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Biomedical subjects

Martín Cammarota

Publications and source records attributed to Martín Cammarota.

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

mTOR signaling in the hippocampus is necessary for memory formation.

It is widely accepted that the formation of long-term memory (LTM) requires mRNA translation, but little is known about the cellular mechanisms in the brain that regulate this process. Mammalian target of rapamycin (mTOR) is a key regulator of translational efficacy and capacity. Here, we show that LTM formation of one-trial inhibitory avoidance (IA) in rats, a hippocampus-dependent fear-motivated learning task, requires mTOR activation. IA training is specifically associated with a rapid increase in the phosphorylation state of mTOR and its substrate ribosomal S6 kinase (p70S6K). Bilateral intra-CA1 infusion of rapamycin, a selective mTOR inhibitor, 15 min before, but not immediately after training completely hinders IA LTM without affecting short-term memory (STM) retention. Therefore, our findings indicate that the regulation of hippocampal mRNA translation is a major control step in memory consolidation.

Analysis of Variance↗
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

Angiotensin II disrupts inhibitory avoidance memory retrieval.

The brain renin-angiotensin system (RAS) is involved in learning and memory, but the actual role of angiotensin II (A(II)) and its metabolites in this process has been difficult to comprehend. This has been so mainly due to procedural issues, especially the use of multi-trial learning paradigms and the utilization of pre-training intracerebroventricular infusion of RAS-acting compounds. Here, we specifically analyzed the action of A(II) in aversive memory retrieval using a hippocampal-dependent, one-trial, step-down inhibitory avoidance task (IA) in combination with stereotaxically localized intrahippocampal infusion of drugs. Rats bilaterally implanted with infusion cannulae aimed to the CA1 region of the dorsal hippocampus were trained in IA and tested for memory retention 24 h later. We found that when given into CA1 15 min before IA memory retention test, A(II), but not angiotensin IV or angiotensin(1-7) induced a dose-dependent and reversible amnesia without altering locomotor activity, exploratory behavior or anxiety state. The effect of A(II) was blocked in a dose-dependent manner by the A(II)-type 2 receptor (AT(2)) antagonist PD123319 but not by the A(II)-type 1 receptor (AT(1)) antagonist losartan. By themselves, neither PD123319 nor losartan had any effect on memory expression. Our data indicate that intra-CA1 A(II) hinders retrieval of avoidance memory through a process that involves activation of AT(2) receptors.

Angiotensin II↗
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

Src family tyrosine kinases differentially modulate exocytosis from rat brain nerve terminals.

We have studied the role of src family tyrosine kinases in regulating synaptic transmitter release from rat brain synaptosomes by using two assays that measure different aspects of synaptic vesicle exocytosis: glutamate release (that directly measures exocytosis of vesicle contents) and release of FM 2-10 styryl dye (that is proportional to the time the synaptic vesicle is fused to the plasma membrane). Depolarisation was induced by KCl (30 mM) or 4-aminopyridine (4AP: 0.3mM) to induce release by full fusion (FF) exocytosis, or by 1 mM 4AP to induce release by both FF and kiss-and-run (KR)-like exocytosis. The src family selective inhibitor, PP1 (10 microM), increased KCl and 0.3 mM 4AP-evoked Ca2+ -dependent release of glutamate, but had little effect upon exocytosis evoked by 1mM 4AP. PP1 did not affect the release of FM 2-10 under any of the depolarisation conditions used. PP1 also had no effect on overall intracellular calcium levels, as measured by FURA2, suggesting that the effects of the inhibitor are downstream of calcium entry. At the same concentration the inactive analogue of this compound, PP3, had no effect on any measure. Immunoblotting with an antibody to phosphotyrosine revealed that phosphorylation of many synaptosomal proteins was reduced by PP1. The immunoreactivity of three protein bands increased upon depolarisation and this increase was blocked by PP1. Phosphorylation of src at tyrosine-416 was reduced by PP1 but changes in its phosphorylation did not correlate with the effects of PP1 on release. These results suggest one or more members of the src family of tyrosine kinases is a negative regulator of the KR mode of exocytosis in synaptosomes, perhaps by tonically inhibiting KR under normal stimulation conditions.

