ABSTRACT Fully consolidated associative memories can undergo a retrieval-dependent reconsolidatio... more ABSTRACT Fully consolidated associative memories can undergo a retrieval-dependent reconsolidation process, which allows for the updating and strengthening of the original association. Limiting, or so-called boundary, conditions determine whether a particular retrieval event triggers reconsolidation. Manipulating memories at reconsolidation may offer an opportunity to improve cognitive capacities in humans by increasing memory persistence, specificity and accuracy. Also, preventing the reconsolidation of maladaptive memories that characterize some neuropsychiatric disorders, such as post-traumatic stress disorder or drug addiction may offer a novel approach to treatment. Here we review recent advances in understanding and manipulating memory reconsolidation in both animals and humans, and discuss the potential of such interventions in cognitive enhancement.
Disrupting maladaptive memories may provide a novel form of treatment for neuropsychiatric disord... more Disrupting maladaptive memories may provide a novel form of treatment for neuropsychiatric disorders, but little is known about the neurochemical mechanisms underlying the induction of lability, or destabilization, of a retrieved consolidated memory. Destabilization has been theoretically linked to the violation of expectations during memory retrieval, which, in turn, has been suggested to correlate with prediction error (PE). It is well-established that PE correlates with dopaminergic signaling in limbic forebrain structures that are critical for emotional learning. The basolateral amygdala is a key neural substrate for the reconsolidation of pavlovian reward-related memories, but the involvement of dopaminergic mechanisms in inducing lability of amygdala-dependent memories has not been investigated. Therefore, we tested the hypothesis that dopaminergic signaling within the basolateral amygdala is required for the destabilization of appetitive pavlovian memories by investigating the effects dopaminergic and protein synthesis manipulations on appetitive memory reconsolidation in rats. Intra-amygdala administration of either the D1-selective dopamine receptor antagonist SCH23390 or the D2-selective dopamine receptor antagonist raclopride prevented memory destabilization at retrieval, thereby protecting the memory from the effects of an amnestic agent, the protein synthesis inhibitor anisomycin. These data show that dopaminergic transmission within the basolateral amygdala is required for memory labilization during appetitive memory reconsolidation.
Several studies support that stored memories undergo a new period of consolidation after retrieva... more Several studies support that stored memories undergo a new period of consolidation after retrieval. It is not known whether this process, termed reconsolidation, requires the same transcriptional mechanisms involved in consolidation. Increasing evidence supports the participation of the transcription factor NF-kappaB in memory. This was initially demonstrated in the crab Chasmagnathus model of associative contextual memory, in which re-exposure to the training context induces a well characterized reconsolidation process. Here we studied the role of NF-kappaB in reconsolidation. NF-kappaB was specifically activated in trained animals re-exposed to the training context but not to a different context. NF-kappaB was not activated when animals were re-exposed to the context after a weak training protocol insufficient to induce long-term memory. A specific inhibitor of the NF-kappaB pathway, sulfasalazine, impaired reconsolidation when administered 20 min before re-exposure to the training context but was not effective when a different context was used. These findings indicate for the first time that NF-kappaB is activated specifically by retrieval and that this activation is required for memory reconsolidation, supporting the view that this molecular mechanism is required in both consolidation and reconsolidation.
The investigation of impulsivity as a core marker of several major neuropsychiatric disorders has... more The investigation of impulsivity as a core marker of several major neuropsychiatric disorders has been greatly influenced by the therapeutic efficacy of drugs that block the reuptake of dopamine and noradrenaline in the brain. As a result, research into the neural mechanisms of impulsivity has focused on the catecholamine systems as the loci responsible for the expression of impulsive behaviour and the primary mechanism of action of clinically effective drugs for attention-deficit hyperactivity disorder (ADHD). However, abnormalities in the catecholamine systems alone are unlikely to account for the full diversity and complexity of impulsivity subtypes, nor can they fully explain co-morbid brain disorders such as drug addiction. Here we review the lesser-studied role of γ-aminobutyric acid (GABA) in impulsivity, a major target of the dopaminergic and noradrenergic systems in the prefrontal cortex and striatum, and consider how abnormalities in this inhibitory neurotransmitter might contribute to several forms of impulsive behaviour in humans and experimental animals. Our analysis reveals several promising leads for future research that may help inform the development of new therapies for disorders of impulse control.
