a new training session the animals reacquired the avoidance response; however, they failed to do so if they received intra-CA1 infusions of PP2 immediately following retraining. Our results indicate that, like the original learning, extinction and reacquisition of the IA response require activity of the Src family in the CA1 region of the hippocampus.

Animals↗

PubMed2005

Retrieval and the extinction of memory.

1. Memory is assessed by measuring retrieval which is often elicited by the solely presentation of the conditioned stimulus (CS). However, as known since Pavlov, presentation of the CS alone generates extinction. 2. One-trial avoidance (IA) is a much used conditioned fear paradigm in which the CS is the safe part of a training apparatus, the unconditioned stimulus (US) is a footshock and the conditioned response (CR) is to stay in the safe area. Retrieval of the memory for the step-down version of this task is measured in the absence of the US, as latency to step-down from the safe area (i.e., a platform). 3. Extinction of the IA response is installed at the moment of the first non-reinforced test session, as clearly shown by the fact that many drugs, including PKA, ERK and protein synthesis inhibitors as well as NMDA receptor antagonists, hinder extinction when infused into the hippocampus or the basolateral amygdala at the moment of the first test session but not later. 4. Some, but not all the molecular systems required for extinction are also activated by retrieval, further endorsing the hypothesis that although retrieval is necessary for the generation of extinction this last process constitutes a new learning secondary to the non-reinforced expression of the original trace.

Animals↗

PubMed2005

Relationship between short- and long-term memory and short- and long-term extinction.

Both the acquisition and the extinction of memories leave short- and long-term mnemonic traces. Here, we show that in male Wistar rats, the short-term memory for a step-down inhibitory avoidance task (IA) is resistant to extinction, and that its expression does not influence retrieval or extinction of long-term memory. It has been known for some time that short- and long-term inhibitory avoidance memory involve separate and parallel processes. Here we show that, instead, short-term extinction of IA long-term memory is the first step towards its long-term extinction, and that this link requires functional NMDA receptors and protein synthesis in the CA1 region of the dorsal hippocampus at the time of the first CS-no US presentation.

Animals↗

PubMed2004

Angiotensin II blocks memory consolidation through an AT2 receptor-dependent mechanism.

RATIONALE AND OBJECTIVES: Several studies suggest that the brain renin-angiotensin system is involved in memory consolidation. However, the participation of angiotensin II (AII) in this process is controversial. This is probably due to the fact that many of the studies carried out to elucidate this matter employed multitrial learning paradigms together with pretraining intracerebroventricular infusions, and therefore were unable to distinguish between consolidation and retrieval related events and lacked anatomical specificity. To circumvent this problem, we analyzed the role played in memory consolidation by AII using the hippocampal-dependent, one-trial, step-down inhibitory avoidance task (IA) in combination with stereotaxically localized intrahippocampal infusion of drugs. METHODS AND RESULTS: Rats bilaterally implanted with infusion cannulae into the CA1 region of the dorsal hippocampus (CA1) were trained in IA and tested for memory retention 24 h later. We found that when infused into CA1 immediately or 30 min after training but not later, AII produced a dose-dependent amnesic effect without altering locomotor activity, exploratory behavior or anxiety state. The amnesic effect of AII was not mimicked by angiotensin IV (AIV) and was totally blocked by the AII-type 2 receptor (AT2) antagonist, PD123319, but not by the AII-type 1 receptor (AT1) antagonist, losartan. Importantly, when infused alone, neither PD123319 nor losartan produced any effect on memory retention. CONCLUSIONS: Our data indicate that, when given into CA1, AII blocks memory formation through a mechanism involving activation of AT2 receptors; however, endogenous AII does not seem to participate in the consolidation of IA long-term memory.

Amnesia↗

PubMed2004

Inhibition of PKC in basolateral amygdala and posterior parietal cortex impairs consolidation of inhibitory avoidance memory.

