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Edi Barkai

Publications and source records attributed to Edi Barkai.

15 recordsLinked to original sources
PubMed2026

Biophysical mechanisms underlying the generation and maintenance of rule-learning engram.

Training rodents in a particularly difficult olfactory-discrimination task results with acquisition of high-skill to perform the task superbly, termed 'rule-learning'. We show that rule-learning occurs abruptly, in a "light-bulb moment". Using whole-cell patch-clamp recordings from the piriform cortex (PC) of Fos2A-iCreER/TRAP2 mice, we target activated-neurons, expressing immediate early genes (IEG). We notice, from the onset of training, IEG-positive neurons from trained animals display enhanced intrinsic excitability. Subsequently, synaptic excitation and inhibition are enhanced in these neurons, in a coordinated, cell-wide process. Additionally, in parallel, we detect the density of IEG-expressing neurons sharply declines. Double labeling with TRAP and c-Fos reveal that nearly two-thirds of the rule-memory cell ensemble neurons are activated from the beginning of training. Silencing TRAP-expressing neurons using inhibitory DREADD leads to a complete loss of rule memory. Hence, we propose that rule learning occurs at a discrete moment and is developed through a gradual process that stabilizes the memory of the rule.

Animals↗
PubMed2006

Learning in the absence of experience-dependent regulation of NMDAR composition.

Olfactory discrimination (OD) learning consists of two phases: an initial N-methyl-D-aspartate (NMDA) receptor-sensitive rule-learning phase, followed by an NMDA receptor (NMDAR)-insensitive pair-learning phase. The rule-learning phase is accompanied by changes in the composition and function of NMDARs at synapses in the piriform cortex, resulting in a high level of the NR2a subunit relative to NR2b. Here we show that the learning-induced changes in NMDAR composition in the adult piriform cortex are due to a decrease in the level of the NR2b subunit protein, rather than an increase in the level of NR2a. Chronic administration of an NMDAR open channel blocker during training delays OD learning and blocks learning-induced changes in NMDAR subunit composition. However, the animals still learn the OD task. Our data demonstrate that learning can occur in the absence of activity-dependent regulation of NMDAR composition, suggesting differences in the mechanism for long-term maintenance of NMDAR-dependent and NMDAR-independent learning.

Analysis of Variance↗
PubMed2006

Learning-induced reversal of the effect of noradrenalin on the postburst AHP.

Pyramidal neurons in the piriform cortex from olfactory-discrimination-trained rats have reduced postburst afterhyperpolarization (AHP), for 3 days after learning, and are thus more excitable during this period. Such AHP reduction is caused by decreased conductance of one or more of the calcium-dependent potassium currents, I(AHP) and sI(AHP), that mediate the medium and slow AHPs. In this study, we examined which potassium current is reduced by learning and how the effect of noradrenalin (NE) on neuronal excitability is modified by such reduction. The small conductance (SK) channels inhibitor, apamin, that selectively blocks I(A)(HP), reduced the AHP in neurons from trained, naïve, and pseudotrained rats to a similar extent, thus maintaining the difference in AHP amplitude between neurons from trained rats and controls. In addition, the protein expression level of the SK1, SK2, and SK3 channels was also similar in all groups. NE, which was shown to enhance I(AHP) while suppressing (S)I(AHP), reduced the AHP in neurons from controls but enhanced the AHP in neurons from trained rats. Our data show that learning-induced enhancement of neuronal excitability is not the result of reduction in the I(AHP) current. Thus it is probably mediated by reduction in conductance of the other calcium-dependent potassium current, sI(AHP). Consequently, the effect of NE on neuronal excitability is reversed. We propose that the change in the effect of NE after learning may act to counterbalance learning-induced hyperexcitability and preserve the piriform cortex ability to subserve olfactory learning.

Animals↗
PubMed2005

A cellular correlate of learning-induced metaplasticity in the hippocampus.