ABSTRACT Once a fear memory is consolidated, exposure to the fear-associated conditioned stimulus... more ABSTRACT Once a fear memory is consolidated, exposure to the fear-associated conditioned stimulus (CS) can induce either memory reconsolidation or extinction depending on the extent of CS exposure. Even though these two memory processes are triggered by a similar experience, the behavioural outcomes are opposite. After reconsolidation, fear responses to the CS are preserved, whereas after extinction they are greatly reduced or disappear. Given the close relationship between reconsolidation and extinction, it may be hypothesized that they interact within specific brain structures and at the cellular and/or molecular level. In the present study, we have investigated the molecular mechanisms underlying the ‘switch’ between reconsolidation and extinction of fear memory in rats. In the basolateral amygdala (BLA), shortly after reconsolidation or extinction induction protocols, phospho-ERK1/2 levels were significantly increased in the cytoplasmic compartment as compared to the control groups, whereas there were no differences in nuclear levels. Systemic administration of an NMDA-type glutamate receptor antagonist, MK-801, which interferes with both reconsolidation and extinction, prevented the cytoplasmic activation of phospho-ERK1/2. There was a significant increase in cytosolic calcineurin levels only 1 hour after the extinction protocol compared to reconsolidation or control groups, with no differences in nuclear levels. Moreover, we found a negative correlation between the level of cytosolic calcineurin in the BLA and the amount of freezing response after an increasing number of CS-presentations. In summary, ERK1/2 activation during reconsolidation and extinction indicates that some mechanisms recruited during the reconsolidation process, can be reoriented to a mechanism having a behaviourally opposite outcome, the extinction process as a consequence of the repeated presentation of the CS. Conversely, the negative correlation between the amount of cytosolic calcineurin and the level of freezing induced by increasing CS-presentations suggests that this phosphatase plays a central role in the behavioural transition from reconsolidation to extinction, possibly determining the switch from fear-maintenance to fear-inhibition via downstream intracellular processes.
Long-term memory formation depends on protein and mRNA synthesis that subserves synaptic reorgani... more Long-term memory formation depends on protein and mRNA synthesis that subserves synaptic reorganization. The removal of pre-existing inhibitory proteins by the ubiquitin-proteasome system (UPS) is proposed as a crucial step to support these modifications. The activation of the constitutive transcription factor nuclear factor kappaB (NF-kappaB) depends on the degradation of the inhibitor of NF-kappaB (IkappaB) by the UPS. Here we study the effect of a UPS inhibitor, MG132, on long-term memory consolidation and NF-kappaB activation in the learning paradigm of the crab Chasmagnathus, a model in which this transcription factor plays a key role. Here we found that administration of MG132 interferes with long-term memory but not with short-term memory, and no facilitatory effects were found. Then we studied the effect of the UPS inhibitor on NF-kappaB pathway, finding that MG132 blocks the activation of NF-kappaB induced by training. These results suggest that the UPS is necessary for long-term memory consolidation, allowing for the activation of NF-kappaB as one of the target molecular pathways.
Although it is generally accepted that memory consolidation requires regulation of gene expressio... more Although it is generally accepted that memory consolidation requires regulation of gene expression, only a few transcription factors (TFs) have been clearly demonstrated to be specifically involved in this process. Increasing research data point to the participation of the Rel/nuclear factor-κB (NF-κB) family of TFs in memory and neural plasticity. Here we found that two independent inhibitors of NF-κB induced memory impairment in the one-trial step-through inhibitory avoidance paradigm in mice: post-training administration of the drug sulfasalazine and 2 h pretraining administration of a double-stranded DNA oligonucleotide containing the NF-κB consensus sequence (κB decoy). Conversely, one base mutation of the κB decoy (mut-κB decoy) injection did not affect long-term memory. Accordingly, the κB decoy inhibited NF-κB in hippocampus 2 h after injection but no inhibition was found with mut-κB decoy administration. A temporal course of hippocampal NF-κB activity after training was determined. Unexpectedly, an inhibition of NF-κB was found 15 min after training in shocked and unshocked groups when compared with the naïve group. Hippocampal NF-κB was activated 45 min after training in both shocked and unshocked groups, decreasing 1 h after training and returning to basal levels 2 and 4 h after training. On the basis of the latter results, we propose that activation of NF-κB in hippocampus is part of the molecular mechanism involved in the storage of contextual features that constitute the conditioned stimulus representation. The results presented here provide the first evidence to support NF-κB activity being regulated in hippocampus during consolidation, stressing the role of this TF as a conserved molecular mechanism for memory storage.