4-Aminopyridine↗
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

The entorhinal cortex plays a role in extinction.

In this study, we analyzed the participation of the entorhinal cortex in extinction of a learned aversive response. Rats with infusion cannulae aimed to the entorhinal cortex were trained in a one-trial step-down inhibitory avoidance task (IA) and submitted to four consecutive daily test sessions without the footshock, a procedure that induced extinction of the conditioned response in control animals. When infused into the entorhinal cortex immediately after the first extinction session at doses able to block consolidation of IA memory, the NMDA receptor antagonist, AP5 (25 nmol/side), the inhibitor of protein synthesis anisomycin (300 nmol/side) and the inhibitor of CaMKII, KN-93 (10 nmol/side), but not the MEK1/2 inhibitor PD-98059 (5 nmol/side) hindered extinction of the IA response. The same results were obtained when the interval between the first and second test session was 48 instead of 24h. The data indicate that normal functionality of the NMDA receptors, together with CaMKII activity and protein synthesis are necessary in the entorhinal cortex at the time of the first test session to generate extinction. Our results also suggest that the ERK1/2 pathway does not play a role in this process.

Amygdala↗
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

Activation of adenosine receptors in the posterior cingulate cortex impairs memory retrieval in the rat.

Adenosine A1 and A2A receptor agonists and antagonists have been reported to alter learning and memory. The aim of our study was to investigate the involvement of adenosinergic system in memory retrieval into posterior cingulate cortex (PCC) of Wistar rats. To clarify this question, we tested specifics agonist and antagonists of adenosine A1 and A2A receptors in rats submitted to a one-trial inhibitory avoidance task. The stimulation of adenosine A1 and A2A receptors by CPA and CGS21680, respectively, impaired memory retrieval for inhibitory avoidance task, into PCC. These findings provide behavioral evidence for the role of adenosinergic system in the memory retrieval into PCC.

Adenosine↗
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

The inhibition of acquired fear.

A conditioned stimulus (CS) associated with a fearsome unconditioned stimulus (US) generates learned fear. Acquired fear is at the root of a variety of mental disorders, among which phobias, generalized anxiety, the posttraumatic stress disorder (PTSD) and some forms of depression. The simplest way to inhibit learned fear is to extinguish it, which is usually done by repeatedly presenting the CS alone, so that a new association, CS-"no US", will eventually overcome the previously acquired CS-US association. Extinction was first described by Pavlov as a form of "internal inhibition" and was recommended by Freud and Ferenczi in the 1920s (who called it "habituation") as the treatment of choice for phobic disorders. It is used with success till this day, often in association with anxiolytic drugs. Extinction has since then been applied, also successfully and also often in association with anxiolytics, to the treatment of panic, generalized anxiety disorders and, more recently, PTSD. Extinction of learned fear involves gene expression, protein synthesis, N-methyl-D-aspartate (NMDA) receptors and signaling pathways in the hippocampus and the amygdala at the time of the first CS-no US association. It can be enhanced by increasing the exposure to the "no US" component at the time of behavioral testing, to the point of causing the complete uninstallment of the original fear response. Some theorists have recently proposed that reiteration of the CS alone may induce a reconsolidation of the learned behavior instead of its extinction. Reconsolidation would preserve the original memory from the labilization induced by its retrieval. If true, this would of course be disastrous for the psychotherapy of fear-motivated disorders. Here we show that neither the CS nor retrieval cause anything remotely like reconsolidation, but just extinction. In fact, our findings indicate that the reconsolidation hypothesis is essentially incorrect, at least for the form of contextual fear most commonly studied in rodents. Therefore, it seems safe to continue using extinction-based forms of therapy for disorders secondary to acquired fear. Further, it is useful and desirable to device procedures by which the "no US" component of the extinction is strengthened in order to alleviate the symptoms of victims of acquired fear.

Adrenocorticotropic Hormone↗