Metaplasticity, the plasticity of synaptic plasticity, is thought to have a pivotal role in activity-dependent modulation of synaptic connectivity, which underlies learning and memory. Metaplasticity is usually attributed to modifications in glutamate receptor-mediated synaptic transmission. However, experimental evidence and theoretical considerations suggest that learning reduces the predisposition for further synaptic strengthening, while behavioral studies show that learning capability is enhanced by prior learning. Here we show that enhanced neuronal excitability in CA1 pyramidal neurons, but not enhanced synaptic transmission, occurs prior to rule learning of an olfactory discrimination task. This transient enhancement lasts for 1 day after rule learning, is apparent throughout the cell population and results from reduction in the medium and slow after-hyperpolarizations that control spike frequency adaptation. Such olfactory learning-induced increased excitability in hippocampal neurons enhances the rats' learning capability in another hippocampus-dependent task, the Morris water maze. Once olfactory discrimination rule learning is acquired, its maintenance is not dependent on the reduced post-burst AHP in hippocampal neurons. However, the enhanced spatial learning capability of olfactory-trained rats in the water maze is diminished once the post burst AHP in CA1 pyramidal cells resumes its initial value. We suggest that enhanced excitability of CA1 neurons may serve as a mechanism for generalized enhancement of hippocampus-dependent learning capability. In the presence of such enhanced neuronal excitability, the hippocampal network enters into a 'learning mode' in which a variety of hippocampus-dependent skills are acquired rapidly and efficiently.

Animals↗
PubMed2005

Dynamics of learning-induced cellular modifications in the cortex.

This aim of this review is to describe the dynamics of learning-induced cellular modifications in the rat piriform (olfactory) cortex after olfactory discrimination learning and to describe their functional significance to long-term memory consolidation. The first change to occur is in the intrinsic properties of the neurons. One day after learning, pyramidal neurons show enhanced neuronal excitability. This enhancement results from reduction in calcium-dependent conductance that mediates the post burst after-hyperpolarization. Such enhanced excitability lasts for 3 days and is followed by a series of synaptic modifications. Several forms of long-term enhancement in synaptic connections between layer II pyramidal neurons in the piriform cortex accompany olfactory learning. Enhanced synaptic release is indicated by reduced paired-pulse facilitation. Post-synaptic enhancement of synaptic transmission is indicated by reduced rise time of post-synaptic potentials and formation of new synaptic connections is indicated by increased spine density along dendrites of these neurons. Such modifications last for up to 5 days. Thus, olfactory discrimination rule learning is accompanied by a series of cellular modifications which occur and then disappear at different times. These modifications overlap partially, allowing the maintenance of the cortical system in a 'learning mode' in which memories for specific odors can be acquired rapidly and efficiently.

Animals↗
PubMed2005

Olfactory learning-related NCAM expression is state, time, and location specific and is correlated with individual learning capabilities.

The notion that long-term synaptic plasticity is generated by activity-induced molecular modifications is widely accepted. It is well established that neural cell adhesion molecule (NCAM) is one of the prominent modulators of synaptic plasticity. NCAM can be polysialylated (PSA-NCAM), a reaction that provides it with anti-adhesion properties. In this study we have focused on NCAM and on its polysialylated state, and their relation to learning of an olfactory discrimination task, which depends on both the piriform (olfactory) cortex and hippocampus. We trained rats to distinguish between pairs of odors until rule learning was achieved, a process that normally lasts 6-8 days. At four time points, during training and after training completion, synaptic NCAM and PSA-NCAM expression were assessed in the piriform cortex and hippocampus. We report that NCAM modulation is specific to PSA-NCAM, which is upregulated in the hippocampus one day after training completion. We also report a correlation between the performance of individual rats in an early training stage and their NCAM expression, both in the piriform cortex and hippocampus. Since individual early performance in our odor discrimination task is correlated with the performance throughout the training period, we conclude that early NCAM expression is associated with odor learning capability. We therefore suggest that early synaptic NCAM expression may be one of the factors determining the capability of rats to learn.

Animals↗
PubMed2005

Dynamics of olfactory learning-induced up-regulation of L1 in the piriform cortex and hippocampus.

L1 is a cell adhesion molecule implicated in the formation of neural circuits and synaptic plasticity. We have examined the sequence and time-frame in which modifications in the synaptic expression of L1 occur in the piriform cortex and hippocampus in the course of rule learning of an olfactory discrimination task. Rats were trained to choose the correct odour in a pair to be rewarded with drinking water. Such training requires 6-8 days on average before rats reach maximal performance. We observed a learning-induced L1 up-regulation that occurred at an early training stage in the piriform cortex but only after rule-learning establishment in the hippocampus. We suggest that the dynamics of L1 up-regulation may reflect the functional role of these brain regions in olfactory rule learning.