ABSTRACT Fully consolidated associative memories can undergo a retrieval-dependent reconsolidatio... more ABSTRACT Fully consolidated associative memories can undergo a retrieval-dependent reconsolidation process, which allows for the updating and strengthening of the original association. Limiting, or so-called boundary, conditions determine whether a particular retrieval event triggers reconsolidation. Manipulating memories at reconsolidation may offer an opportunity to improve cognitive capacities in humans by increasing memory persistence, specificity and accuracy. Also, preventing the reconsolidation of maladaptive memories that characterize some neuropsychiatric disorders, such as post-traumatic stress disorder or drug addiction may offer a novel approach to treatment. Here we review recent advances in understanding and manipulating memory reconsolidation in both animals and humans, and discuss the potential of such interventions in cognitive enhancement.
Disrupting maladaptive memories may provide a novel form of treatment for neuropsychiatric disord... more Disrupting maladaptive memories may provide a novel form of treatment for neuropsychiatric disorders, but little is known about the neurochemical mechanisms underlying the induction of lability, or destabilization, of a retrieved consolidated memory. Destabilization has been theoretically linked to the violation of expectations during memory retrieval, which, in turn, has been suggested to correlate with prediction error (PE). It is well-established that PE correlates with dopaminergic signaling in limbic forebrain structures that are critical for emotional learning. The basolateral amygdala is a key neural substrate for the reconsolidation of pavlovian reward-related memories, but the involvement of dopaminergic mechanisms in inducing lability of amygdala-dependent memories has not been investigated. Therefore, we tested the hypothesis that dopaminergic signaling within the basolateral amygdala is required for the destabilization of appetitive pavlovian memories by investigating the effects dopaminergic and protein synthesis manipulations on appetitive memory reconsolidation in rats. Intra-amygdala administration of either the D1-selective dopamine receptor antagonist SCH23390 or the D2-selective dopamine receptor antagonist raclopride prevented memory destabilization at retrieval, thereby protecting the memory from the effects of an amnestic agent, the protein synthesis inhibitor anisomycin. These data show that dopaminergic transmission within the basolateral amygdala is required for memory labilization during appetitive memory reconsolidation.
Several studies support that stored memories undergo a new period of consolidation after retrieva... more Several studies support that stored memories undergo a new period of consolidation after retrieval. It is not known whether this process, termed reconsolidation, requires the same transcriptional mechanisms involved in consolidation. Increasing evidence supports the participation of the transcription factor NF-kappaB in memory. This was initially demonstrated in the crab Chasmagnathus model of associative contextual memory, in which re-exposure to the training context induces a well characterized reconsolidation process. Here we studied the role of NF-kappaB in reconsolidation. NF-kappaB was specifically activated in trained animals re-exposed to the training context but not to a different context. NF-kappaB was not activated when animals were re-exposed to the context after a weak training protocol insufficient to induce long-term memory. A specific inhibitor of the NF-kappaB pathway, sulfasalazine, impaired reconsolidation when administered 20 min before re-exposure to the training context but was not effective when a different context was used. These findings indicate for the first time that NF-kappaB is activated specifically by retrieval and that this activation is required for memory reconsolidation, supporting the view that this molecular mechanism is required in both consolidation and reconsolidation.
The investigation of impulsivity as a core marker of several major neuropsychiatric disorders has... more The investigation of impulsivity as a core marker of several major neuropsychiatric disorders has been greatly influenced by the therapeutic efficacy of drugs that block the reuptake of dopamine and noradrenaline in the brain. As a result, research into the neural mechanisms of impulsivity has focused on the catecholamine systems as the loci responsible for the expression of impulsive behaviour and the primary mechanism of action of clinically effective drugs for attention-deficit hyperactivity disorder (ADHD). However, abnormalities in the catecholamine systems alone are unlikely to account for the full diversity and complexity of impulsivity subtypes, nor can they fully explain co-morbid brain disorders such as drug addiction. Here we review the lesser-studied role of γ-aminobutyric acid (GABA) in impulsivity, a major target of the dopaminergic and noradrenergic systems in the prefrontal cortex and striatum, and consider how abnormalities in this inhibitory neurotransmitter might contribute to several forms of impulsive behaviour in humans and experimental animals. Our analysis reveals several promising leads for future research that may help inform the development of new therapies for disorders of impulse control.