Hippocampal alpha- and betaI/betaII protein kinase C (PKC) are crucial for the formation of different types of memory in several species, including that for a one trial inhibitory avoidance (IA) task in rats. Many studies, however, have shown that other brain structures besides the hippocampus, notably the basolateral amygdala (BLA) and posterior parietal cortex (PC) are also necessary for memory consolidation. Here, we examine the role of alpha- and betaI/betaII PKC in the BLA and PC on the consolidation of the memory for IA in rats. The selective inhibitor of alpha- and betaI/betaII-PKC Go 6976 and the nonselective PKC inhibitor Go 7874 were administered into these structures at different times after training at concentrations known to inhibit PKC and to produce retrograde amnesia when given into the hippocampus. Go 7874 blocked consolidation of IA memory when infused into BLA immediately and 30 min or into PC 180 to 360 min posttraining. Go 6976 caused amnesia when given into the BLA also immediately or 30 min posttraining but in the PC hindered memory retention only when infused 270 and 360 min after the training session. Our data indicate that alpha- and betaI/betaII-PKC are critical for consolidation of IA memory shortly after training in BLA and that, first other isoforms and subsequently the alpha- and betaI/betaII PKC are required 3 or more hours after training in the PC. The findings on BLA are similar to those previously reported in the hippocampus, but those on PC suggest an entirely different molecular dynamics for memory formation in that area.

Amygdala↗

PubMed2004

The transition from memory retrieval to extinction.

Memory is measured by measuring retrieval. Retrieval is often triggered by the conditioned stimulus (CS); however, as known since Pavlov, presentation of the CS alone generates extinction. One-trial avoidance (IA) is a much used conditioned fear paradigm in which the CS is the safe part of a training apparatus, the unconditioned stimulus (US) is a footshock and the conditioned response is to stay in the safe area. In IA, retrieval is measured without the US, as latency to step-down from the safe area (i.e., a platform). Extinction is installed at the moment of the first unreinforced test session, as clearly shown by the fact that many drugs, including PKA, ERK and protein synthesis inhibitors as well as NMDA receptor antagonists, hinder extinction when infused into the hippocampus or the basolateral amygdala at the moment of the first test session but not later. Some, but not all the molecular systems required for extinction are also activated by retrieval, further endorsing the hypothesis that although retrieval is behaviorally and biochemically necessary for the generation of extinction, this last process constitutes a new learning secondary to the unreinforced expression of the original trace.

Animals↗

PubMed2004

Hippocampal glutamate receptors in fear memory consolidation.

It is thought that activity-dependent changes in synaptic efficacy driven by biochemical pathways responsive to the action of the excitatory neurotransmitter glutamate are critical components of the mechanisms responsible for memory formation. In particular, the early activation of the NMDA (rNMDA) and AMPA (rAMPA) subtypes of ionotropic glutamate receptors has been demonstrated to be a necessary event for the acquisition of several types of memory. In the rat, consolidation of the long-term memory for a one-trial, step-down inhibitory avoidance task is blocked by antagonists of the rNMDA and rAMPA infused into the CA1 region of the dorsal hippocampus early after training and is associated with a rapid and reversible increase in the total number of [3H]AMPA binding sites. The learning-induced increase in [[3H]AMPA is accompanied by translocation of the GluR1 subunit of the rAMPA to the post-synaptic terminal together with its phosphorylation at Ser831. In addition, learning of the mentioned fear-motivated task induces the activation and rNMDA-dependent translocation of CaMKII to the post-synaptic density. Inhibition of this protein kinase as well as blockade of the rNMDA abolishes both the learning-induced translocation of GluR1 and its phosphorylation. Our data suggest that learning of an avoidance task enhances hippocampal rAMPA signaling through rNMDA and CaMKII-dependent mechanisms.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2004

Pharmacological findings on the biochemical bases of memory processes: a general view.