Analysis of Variance↗
PubMed2005

Dynamics of learning-induced spine redistribution along dendrites of pyramidal neurons in rats.

We have previously shown that olfactory-discrimination (OD) learning is accompanied by enhanced spine density along proximal apical dendrites of layer II pyramidal neurons in the piriform (olfactory) cortex. Here we studied the temporal dynamics of learning-induced modifications in dendritic spine density throughout the dendritic trees of these neurons. We observed a transient increase in proximal apical spine density after OD learning, suggesting a strengthening of intrinsic excitatory inputs interconnecting neurons within the olfactory cortex. By contrast, the afferent pathway receiving direct input from the olfactory bulb shows spine pruning, suggesting that the connectivity is weakened. The changes in spine density can be attributed to a net change in number of spines, as the morphometric parameters of the dendrites are unaffected by learning. We suggest that spine density changes may represent a mechanism of selective synaptic reorganization required for olfactory learning consolidation.

Animals↗
PubMed2005

Olfactory learning-induced morphological modifications in single dendritic spines of young rats.

Learning-related morphological modifications in single dendritic spines were studied quantitatively in the brains of young Sprague-Dawley rats. We have previously shown that olfactory discrimination rule-learning results in transient physiological and morphological modifications in piriform cortex pyramidal neurons. In particular, spine density along the apical dendrites of neurons from trained rats is increased after learning. The aim of the present study was to identify and describe olfactory learning-induced modifications in the morphology of single spines along apical dendrites of the same type of neurons. By using laser-scanning confocal microscopy, we show that 3 days after training completion spines on neurons from olfactory discrimination trained rats are shorter as compared to spines on neurons from control rats. Further analysis revealed that spine shortening attributed to olfactory discrimination learning derives from shortening of spine head and not from shortening of spine neck. In addition, detailed analysis of spine head volume suggests that spines with large heads are absent after learning. As spine head size may be related to the efficacy of the synapse it bears, we suggest that modifications in spine head dimensions following olfactory rule-learning enhance the cortical network ability to enter into a 'learning mode', in which memories of new odours can be acquired rapidly and efficiently.

Analysis of Variance↗
PubMed2004

A molecular mechanism for stabilization of learning-induced synaptic modifications.

Olfaction is a principal sensory modality in rodents, and rats quickly learn to discriminate between odors and to associate odor with reward. Here we show that such olfactory discrimination (OD) learning consists of two phases with distinct cellular mechanisms: an initial NMDAR-sensitive phase in which the animals acquire a successful behavioral strategy (rule learning), followed by an NMDAR-insensitive phase in which the animals learn to distinguish between individual odors (pair learning). Rule learning regulates the composition of synaptic NMDARs in the piriform cortex, resulting in receptors with a higher complement of the NR2a subunit protein relative to NR2b. Rule learning also reduces long-term potentiation (LTP) induced by high-frequency stimulation of the intracortical axons in slices of piriform cortex. As NR2a-containing NMDARs mediate shorter excitatory postsynaptic currents than those containing NR2b, we suggest that learning-induced regulation of NMDAR composition constrains subsequent synaptic plasticity, thereby maintaining the memory encoded by experience.

Animals↗
PubMed2004

Olfactory learning-induced increase in spine density along the apical dendrites of CA1 hippocampal neurons.

We have previously shown that rule learning of an olfactory discrimination task is accompanied by increased spine density along the apical dendrites of piriform cortex pyramidal neurons. The purpose of the present study was to examine whether such olfactory learning task, in which the hippocampus is actively involved, induces morphological modifications in CA1 pyramidal neurons as well. Rats were trained to discriminate positive cues in pairs of odors for a water reward. Morphological modifications were studied in Golgi-impregnated neurons with light microscopy, 1 and 3 days after training completion. Spine densities were measured on the proximal region of apical dendrites and on basal dendrites after rule learning. Three days after training completion, the mean spine density on apical dendrites in neurons from trained rats was significantly higher by 20.5% than in neurons from pseudo-trained and naive animals, which did not differ from each other. By contrast, there was no significant difference in spine density of basal dendrites among the three groups. As length and diameter of spiny dendritic segments did not change after learning, the learning-related increase in spine density in neurons from trained rats may reflect a net increase in the number of excitatory synapses in the hippocampus following olfactory rule learning.

Animals↗
PubMed2004

Learning-induced long-term synaptic modifications in the olfactory cortex.