ABSTRACT Once a fear memory is consolidated, exposure to the fear-associated conditioned stimulus... more ABSTRACT Once a fear memory is consolidated, exposure to the fear-associated conditioned stimulus (CS) can induce either memory reconsolidation or extinction depending on the extent of CS exposure. Even though these two memory processes are triggered by a similar experience, the behavioural outcomes are opposite. After reconsolidation, fear responses to the CS are preserved, whereas after extinction they are greatly reduced or disappear. Given the close relationship between reconsolidation and extinction, it may be hypothesized that they interact within specific brain structures and at the cellular and/or molecular level. In the present study, we have investigated the molecular mechanisms underlying the ‘switch’ between reconsolidation and extinction of fear memory in rats. In the basolateral amygdala (BLA), shortly after reconsolidation or extinction induction protocols, phospho-ERK1/2 levels were significantly increased in the cytoplasmic compartment as compared to the control groups, whereas there were no differences in nuclear levels. Systemic administration of an NMDA-type glutamate receptor antagonist, MK-801, which interferes with both reconsolidation and extinction, prevented the cytoplasmic activation of phospho-ERK1/2. There was a significant increase in cytosolic calcineurin levels only 1 hour after the extinction protocol compared to reconsolidation or control groups, with no differences in nuclear levels. Moreover, we found a negative correlation between the level of cytosolic calcineurin in the BLA and the amount of freezing response after an increasing number of CS-presentations. In summary, ERK1/2 activation during reconsolidation and extinction indicates that some mechanisms recruited during the reconsolidation process, can be reoriented to a mechanism having a behaviourally opposite outcome, the extinction process as a consequence of the repeated presentation of the CS. Conversely, the negative correlation between the amount of cytosolic calcineurin and the level of freezing induced by increasing CS-presentations suggests that this phosphatase plays a central role in the behavioural transition from reconsolidation to extinction, possibly determining the switch from fear-maintenance to fear-inhibition via downstream intracellular processes.
Long-term memory formation depends on protein and mRNA synthesis that subserves synaptic reorgani... more Long-term memory formation depends on protein and mRNA synthesis that subserves synaptic reorganization. The removal of pre-existing inhibitory proteins by the ubiquitin-proteasome system (UPS) is proposed as a crucial step to support these modifications. The activation of the constitutive transcription factor nuclear factor kappaB (NF-kappaB) depends on the degradation of the inhibitor of NF-kappaB (IkappaB) by the UPS. Here we study the effect of a UPS inhibitor, MG132, on long-term memory consolidation and NF-kappaB activation in the learning paradigm of the crab Chasmagnathus, a model in which this transcription factor plays a key role. Here we found that administration of MG132 interferes with long-term memory but not with short-term memory, and no facilitatory effects were found. Then we studied the effect of the UPS inhibitor on NF-kappaB pathway, finding that MG132 blocks the activation of NF-kappaB induced by training. These results suggest that the UPS is necessary for long-term memory consolidation, allowing for the activation of NF-kappaB as one of the target molecular pathways.
Although it is generally accepted that memory consolidation requires regulation of gene expressio... more Although it is generally accepted that memory consolidation requires regulation of gene expression, only a few transcription factors (TFs) have been clearly demonstrated to be specifically involved in this process. Increasing research data point to the participation of the Rel/nuclear factor-κB (NF-κB) family of TFs in memory and neural plasticity. Here we found that two independent inhibitors of NF-κB induced memory impairment in the one-trial step-through inhibitory avoidance paradigm in mice: post-training administration of the drug sulfasalazine and 2 h pretraining administration of a double-stranded DNA oligonucleotide containing the NF-κB consensus sequence (κB decoy). Conversely, one base mutation of the κB decoy (mut-κB decoy) injection did not affect long-term memory. Accordingly, the κB decoy inhibited NF-κB in hippocampus 2 h after injection but no inhibition was found with mut-κB decoy administration. A temporal course of hippocampal NF-κB activity after training was determined. Unexpectedly, an inhibition of NF-κB was found 15 min after training in shocked and unshocked groups when compared with the naïve group. Hippocampal NF-κB was activated 45 min after training in both shocked and unshocked groups, decreasing 1 h after training and returning to basal levels 2 and 4 h after training. On the basis of the latter results, we propose that activation of NF-κB in hippocampus is part of the molecular mechanism involved in the storage of contextual features that constitute the conditioned stimulus representation. The results presented here provide the first evidence to support NF-κB activity being regulated in hippocampus during consolidation, stressing the role of this TF as a conserved molecular mechanism for memory storage.
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Papers by Emiliano Merlo