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ABSTRACT: Although much has been learned regarding the molecular and cellular mechanisms of memory reconsolidation, its actual biological function remains unclear. In this work we investigate the possibility that three different mnemonic processes - updating, precision-keeping and trace strengthening - are mediated by reconsolidation in contextual fear conditioning. Reconsolidation involves the activation of calcium channels for the destabilization during the reactivation. Our results show that when memory is reactivated in a situation that does not match the original information, content is modified, i.e., "updated". However, when the contextual condition matches the original one, memory reactivation contributes either to its strengthening or to the maintenance of its precision content over time. Since the LVGCC antagonist nimodipine blocked these effects, we suggest that reconsolidation is the mechanism supporting these processes.
Neuroscience 04/2013; · 3.38 Impact Factor
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ABSTRACT: Despite the fact that TRPV1 receptors are widely expressed in brain structures such as the hippocampus, its functions remain largely unknown. In the present study, we have investigated the possible modulatory role of the hippocampal endovanilloid system upon memory consolidation of two different behavioral tasks in rats. Post-training infusion of the TRPV1 antagonist capsazepine disrupted memory consolidation with a strong training protocol, but not with a weak one in the contextual fear conditioning or in the step-down inhibitory avoidance task. These results provide evidence that the modulation of the hippocampal memory consolidation through TRPV1 receptors takes place only in presence of a strong emotional experience, suggesting that a certain aversiveness level is required in order to recruit endovanilloids to exert this function. A possible synergic role of hippocampal endovanilloid and endocannabinoid system on memory consolidation is discussed.
Neurobiology of Learning and Memory 01/2012; 97(4):355-60. · 3.42 Impact Factor
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ABSTRACT: Hippocampus is hypothesized to play a temporary role in the retrieval of context memories. Similarly, previous studies have reported that the expression of context memories becomes more generalized as memory ages. We report, first, that contextual fear memory expression changes from being sensitive to dorsal hippocampus inactivation by muscimol at 2 days post-conditioning, to insensitive at 28 days, and second, that over the same period rats lose their ability to discriminate between a novel and conditioned context. Furthermore, we show that repeated brief memory reactivation sessions prevent memory from becoming both hippocampus-independent and generalized.
Hippocampus 11/2011; 22(5):1092-5. · 5.18 Impact Factor
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ABSTRACT: The modulation of memory processes is one of the several functions of the endocannabinoid system (ECS) in the brain, with CB1 receptors highly expressed in areas such as the dorsal hippocampus. Experimental evidence suggested an important role of the ECS in aversively motivated memories. Similarly, glucocorticoids released in response to stress exposure also modulates memory formation, and both stress and dexamethasone activate the ECS. Here, we investigate the interaction between the ECS and glucocorticoids in the hippocampus in the modulation of fear memory consolidation. Two protocols with different shock intensities were used in order to control the level of aversiveness. Local infusion of AM251 into the hippocampus immediately after training was amnestic in the strong, but not in the weak protocol. Moreover, AM251 was amnestic in animals stressed 0, but not 30-min prior to the weak protocol, reverting the stress-induced facilitatory effect. Finally, intrahippocampal AM251 infusion reduced memory in animals that received dexamethasone immediately, but not 30 min before training. These results are (1) consistent with the view that the dorsal hippocampus ECS is activated on demand, in a rapid and short-lived fashion in order to modulate the consolidation of an aversive memory, and (2) show that this recruitment seems to be mediated by glucocorticoids, either in the hippocampus or in other brain regions functionally associated with the hippocampus.
Learning & memory (Cold Spring Harbor, N.Y.) 01/2010; 17(4):202-9. · 4.08 Impact Factor
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ABSTRACT: Memory reconsolidation has been demonstrated in various tasks and species, suggesting it is a fundamental process. However, there are experimental parameters that can inhibit reconsolidation from occurring (boundary conditions). These conditions and their mechanisms remain poorly defined. Here, we characterize the ability of strong training to inhibit reconsolidation at the behavioral, systems and molecular levels. We demonstrate that strong memories in rats initially are resistant to reconsolidation, but after sufficient time will undergo reconsolidation, suggesting that boundary conditions can be transient. At the systems level, we show that the hippocampus is necessary for inhibiting reconsolidation in the amygdala. At the molecular level, we demonstrate that NR2B NMDA-receptor subunits which are critical for the induction of reconsolidation of auditory memories in the amygdala, are downregulated only under conditions when strong memories do not undergo reconsolidation. This suggests that one molecular mechanism for mediating boundary conditions is through downregulation of reconsolidation induction mechanisms.
