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Eric R Kandel

Publications and source records attributed to Eric R Kandel.

At least 19 recordsLinked to original sources
PubMed2006

Neuronal transcriptome of Aplysia: neuronal compartments and circuitry.

Molecular analyses of Aplysia, a well-established model organism for cellular and systems neural science, have been seriously handicapped by a lack of adequate genomic information. By sequencing cDNA libraries from the central nervous system (CNS), we have identified over 175,000 expressed sequence tags (ESTs), of which 19,814 are unique neuronal gene products and represent 50%-70% of the total Aplysia neuronal transcriptome. We have characterized the transcriptome at three levels: (1) the central nervous system, (2) the elementary components of a simple behavior: the gill-withdrawal reflex-by analyzing sensory, motor, and serotonergic modulatory neurons, and (3) processes of individual neurons. In addition to increasing the amount of available gene sequences of Aplysia by two orders of magnitude, this collection represents the largest database available for any member of the Lophotrochozoa and therefore provides additional insights into evolutionary strategies used by this highly successful diversified lineage, one of the three proposed superclades of bilateral animals.

Animals↗
PubMed2006

Transgenic inhibition of neuronal protein kinase A activity facilitates fear extinction.

Much is known about the neurobiology of memory storage for learned fear. In contrast, the molecular mechanisms underlying extinction of fear memory are just beginning to be delineated. Here, we investigate the role of protein kinase A (PKA) in extinction of memory for contextual fear by using conventional and temporally regulated transgenic approaches that allow us to inhibit PKA activity in neurons within brain regions thought to be involved in extinction. Strikingly, reduction of PKA activity facilitated the development of extinction, without interfering with storage of the original fear memory. Moreover, inhibition of PKA facilitated extinction of both recent and remote contextual fear memories. The finding that PKA, which is required for the acquisition of fear memory, is a constraint for extinction provides the first genetic support for the idea that fear extinction is itself a genuine learning process with its own specific molecular requirements, rather than simply the erasure of a previously learned process. Further, these experiments represent the first genetic evidence that protein kinases may be constraints for the extinction of fear.

Animals↗
PubMed2006

DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability.

The C957T polymorphism in the dopamine D2 receptor (DRD2) gene and the Val158Met polymorphism in the Catechol-O-Methyl-Transferase (COMT) gene affect dopamine transmission and have been found to be associated with schizophrenia. Since DRD2 in mice and the COMT gene in humans modulate working memory, we examined the relationship and possible interaction of both polymorphisms to working memory performance in 188 healthy adults. Subjects having the DRD2 C/C allele showed the poorest performance in a word serial position test. Moreover, the effect of the C957T genotype was strengthened when interaction with the COMT Val158Met polymorphism was included in the analysis. We propose that an interaction of the DRD2 C957T and COMT Val158Met may be involved in the generation of some working memory deficits in schizophrenia.

Adolescent↗
PubMed2006

Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus.

Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.

Animals↗
PubMed2006

Synaptically released zinc gates long-term potentiation in fear conditioning pathways.

The functional role of releasable Zn2+ in the central nervous system remains unknown. Here we show that zinc transporter 3 (ZnT-3), which maintains a high concentration of Zn2+ in synaptic vesicles and serves as a marker for zinc-containing neurons, is enriched in the lateral nucleus of the amygdala and in the temporal area 3 of the auditory cortex, an area that conveys information about the auditory conditioned stimulus to the lateral nucleus of the amygdala, but not in other conditioned stimulus areas located in the auditory thalamus. Using whole-cell recordings from amygdala slices, we demonstrated that activity-dependent release of chelatable Zn2+ is required for the induction of spike timing-dependent long-term potentiation in cortical input to the amygdala implicated in fear learning. Our data indicate that synaptically released Zn2+ enables long-term potentiation at the cortico-amygdala synapses by depressing feed-forward GABAergic inhibition of principal neurons. This regulatory mechanism, implicating pathway-dependent release of Zn2+, may serve an essential control function in assuring spatial specificity of long-lasting synaptic modifications in the neural circuit of a learned behavior.