The idea that memory is manifested at the cellular level by enhancement of synaptic connections between simultaneously activated neurons has been suggested half a century ago by Hebb, and is widely accepted since. Much effort is done to describe such enhancement and reveal the underlying mechanisms. Learning-induced synaptic modifications were studied in the last decade with in-vitro brain slices preparations. Several forms of long-term enhancement of synaptic connections between layer II pyramidal neurons in the piriform cortex accompany olfactory learning. Such modifications were described also in other brain areas, following other training paradigms. Post-synaptic enhancement of synaptic transmission is indicated by reduced rise time of (post synaptic potentials) PSPs and formation of new synaptic connections is indicated by increased spine density along dendrites of these neurons. Enhanced synaptic release is indicated by reduced paired-pulse facilitation. In slices from trained rats predisposition for long-term potentiation is decreased and predisposition for long-term depression is increased. These modifications are attributed to olfactory-discrimination rule learning, rather than to memories for specific odors, and may be subsequent to intrinsic modifications in pyramidal neurons that create favorable conditions for activity-dependent synaptic enhancement.

Animals↗
PubMed2002

Learning-induced reduction in post-burst after-hyperpolarization (AHP) is mediated by activation of PKC.

We studied the role of protein kinase C (PKC) and protein kinase A (PKA) in mediating learning-related long lasting reduction of the post-burst after-hyperpolarization (AHP) in cortical pyramidal neurons. We have shown previously that pyramidal neurons in the rat piriform (olfactory) cortex from trained (TR) rats have reduced post-burst AHP for 3 days after odour-discrimination learning, and that this reduction is due to decreased conductance of calcium-dependent potassium current. In the present study, we examined whether this long-lasting reduction in AHP is mediated by second messenger systems. The broad-spectrum kinase inhibitor, H7, increased the AHP in neurons from TR rats, but not in neurons from pseudo-trained (pseudo-TR) and naive rats. Consequently, the difference in AHP amplitude between neurons from TR and control animals was diminished. This effect was also obtained by application of the specific PKC inhibitor, GF-109203x. The PKC activator, 1-Oleoyl-2-acetyl-sn-glycerol (OAG), significantly reduced the AHP in neurons from naive and pseudo-TR rats, but not in neurons from TR rats, so that the difference between the groups was abolished. The PKA-specific inhibitor, H-89, increased the AHP in neurons from all groups to a similar extent, and the difference in AHP amplitude between neurons from TR rats and neurons from controls was maintained. We suggest that while the post-burst AHP in piriform cortex pyramidal neurons is modulated by both PKC and PKA, a PKC-dependent process maintains the learning-related reduction of the AHP in these cells.

Action Potentials↗
PubMed2002

Learning-induced enhancement of postsynaptic potentials in pyramidal neurons.

We studied the effect of olfactory learning-induced modifications in piriform (olfactory) cortex pyramidal neurons on the propagation of postsynaptic potentials (PSPs). Rats were trained to distinguish between odors in pairs, in an olfactory discrimination task. Three days after training completion, PSPs were evoked in layer II pyramidal cells in piriform cortex brain slices by electrical stimulation of two pathways. Stimulation of layer Ib activated the intra-cortical fibers that terminate on the proximal region of the apical and basal dendrites. Stimulation of layer Ia activated the afferent axons that originate from the olfactory bulb and terminate on the distal apical dendrites. We have previously shown that olfactory training is accompanied by enhanced synaptic transmission in the intrinsic pathway, but not in the afferent pathway at 3 days after training. Here we show that at this stage, in both pathways PSPs evoked in neurons from trained rats had significantly faster rise time measured at the soma compared with PSPs in neurons from pseudo-trained and naive rats. Activation of the slow afterhyperpolarization (AHP), which is generated by potassium channels probably located at the proximal region of both apical and basal dendrites, reduced the amplitude measured at the soma of the proximal intrinsic pathway PSPs more effectively than PSPs that were generated distally by the afferent fibers. Thus the amount of reduction by AHP was used as a measure for the relative distance of PSP-generating sites from the soma. In neurons from trained rats, despite the previously reported reduction in AHP amplitude, AHP conductance shunted the PSPs from both synaptic pathways more efficiently compared with neurons from the control rats. We suggest that in neurons from trained rats PSPs are electrotonicly closer to the soma.

Animals↗