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Memory and Learning mechanism in the Hippocampal Network

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【Memory and Learning Systems Group】Research Themes

Minoru Tsukada

Tamagawa University Brain Science Institute

Memory and Learning Systems Group


When confronted with a variety of situations, we naturally compare them to our prior experiences, attempt to predict what may happen, and plan our actions and responses accordingly to lead to favorable outcomes. In this way, our past, present, and immediate future act as one to influence our actions. Physiologically, it is believed that this contextual information is temporarily stored in the hippocampus as short-term memory and then is consolidated in the association cortex as long term memory.

The main focus of our research group is to examine learning and memory function at all levels of analysis – from single cells to the system level and from brain slice to behavioral levels – and to develop theoretical accounts that integrate the findings obtained at various levels. For this purpose, we study learning and memory primarily in guinea pigs and rats, but also in humans. The majority of our research focuses on the mechanism of learning and memory in the hippocampus and cortex. To facilitate our cutting edge research, we have allocated significant research efforts to the development of new measurement tools for investigating neural activity.


Hippocampus

The hippocampal network consists of three types of synapses that form a circuit. A spatial signal serves as the input to the hippocampus and is transmitted through a synapse in the dentate gyrus (DG) to the CA3 and then through another synapse to the CA1. There also exists a parallel input path that connects directly to the CA1. The CA3 is characterized by a distinct biological neural network which has a recurrent (feedback) connection. It is thought that this circuitry compiles past memory into the present. Nakazawa et al. (2002) reported that after disrupting feedback in the CA3 using genetic knock-out techniques in mice, an extremely large number of cues became required to accomplish a single action. This suggests that the hippocampal CA3 network forms a context of time sequence, whereas the CA1 maps the spatiotemporal context into its synaptic weight space. For the CA3→CA1 network, Tsuda (1996, 2001) proposed a computational model of chaos-driven contracting systems in which the unstable network (chaos-driven network, CA3) forms a context of events via chaotic itinerary and the stable network (contracting dynamics, CA1) encodes its information as Cantor coding. For the CA1, Tsukada et al. (1996), proposed a spatio-temporal learning rule(STLR), which maps spatio-temporal information onto CA1 synaptic weight space.


Our studies of learning and memory mechanisms in the hippocampus focus on the following research themes:

1.Characteristics of spatio-temporal pattern discrimination of the spatiotemporal learning rule (STLR) by computer simulations (cell, network, and system levels)

2.Experimental verification of STLR in the CA1 (slice, cell, network, and system levels)

3.Characteristics of spike timing dependent long term potentiation (LTP) (Hebb type) in the CA1 pyramidal cells (slice, cell, network and system levels)

4.Interaction between STLR and Hebb type in the CA1 pyramidal cells (slice, cell, network, and system levels)

5.Experimental possibility of Cantor coding in hippocampal CA1 pyramidal neurons (slice, cell, network, and system levels)

6.Phase shift of theta oscillation in hippocampal CA1 pyramidal cell membrane (slice, cell, network, and system levels)

7.The basic mechanisms of synaptic transmission and its regulation

8.Behavioral experiments of the contextual formation of space, reward and policy (behavior, cell. network and system)

Cortex

Sensory cortices respond to physical stimuli in specific modalities. Recent human neuroimaging studies have shown, however, that auditory cortex can be active even in the absence of sound stimulation, but little is known about how the brain produces such ‘phantom’ activity. Our research seeks to understand this phenomenon.


Specifically, our research themes include:

9.Consolidation of classical conditioning information in the cortex (in vivo, network)

10.Interactions of sensory and hippocampal information in the cortex (in vivo, network, system)

11.Development of a new theoretical model of the hippocampal-cortical memory system based on physiological data (cell, network, system)

Measurement systems

To investigate the integration of learning and memory functions from single cells to the system level and from slice to behavioral experiments, we needed to develop a measurement system with spatiotemporal resolution of neural activity.


Accordingly, our research focused on:

12.Development of fast multi-point uncaging system with galvanometer-mirrors, two-photon microscopy, optical recording system with voltage sensitive dye, and multiunit recording system (slice, in vivo, cells, networks, and systems)


Human Investigations

To understand mechanisms underlying memory function in both animals and humans, one of our research themes focuses on investigations of human episodic memory using functional Magnetic Resonance Imaging.


Specifically, our research has focused on:

13.Functional properties of sensory cortices and hippocampal regions in human episodic memory

Additionally, in a psychophysically oriented research theme, we focus on:

14. The influence of semantics on the orienting of attention, or how the meaning of irrelevant stimuli can have an impact on ongoing perceptual discrimination tasks

Cross-Species

Finally, in a systems-oriented project, we bring together data from several species to develop a large-scale theory of how contextual information impacts on decision-making.


This research theme is focused on:

15. The anatomy of bias, or how neural circuits weigh different information-processing streams.

We discuss each of these research themes in the following paragraphs.