Animals↗
PubMed2006

Resolving emotional conflict: a role for the rostral anterior cingulate cortex in modulating activity in the amygdala.

Effective mental functioning requires that cognition be protected from emotional conflict due to interference by task-irrelevant emotionally salient stimuli. The neural mechanisms by which the brain detects and resolves emotional conflict are still largely unknown, however. Drawing on the classic Stroop conflict task, we developed a protocol that allowed us to dissociate the generation and monitoring of emotional conflict from its resolution. Using functional magnetic resonance imaging (fMRI), we find that activity in the amygdala and dorsomedial and dorsolateral prefrontal cortices reflects the amount of emotional conflict. By contrast, the resolution of emotional conflict is associated with activation of the rostral anterior cingulate cortex. Activation of the rostral cingulate is predicted by the amount of previous-trial conflict-related neural activity and is accompanied by a simultaneous and correlated reduction of amygdalar activity. These data suggest that emotional conflict is resolved through top-down inhibition of amygdalar activity by the rostral cingulate cortex.

Adult↗
PubMed2006

PKA-activated ApAF-ApC/EBP heterodimer is a key downstream effector of ApCREB and is necessary and sufficient for the consolidation of long-term facilitation.

Long-term memory requires transcriptional regulation by a combination of positive and negative transcription factors. Aplysia activating factor (ApAF) is known to be a positive transcription factor that forms heterodimers with ApC/EBP and ApCREB2. How these heterodimers are regulated and how they participate in the consolidation of long-term facilitation (LTF) has not, however, been characterized. We found that the functional activation of ApAF required phosphorylation of ApAF by PKA on Ser-266. In addition, ApAF lowered the threshold of LTF by forming a heterodimer with ApCREB2. Moreover, once activated by PKA, the ApAF-ApC/EBP heterodimer transactivates enhancer response element-containing genes and can induce LTF in the absence of CRE- and CREB-mediated gene expression. Collectively, these results suggest that PKA-activated ApAF-ApC/EBP heterodimer is a core downstream effector of ApCREB in the consolidation of LTF.

Animals↗
PubMed2006

Dishabituation in Aplysia can involve either reversal of habituation or superimposed sensitization.

Dishabituation has been thought to be due either to reversal of the process of habituation or to a second process equivalent to sensitization superimposed on habituation. One way to address this question is by testing whether dishabituation and sensitization can be dissociated. Previous studies using this approach in Aplysia have come to different conclusions about the nature of dishabituation, perhaps because those studies differed in many respects, including (1) whether they also observed transient behavioral inhibition, and (2) whether they used test stimuli that activated the LE siphon sensory neurons or as yet unidentified sensory neurons. To attempt to resolve the apparent contradictions between the previous studies, we have explored the importance of these two factors by performing a parametric study of dishabituation and sensitization of gill withdrawal in a simplified preparation that does not exhibit transient behavioral inhibition, using two different test stimuli that are known to activate the LE (Touch) or unidentified (Not Touch) sensory neurons. We find that dishabituation and sensitization in this preparation have similar time courses and generally similar functions of shock intensity. However, under one condition, with the Not Touch stimulus 2.5 min after the shock, dishabituation has a reverse effect of shock intensity. Additional analyses suggest that dishabituation with the Not Touch stimulus 2.5 min after the shock is due to reversal of habituation, whereas 12.5 min after the shock, dishabituation is due to superimposed sensitization. These results thus suggest that dishabituation may involve either process in the same preparation, and begin to define the conditions that favor one or the other.

Animals↗
PubMed2006

mGluR2 acts through inhibitory Galpha subunits to regulate transmission and long-term plasticity at hippocampal mossy fiber-CA3 synapses.