We have advanced considerably in the past 2 to 3 years in understanding the molecular mechanisms of consolidation, retrieval, and extinction of memories, particularly of fear memory. This advance was mainly due to pharmacological studies in many laboratories using localized brain injections of molecularly specific substances. One area in which significant advances have been made is in understanding that many different brain structures are involved in different memories, and that often several brain regions are involved in processing the same memory. These regions can cooperate or compete with each other, depending on circumstances that are beginning to be identified quite clearly. Another aspect in which major advances were made was retrieval and post-retrieval events, especially extinction, pointing to new therapeutic approaches to fear-motivated mental disorders.

Animals↗

PubMed2003

Memory formation requires p38MAPK activity in the rat hippocampus.

Using the specific inhibitor of p38MAPK, SB203580, we show a direct involvement of this protein kinase in short- and long-term memory. When given into the CA1 region of the rat dorsal hippocampus immediately, but not 30 or 120 min after training in a one-trial inhibitory avoidance task, SB203580 blocked short- and long-term memory formation. The SB203580 inactive analog, SB202474, had no effect whatsoever. Learning of the avoidance task was accompanied by an immediate and transient increase in hippocampal p38MAPK phosphorylation. No change in p38MAPK phosphorylation was detected in control animals that only received the electric foot-shock associated with the learning paradigm. Therefore, formation of short and long-term memory for inhibitory avoidance requires p38MAPK activation in the rat hippocampus.

Animals↗

PubMed2003

Inhibition of mRNA and protein synthesis in the CA1 region of the dorsal hippocampus blocks reinstallment of an extinguished conditioned fear response.

Memories are extinguished by the repeated presentation of a conditioned stimulus in the absence of an unconditioned stimulus to which it has been associated. It is believed that extinction establishes a new hierarchy of responses rather than an actual forgetting of the original response, which can usually reappear spontaneously after interruption of the extinction process. In this study, our aim was to analyze how profound extinction can be. Rats were trained in a one-trial, step-down inhibitory avoidance paradigm and then were exposed to several extinction sessions in which they were allowed to freely explore the apparatus for 30 sec after having stepped down. Extinction was complete enough so that there was no spontaneous recovery, and test session performance could not be enhanced by pharmacological agents with well known facilitative actions on retrieval. After being submitted to a new training session, control animals reacquired the avoidance response; however, animals failed to do so after receiving bilateral intra-CA1 infusions of either the protein synthesis inhibitor anisomycin or the mRNA synthesis blocker 5,6-dichloro-1-beta-d-ribofuranosyl benzimidazole 15 min before the retraining session. Our results indicate that extinction can be carried to a point at which reinstallment of the conditioned response requires, like the original learning, de novo gene expression and protein synthesis in the CA1 region of the dorsal hippocampus.

Animals↗

PubMed2003

Discriminative taste aversion learning: a learning task for older chickens.

The study of learning and memory using the chicken model has relied on three learning paradigms, passive avoidance learning, imprinting and the pebble floor task. Passive avoidance learning and imprinting have been used predominantly in very young chickens and cannot be used to access learning and memory in older chickens. We have established a new behavioural learning paradigm, Discriminative Taste Aversion Learning (DTAL), that can be used with both young and older animals. The task requires chickens to discriminate between food crumbs dyed either red or yellow with one colour being associated with the aversive tasting substance, methylanthranilate. Learning can be tested at various times after the training session by presenting chickens with the coloured food crumbs without an aversive taste. Both chickens tested at 5 and 15 days post-hatch learned to avoid the aversive crumbs. Furthermore, the protein synthesis inhibitor anisomycin (30 mM; 10 microl per hemisphere) injected into the intermediate medial hyperstriatum ventrale 15 min pre-training or 45 min post-training blocked long-term memory for the DTAL task when tested 24 h later. Memory for the task was unaffected by anisomycin injection 120 min post-training or in control animals injected with saline at similar times. The timing of the cellular processes of protein synthesis needed for consolidation of the DTAL appears to be similar to those described for the other behavioural paradigms in young chickens.

Age Factors↗