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Karim Nader

Publications and source records attributed to Karim Nader.

10 recordsLinked to original sources
PubMed2005

Consolidation and reconsolidation of incentive learning in the amygdala.

Incentive learning is the process via which animals update changes in the value of rewards. Current evidence suggests that, for food rewards in rats, this learning process involves the amygdala. However, it remains unclear whether this learning undergoes protein synthesis-dependent consolidation and "reconsolidation" processes in the lateral and basal nuclei of amygdala. Accordingly, we examined this hypothesis by local infusion of protein-synthesis inhibitor after devaluation of a food reward induced by a shift from a food-deprived to a food-sated state in an instrumental conditioning paradigm. Our results show that intra-amygdala infusions of anisomycin, whether given after the initial devaluation or after a second devaluation session, abolished the changes in the value of the food reward produced by incentive learning. This study provides direct evidence that instrumental incentive learning depends on protein synthesis within the amygdala for both consolidation and reconsolidation and extends the demonstrations of protein synthesis-dependent reconsolidation to reward-related memories.

Amygdala↗
PubMed2005

Activation of extracellular signal-regulated kinase- mitogen-activated protein kinase cascade in the amygdala is required for memory reconsolidation of auditory fear conditioning.

Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of amygdala (LA). Recently we have demonstrated that consolidated fear memories, when reactivated, return to a labile state which is sensitive to disruption by the protein synthesis inhibitor anisomycin. The specific molecular mechanisms that underlie this reconsolidation of fear memories are still largely unknown. The activation of extracellular signal-regulated kinase-mitogen-activated protein kinase (ERK-MAPK) pathway in the LA is required for the consolidation of auditory fear memories. In the present study, we examined the role of ERK-MAPK cascade in the LA during reconsolidation of auditory fear conditioning. We show that intra-LA infusions of the MAPK kinase (MEK) inhibitor U0126, a manipulation which inhibits activation of ERK-MAPK, impairs postreactivation long-term memory (PR-LTM) but leaves the postreactivation short-term memory (PR-STM) intact. The same treatment with U0126, in the absence of memory reactivation, has no effect. Furthermore, we verified that reconsolidation requires translation using a second protein synthesis inhibitor, cycloheximide. Post-reactivation infusions of cycloheximide blocked PR-LTM but not PR-STM and, in the absence of reactivation, had no effect. Our data show that activation of ERK-MAPK signalling pathway and protein synthesis in the LA are required for reconsolidation of auditory fear memories.

Acoustic Stimulation↗
PubMed2004

Characterization of fear memory reconsolidation.

Reactivation of consolidated memories returns them to a protein synthesis-dependent state. One interpretation of these findings is that the memory reconsolidates after use. Two alternative interpretations are that protein synthesis inhibition facilitates extinction and that postreactivation protein synthesis inhibition leads to an inability to retrieve the consolidated memory. First, using two different approaches, we report that reconsolidation cannot be reduced down to facilitated extinction. We show that the reconsolidation deficit does not show renewal after a contextual shift, whereas an extinguished auditory fear memory does under the same conditions and the deficit occurs regardless of whether the memory is reactivated with an extinction [conditioned stimulus (CS) alone] or a reinforced trial (CS-unconditioned stimulus). To address the issue of whether postreactivation anisomycin leads to an inability to retrieve the consolidated memory, we used two traditional assays for retrieval deficits. First, we demonstrate that the amnesia induced by blockade of reconsolidation does not show any spontaneous recovery. Second, we show that application of reminder shock does not result in the reinstatement of the memory. These findings support the idea that reactivation of consolidated memories initiates a second time-dependent memory formation process.

Amygdala↗
PubMed2003

Functional organization of adult motor cortex is dependent upon continued protein synthesis.

The functional organization of adult cerebral cortex is characterized by the presence of highly ordered sensory and motor maps. Despite their archetypical organization, the maps maintain the capacity to rapidly reorganize, suggesting that the neural circuitry underlying cortical representations is inherently plastic. Here we show that the circuitry supporting motor maps is dependent upon continued protein synthesis. Injections of two different protein synthesis inhibitors into adult rat forelimb motor cortex caused an immediate and enduring loss of movement representations. The disappearance of the motor map was accompanied by a significant reduction in synapse number, synapse size, and cortical field potentials and caused skilled forelimb movement impairments. Further, motor skill training led to a reappearance of movement representations. We propose that the circuitry of adult motor cortex is perpetually labile and requires continued protein synthesis in order to maintain its functional organization.

Age Factors↗
PubMed2003

NMDA receptor blockade in intact adult cortex increases trafficking of NR2A subunits into spines, postsynaptic densities, and axon terminals.