Presynaptic inhibitory G protein-coupled receptors play a critical role in regulating transmission at a number of synapses in the central and peripheral nervous system. We generated transgenic mice that express a constitutively active form of an inhibitory Galpha subunit to examine the molecular mechanisms underlying the actions of one such receptor, metabotropic glutamate receptor (mGluR) 2, at mossy fiber-CA3 synapses in the hippocampus. mGluR2 participates in at least three types of mossy fiber synaptic plasticity, (i) transient suppression of synaptic transmission, (ii) long-term depression (LTD), and (iii) inhibition of long-term potentiation (LTP), and we find that inhibitory Galpha signaling is sufficient to account for the actions of mGluR2 in each. The fact that constitutively active Galphai2 occludes the transient suppression of synaptic transmission by mGluR2, while enhancing LTD, suggests further that these two forms of plasticity are expressed via different mechanisms. In addition, the LTP deficit observed in constitutively active Galphai2-expressing mice suggests that mGluR2 activation may serve as a metaplastic switch to permit the induction of LTD by inhibiting LTP.

Adenylyl Cyclase Inhibitors↗
PubMed2006

A role in learning for SRF: deletion in the adult forebrain disrupts LTD and the formation of an immediate memory of a novel context.

Whereas significant insight exists as to how LTP-related changes can contribute to the formation of long-term memory, little is known about the role of hippocampal LTD-like changes in learning and memory storage. We describe a mouse lacking the transcription factor SRF in the adult forebrain. This mouse could not acquire a hippocampus-based immediate memory for a novel context even across a few minute timespan, which led to a profound but selective deficit in explicit spatial memory. These animals were also impaired in the induction of LTD, including LTD triggered by a cholinergic agonist. Moreover, genes regulating two processes essential for LTD-calcium release from intracellular stores and phosphatase activation-were abnormally expressed in knockouts. These findings suggest that for the hippocampus to form associative spatial memories through LTP-like processes, it must first undergo learning of the context per se through exploration and the learning of familiarity, which requires LTD-like processes.

Animals↗
PubMed2006

Impaired bidirectional synaptic plasticity and procedural memory formation in striatum-specific cAMP response element-binding protein-deficient mice.

The striatum has a well documented role in procedural learning and memory. However, the synaptic and molecular mechanisms of acquisition and storage of this form of memory remain poorly understood. We examined procedural memory and plasticity in transgenic mice reversibly expressing a dominant-negative cAMP response element-binding protein (CREB) mutant in the dorsal striatum. In these transgenic mice, corticostriatal long-term potentiation and depression are abolished, indicating that CREB function is essential for bidirectional long-term synaptic plasticity in this structure. Importantly, CREB-deficient animals show reversible alterations in several forms of striatum-dependent memory, including footshock avoidance learning and "response" learning in the cross maze. These findings implicate transcriptional regulation by CREB family transcription factors in striatum-dependent information processing and provide the first clear correlation between procedural learning and memory and synaptic plasticity at the corticostriatal synapse.

Animals↗
PubMed2006

Operant conditioning of gill withdrawal in Aplysia.

A basic question in neuroscience is how different forms of learning are related. To further address that question, we examined whether gill withdrawal in Aplysia, which has already been studied extensively for neuronal mechanisms contributing to habituation, sensitization, and classical conditioning, also undergoes operant conditioning. Animals were run in pairs. During the initial training period, the contingent (experimental) animal received a siphon shock each time its gill relaxed below a criterion level, and the yoked control animal received a shock whenever the experimental animal did, regardless of its own gill position. This was followed by an extinction period when there was no shock, a retraining period when both animals were contingent, and another extinction period. The experimental animals spent more time with their gills contracted above the criterion level than did the control animals during each period, demonstrating operant conditioning. The type of gill behavior modified by learning shifted over time: the experimental animals had a larger increase in the frequency and duration of spontaneous contractions than did the control animals during the first but not the last extinction period and a larger increase in the level of tonic contraction during the last but not the first extinction period. Because many of the neurons controlling spontaneous and tonic gill withdrawal have already been identified, it should now be possible to examine the cellular locus and mechanism of operant conditioning and compare them with those for other forms of learning of the same behavior.

Animals↗
PubMed2006

Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning.