Hippocampus

The Functional Differences between STLR and Hebb

We applied two rules to a single-layered neural network and compared its ability to separate spatiotemporal patterns with that of other rules, including the Hebbian learning rule and its extended rules. The simulation results (Tsukada & Pan, 2005) showed that the spatiotemporal learning rule rather than the Hebbian learning rule or its extensions had the highest efficiency in discriminating spatiotemporal pattern sequences. The novel features of this learning rule were induction of cooperative plasticity without a postsynaptic spike and the time history of its input sequences.

According to the Hebbian rule, connections strengthen only if the pre- and post-synaptic elements are activated simultaneously, and thus, the Hebbian rule tends to map all of the spatio-temporal input patterns with identical firing rates into one output pattern. In contrast, the spatio-temporal rule produces different output patterns depending on each individual input pattern. Based on these findings, we can conclude that STLR has a greater ability to separate spatio-temporal patterns than the Hebbian learning rule.

The extension of the theoretical simulation results imply that this phenomenon occurs in a dendrites-soma system in a single pyramidal cell with many independent local dendrites in the CA1 area of the hippocampus. This system includes a spine structure, NMDA receptors (NMDAR), and Sodium and Calcium channels. The pyramidal cell integrates all of these local dendrite functions. The Hebbian Learning Rule predicts that if the post-neuron fires due to some spatial input pattern then all synapses that received its input are strengthened. Their weights change and substantially influence the next input to fire. Next, if similar inputs arrived on the pre-synapses of the dendrite, the post-neuron continues to fire and the same synapses are further strengthened. The next input must further increase synaptic weights. Since the same synapses continue to be strengthened in this way, pattern separation becomes increasingly difficult, though the ability to produce analogous patterns is strengthened. In contrast, the STLR predicts that the size of the synaptic weight is strengthened according to the correlation between the stimulus pattern and the postsynaptic weight, independent of the firing of the post-neuron. If the stimulus changes slightly, the synaptic weight in a different area is strengthened because of randomly distributed synaptic weights, and different synapses are strengthened depending on the arriving input pattern. Accordingly, the STLR has an increased ability to separate spatio-temporal patterns (Tsukada & Pan, 2005,Tsukada & Yamazaki, 2006).

Experimental support for STLR (non-Hebb)

The spatiotemporal learning rule (non-Hebb,) proposed by Tsukada et al. (1994, 1996, 2005) consisted of two defining factors: (a) cooperative plasticity without a postsynaptic spike and (b) temporal summation. We have obtained evidence for temporal summation from neurophysiological experiments by applying temporal stimuli to Schaffer collaterals of CA3 (Tsukada et al., 1994, 1996). However, the evidence for the cooperative plasticity without postsynaptic spikes has been lacking. In our research, the coincidence of spike timing of Schaffer collateral paired stimuli of CA3 played a crucial role in inducing associative LTP (Tsukada & Yamazaki, 2006). The homosynaptic and heterosynaptic associative LTP could be induced under conditions which inhibited the activation of dendritic Na+ channels. Our results show that LTP can indeed occur at dendritic synapses of hippocampal CA1 pyramidal neurons even in the absence of a postsynaptic somatic spike. These results suggest that if the two inputs synchronize at the dendritic synapse of CA1 pyramidal cells then the synapse is strengthened and the functional connection is organized on the dendrite. If the two inputs are asynchronous then the connection is weakened. The functional connection/disconnection depends on the input-input timing dependent LTP. This differs from the Hebbian learning rule that requires coactivity of presynaptic and postsynaptic neurons. The spatiotemporal learning rule (non-Hebb) incorporated two dynamic processes: fast (10 to 30ms) and slow (150 to 250ms) processes. The fast process works as a time window to detect a spatial coincidence among various inputs projected to a weight space of the hippocampal CA1 dendrites, while the slow process works as a temporal integrator of a sequence of events. By fitting parameters to the physiological data of the LTP time scale, we determined the decay constant of fast dynamics to be 17 ms, which corresponds to the period of hippocampal gamma oscillations (Aihara et al., 2000). In contrast, the decay constant of the slow dynamics is 169 ms, which corresponds to a theta rhythm. In combination, these findings suggest that cell assemblies are synchronized at two time scales in the hippocampal-cortical memory system and that this is closely related to the memory formation of spatio-temporal context.

Spike timing dependent LTP (STDP-Hebb type)

Hebbian learning is characterized by coincident pre- and post-synaptic activity; the interconnected weights are strengthened according to the delta rule. In support of this view, a series of experiments revealed that synaptic modification can be induced by repetitive pairing of EPSPs and back-propagating dendritic spikes (BPDSs) (Markram et al., 1997; Magee & Johnston, 1997; Zhang et al., 1998; Debanne et al., 1998; Bi & Poo, 1998; Feldman, 2000; Boettiger & Doupe, 2001; Sjostrom et al., 2001; Froemke & Dan, 2002). Debanne et al. (1998) and Bi and Poo (1998) found an asymmetric profile of LTP and LTD in relation to the relative timing between EPSPs and BPDSs in hippocampal cultures. In slice experiments, Tsukada et al. (2005) found symmetric and asymmetric profiles depending on the location from proximal to distal dendrite. The different profiles are closely related to CA1 network structures with inhibitory connection. LTP in a distal dendrite was more sensitive to the temporal pattern given by Markov stimuli than that in a proximal dendrite (Aihara et al., 2005). In this process, the magnitude of BADSs was a hippocampal slice using optical imaging when back propagating spikes given by electric enhanced/attenuated depending on the relative timing between proximal inputs and BADSs (Aihara et al. 2006).