Past in vitro studies have used immunofluorescence to show increased clustering of the NR1 subunits of NMDA receptors (NMDAR) following NMDAR blockade, indicating that NMDARs self-regulate trafficking to and from spines. However, since a substantial portion of spinous NMDAR subunits can reside at sites removed from plasma membranes, whether or not these immunofluorescent clusters are synaptic remains to be shown. Also, the NR2A/B subunits undergo activity-dependent switching at synapses, indicating that their subcellular distribution may be regulated differently from the NR1 subunits. We examined the issue of NMDAR autoregulation by determining whether in vivo NMDAR blockade enhances trafficking of the NR2A subunits toward spines and more specifically to postsynaptic densities (PSDs) of already mature synapses. Seven adult rats received unilateral intra-cortical infusion of the NMDAR antagonist, D-AP5 for 1/2-2 h and the inactive enantiomer or the solvent, alone, in the contralateral cortex. Using an electron microscope, approximately 5600 cortical spines originating from the two hemispheres of the seven adult animals were analyzed for the location of NR2A subunits. In six out of the seven cases analyzed, the D-AP5-treated neuropil exhibited increased immunolabeling at PSDs and a concomitantly great increase at non-synaptic sites within spines. NR2A subunits also increased presynaptically within 1/2 h but not after 1 h. These findings indicate that NR2A subunits in intact, adult cortical neurons are prompted to become trafficked into spines and axon terminals by NMDAR inactivity, yielding an increase of a readily available reserve pool and greater localization at both sides of synapses.

2-Amino-5-phosphonovalerate↗
PubMed2003

Memory traces unbound.

The idea that new memories are initially 'labile' and sensitive to disruption before becoming permanently stored in the wiring of the brain has been dogma for >100 years. Recently, we have revisited the hypothesis that reactivation of a consolidated memory can return it to a labile, sensitive state - in which it can be modified, strengthened, changed or even erased! The data generated from some of the best-described paradigms in memory research, in conjunction with powerful neurobiological technologies, have provided striking support for a very dynamic neurobiological basis of memory, which is beginning to overturn the old dogma.

Animals↗
PubMed2002

Cellular and systems reconsolidation in the hippocampus.

Cellular theories of memory consolidation posit that new memories require new protein synthesis in order to be stored. Systems consolidation theories posit that the hippocampus has a time-limited role in memory storage, after which the memory is independent of the hippocampus. Here, we show that intra-hippocampal infusions of the protein synthesis inhibitor anisomycin caused amnesia for a consolidated hippocampal-dependent contextual fear memory, but only if the memory was reactivated prior to infusion. The effect occurred even if reactivation was delayed for 45 days after training, a time when contextual memory is independent of the hippocampus. Indeed, reactivation of a hippocampus-independent memory caused the trace to again become hippocampus dependent, but only for 2 days rather than for weeks. Thus, hippocampal memories can undergo reconsolidation at both the cellular and systems levels.

Amnesia, Retrograde↗
PubMed2002

Motivational state determines the functional role of the mesolimbic dopamine system in the mediation of opiate reward processes.

We have previously reported that mesolimbic dopamine (DA) substrates are critically involved in the rewarding effects of opiates only during states of opiate-dependence and withdrawal. However, in previously drug-naive animals, opiate reward is mediated through a DA-independent neural system. In the present study, we report that bilateral microinjections of a DA receptor antagonist, alpha-flupenthixol (0.3-3 microg/0.5 microl) into the nucleus accumbens (NAc), blocks morphine reward (10 mg/kg, i.p.) in opiate-withdrawn animals, but not in opiate-naive animals, suggesting that accumbal dopamine receptors are required for opiate reward signaling in drug-deprived motivational states. Next, the role of dopamine was examined in the development of opiate dependence and somatic withdrawal, and expression of withdrawal aversions. Pretreatment with alpha-flupenthixol (0.8 mg/kg, i.p.) before morphine injections during the development of opiate dependence did not effect expression of withdrawal aversions or the expression of somatic withdrawal. We have previously reported that pretreatment with a dopamine receptor antagonist, alpha-flupenthixol, blocks the aversive effects of opiate withdrawal. We now report that pretreatment with a direct dopamine receptor agonist, apomorphine (1.0-5.0 mg/kg, i.p.) before conditioning in a state of withdrawal, also blocks the aversive effects of opiate withdrawal. We propose that the aversive motivational effects of opiate withdrawal may be mediated by a specific dopaminergic neuronal signal.

Animals↗
PubMed2002

A-kinase anchoring proteins in amygdala are involved in auditory fear memory.

A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that bind the regulatory subunits of protein kinase A (PKA). AKAP binding to PKA regulates the phosphorylation of various proteins, some of which have been implicated in synaptic plasticity and memory consolidation. Here we show that the regulatory subunits of PKA are colocalized with AKAP150 (an AKAP isoform that is expressed in the brain) in the lateral amygdala (LA) and that infusion to the LA of the peptide St-Ht31, which blocks PKA anchoring onto AKAPs, impairs memory consolidation of auditory fear conditioning.

A Kinase Anchor Proteins↗