Increased activity of D2 receptors (D2Rs) in the striatum has been linked to the pathophysiology of schizophrenia. To determine directly the behavioral and physiological consequences of increased D2R function in the striatum, we generated mice with reversibly increased levels of D2Rs restricted to the striatum. D2 transgenic mice exhibit selective cognitive impairments in working memory tasks and behavioral flexibility without more general cognitive deficits. The deficit in the working memory task persists even after the transgene has been switched off, indicating that it results not from continued overexpression of D2Rs but from excess expression during development. To determine the effects that may mediate the observed cognitive deficits, we analyzed the prefrontal cortex, the brain structure mainly associated with working memory. We found that D2R overexpression in the striatum impacts dopamine levels, rates of dopamine turnover, and activation of D1 receptors in the prefrontal cortex, measures that are critical for working memory.

Adenylyl Cyclases↗
PubMed2006

Capture of the late phase of long-term potentiation within and across the apical and basilar dendritic compartments of CA1 pyramidal neurons: synaptic tagging is compartment restricted.

Studies in the rodent hippocampus have demonstrated that when the late phase of long-term potentiation (L-LTP) is induced in a set of synapses by suprathreshold stimulation, L-LTP can also be expressed by other synapses receiving subthreshold stimulation, a phenomenon usually referred as "capture of L-LTP." Because the pyramidal neurons in the mammalian hippocampus have both apical and basal dendrites, we have now investigated whether capture of L-LTP, previously described only within the apical dendritic compartment, can also take place within the basilar dendritic compartment and, if so, whether capture can be accomplished from one dendritic compartment to the other. We found that capture of L-LTP can also occur within the basilar dendritic compartment and that the tagging signal that enables capture appears to be the same in both dendritic compartments. However, capture across compartments, between the apical and basilar dendrites, follows different rules and requires a stronger triggering stimulation than capture within a compartment. These results suggest that the tag appears specific to a compartment either apical or basilar and that an additional mechanism may be required to capture across compartments.

Animals↗
PubMed2006

Common molecular mechanisms in explicit and implicit memory.

Cellular and molecular studies of both implicit and explicit memory suggest that experience-dependent modulation of synaptic strength and structure is a fundamental mechanism by which these memories are encoded and stored within the brain. In this review, we focus on recent advances in our understanding of two types of memory storage: (i) sensitization in Aplysia, a simple form of implicit memory, and (ii) formation of explicit spatial memories in the mouse hippocampus. These two processes share common molecular mechanisms that have been highly conserved through evolution.

Animals↗
PubMed2006

Molecular mechanisms of memory storage in Aplysia.

Cellular studies of implicit and explicit memory suggest that experience-dependent modulation of synaptic strength and structure is a fundamental mechanism by which these memories are encoded, processed, and stored within the brain. In this review, we focus on recent advances in our understanding of the molecular mechanisms that underlie short-term, intermediate-term, and long-term forms of implicit memory in the marine invertebrate Aplysia californica, and consider how the conservation of common elements in each form may contribute to the different temporal phases of memory storage.

Animals↗
PubMed2005

CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum.

Remodeling chromatin is essential for cAMP-regulated gene expression, necessary not only for development but also for memory storage and other enduring mental states. Histone acetylation and deacetylation mediate long-lasting forms of synaptic plasticity in Aplysia as well as cognition in mice. Here, we show that histone acetylation by the cAMP-response element binding protein (CREB)-binding protein (CBP) mediates sensitivity to cocaine by regulating expression of the fosB gene and its splice variant, DeltafosB, a transcription factor previously implicated in addiction. Using the chromatin immunoprecipitation assay with antibodies against histone H4 or CBP, we find that CBP is recruited to the fosB promoter to acetylate histone H4 in response to acute exposure to cocaine. We show that mutant mice that lack one allele of the CBP gene and have normal levels of fosB expression are less sensitive to chronic (10-day) administration of cocaine than are wild-type mice. This decreased sensitivity is correlated with decreased histone acetylation and results in decreased fosB expression and diminished accumulation of DeltafosB. Thus, CBP, which forms part of the promoter complex with CREB, mediates sensitivity to cocaine by acetylating histones.

Acetylation↗