Nature Neuroscience 08/2009; 12(7):905-12. · 15.53 Impact Factor
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ABSTRACT: CB1 cannabinoid receptors are abundantly expressed in the brain, with large concentrations present in the hippocampus, a brain structure essential for memory processing. In the present study, we have investigated the possible modulatory role of the endocannabinoid system in the dorsal hippocampus upon the different phases of memory processing of an aversive task. AM251, a selective antagonist of CB1 receptors, and anandamide, an endogenous agonist of cannabinoid receptors, were bilaterally infused into the dorsal hippocampus of male Wistar rats either before training, immediately after training, or before test in the step-down inhibitory avoidance (IA) task. Results showed that pre-training infusion of CB1 drugs did not influence the acquisition of the task. In contrast, post-training infusion of the CB1 antagonist disrupted while the antagonist facilitated memory consolidation of IA. The post-training results demonstrate that memory consolidation depends on the integrity of the endocannabinoid system in the CA1 region of the dorsal hippocampus. While we still have no direct proof of endocannabinoids released there after an aversive task such as IA, these results suggests that (a) AM251 acts blocking the binding of endogenously released cannabinoids and (b) exogenously supplemented anandamide may be adding its contribution to the action of the endogenously released pool. Considering our data and the higher density of CB1 receptors present in the GABAergic interneurons, we propose them as the putative target of the endocannabinoid modulation of memory, a hypothesis that needs to be proven. In addition, pre-test infusion of the CB1 receptor antagonist facilitated while infusion of the agonist did not affect memory retrieval of IA. The completely opposite action of the same drug upon memory at the post-training (consolidation) and pre-test (recall) contexts suggests that some durable change took place in the CA1 region during the consolidation process that modified the logical attributes of the pharmacological response, i.e., the drug response changed from memory disruption to memory facilitation. A similar phenomenon was previously described by us in the M4 cholinergic muscarinic subsystem in the hippocampus for the same task (Diehl, F., Fürstenau, L. O., Sanchez, G., Camboim, C., de Oliveira Alvares, L., Lanziotti, V. B., et al. (2007). Facilitatory effect of the intra-hippocampal pretest administration of MT3 in the inhibitory avoidance task. Behavioral Brain Research, 177(2), 227-231), but the biological nature of such change in the local neural circuitry remains to be investigated.
Neurobiology of Learning and Memory 08/2008; 90(1):1-9. · 3.42 Impact Factor
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ABSTRACT: The cholinergic system plays a crucial role in learning and memory. Modulatory mechanisms of this system in the acquisition and consolidation processes have been extensively studied, but their participation in the memory retrieval process is still poorly understood. Conventional pharmacological agents are not highly selective for particular muscarinic acetylcholine receptor subtypes. Muscarinic toxins (MTs) that are highly selective for muscarinic receptors were extracted from the venom of the mamba snake, like the toxin MT3, selective for the M4 receptor subtype. These toxins are useful tools in studies of the specific functions of the M4 mediated transmission. The M4 receptor selective antagonist MT3, given into the dorsal hippocampus before the test, have enhanced the memory retrieval of an inhibitory avoidance task in rats. MT3 had no effect in the habituation to a new environment, including basic motor parameters, meaning that the effect in he inhibitory avoidance is purely cognitive. Our results suggest an endogenous negative modulation of the cholinergic muscarinic system upon the retrieval of previously consolidated aversive memories, hereby shown by the facilitatory effect of MT3.
Behavioural Brain Research 03/2007; 177(2):227-31. · 3.42 Impact Factor
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ABSTRACT: Long-term potentiation (LTP) has a long history as putative mechanism of memory formation, specially in the hippocampus, a structure essential for memory formation. Endocannabinoids are one of the endogenous systems that modulate this plasticity event: the activation of hippocampal CB1 receptors may inhibit local GABA release. Here, we have studied both (1) the role of the selective CB1 antagonist AM251 upon LTP induction in a hippocampal slice preparation, and (2) the effect of its intrahippocampal administration in the step-down inhibitory avoidance (IA) and the open field habituation tasks (OF). Standard extracellular electrophysiology techniques were used to record field excitatory postsynaptic potentials from the dendritic region of CA1 neurons in response to a high frequency stimulation of Schaffer's collaterals; a micropipette ejected 0.2 microM of AM251 (in DMSO/PBS) 2 min before the stimulus: LTP was induced and lasted more than 30 min in the control, but not in the AM251-treated group. Immediately after training, either in IA (footshock, 0.5 mA) or OF, animals received a bilateral infusion of 0.55 or 5.5 ng/side of AM251 or its vehicle in the CA1 region, and test was performed 24 h later. AM251 has caused a significative decrease in the test step-down latency when compared to the control group, but no differences were detected in the OF task, including the number of crossings, i.e., there were no motor effects. The LTP supression could be caused by AM251 acting over GABAergic interneurons that modulate the LTP-bearing glutamatergic neurons. Endocanabinoids would then be the natural dis-inhibitors of local plasticity in the dorsal hippocampus, and the amnestic action of AM251 would be due to a disruption of this endogenous modulatory system.
Brain Research 03/2006; 1075(1):60-7. · 2.73 Impact Factor
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ABSTRACT: CB1 is the most abundant metabotropic receptor of the brain, being found in areas classically involved in learning and memory and present at higher density at presynaptic terminals. Different sets of evidence support the idea that endogenous ligands (endocannabinoids) to the CB1 receptors act as modulators of neurotransmission. In hippocampus, endocannabinoids seem to act as retrograde messengers mediating down-regulation of GABA release. Previous reports have described a cognitive impairment effect of cannabinoid agonists, or facilitation by antagonists. The scope of the present study is to investigate the effect of intrahippocampal administration of the CB1-selective antagonist, AM251, in two behavioral tasks. One hundred and twelve male Wistar rats with bilateral cannulae implanted in the CA1 region of the dorsal hippocampus were trained in a step-down inhibitory avoidance task (IA, footshock, 0.5 mA) or an open field habituation task (OF). Immediately, after training, animals received an infusion of 0.55, 5.5, and 55.5 ng/side of AM251 (Tocris), or its vehicle (DMSO/saline), via these cannulae. Our results show that AM251 disrupted memory consolidation of the IA task, but not the OF task, an effect that seems to be purely mnemonic since the drug showed no motor performance effects. Only the intermediate dose (5.5 ng/side) of AM251 was effective in IA and the absence of effect with the larger dose may be the consequence of non-specific binding. The fact that OF was not affected raises the possibility that this endogenous system requires some degree of aversiveness to be recruited. We propose that increased levels of endogenous cannabinoids in the hippocampus, following a training session, contribute to facilitate memory consolidation, a process that may have been disrupted with AM251.
Neurobiology of Learning and Memory 04/2005; 83(2):119-24. · 3.42 Impact Factor