STLR(non-Hebb) and Hebb can coexist in the CA1 pyramidal cells of the hippocampus

In our research, spike timing dependent LTP was induced in the CA1 area when stimulation was applied within a time window of 15 ms before and after the onset of electrical stimulation of Schaffer-commissural collateral of CA3. The heterosynaptically induced LTP in association with conditioning bursts was significantly reduced in the presence of low TTX which blocked BPDSs (Tsukada & Yamazaki, 2006). Based on these results, we can conclude that the two learning rules, STLR and STDL-Hebb, must coexist in single pyramidal neurons of the hippocampal CA1 area, and STLR is involved in pattern separation while Hebb is involved in pattern completion.

Experimental possibility of Cantor coding

Tsuda and Kuroda (2001) proposed a mathematical model that predicts Cantor coding in the hippocampal CA1. Following up on Tsuda and Kuroda’s theoretical proposal, we have tried to obtain Cantor-like patterns of activity in experiments with CA1 pyramidal neurons. Our results suggest that the potentials of pyramidal neurons in hipocampal CA1 show Cantor-like coding of successive spatiotemporal information (Fukushima et al., 2007a,2007b).

Phase shift of theta oscillation

The theta and gamma rhythms are fundamental clocks of the hippocampus. Sensory information is sampled as single events by gamma oscillation and several events are grouped by theta oscillation. We have investigated how the theta rhythm of CA3 given by a cyclic Gaussian stimulation affects oscillation properties in membrane potential of the CA1 pyramidal cell. Watanabe et al. (2006) showed that phase of the membrane potential oscillation of CA1 pyramidal cells are modulated by CA3 excitatory inputs.

The basic mechanisms of synaptic transmission and its regulation

We made three advances in our investigation of the mechanisms of synaptic transmission and regulation. First, we described the transmitter release mechanisms of the presynaptic nerve terminal using electrophysiological and molecular biological experiments. Second, we found that the high sensitivity of mouse neuronal cells to tetanus toxin requires a GPI-anchored protein. These findings were obtained by measuring EPCSs from buccal ganglion of Aplysia and applying non-stationary noise analysis to the amplitudes of these synaptic currents. Third, we analyzed the optical signal from hippocampal CA1 region of CaMKII-transgenic mouse using voltage-sensitive dye and photo-diode array recording system in order to investigate spatio-temporal pattern information processing.

Behavioral experiments of contextual formation

In the hippocampus, the context of visual cues, space, and reward plays an important role in storing and retrieving memory information as long term memory. We found single units that increase their firing rates depending on a special context of visual cue, space, and reward during a retrieval process (Takahashi et al. 2006).

Cortex

Classical conditioning in sensory cortex

To investigate effects of conditioning on auditory cortex activity, we used a fear conditioning paradigm in guinea pigs by pairing pure tones with foot shocks. Fear conditioning (Galván & Weinberger, 2002) and other behavioral and pharmacological paradigms (Kacelnik et al., 2006; Ma & Suga, 2005; Rutkowski & Weinberger, 2005) have induced plasticity in various aspects of mammalian auditory cortical representations but the possibility of phantom signals from auditory fear conditioning remained unexplored. To measure auditory cortex activity, we employed the optical imaging technique (Hosokawa et al., 2004) that registers electrophysiological activity of neuron populations with millisecond precision by recording fluorescent signals from the cortical surface after the application of a voltage-sensitive dye.

In the conditioning phase, the guinea pigs were presented with a pure tone of 4, 8 or 12 kHz for 5s followed immediately by a foot shock. This pairing was carried out 70 times with intervals of 60 to 120s. In four guinea pigs, fear conditioning was performed under anesthesia during the optical-imaging experiment, allowing us to compare auditory cortex responses to foot-shock alone before and after conditioning within the same guinea pig (Ide et al., 2006). Before conditioning, the foot shocks, unaccompanied by any sound stimuli, failed to activate the auditory cortex. After conditioning, the foot shocks produced significant signals in auditory cortex, even though they were presented during silence.


Interaction between sensory and hippocampal information in the cortex

The cortical memory system receives two inputs: a series of event (local, bottom-up) information from the sensory system and context (global, top-down) information from hippocampus. These two inputs interact dynamically in the cortex. The interactive information is stored in the cortex as long term memory.

To investigate how these inputs interact in the auditory cortex, we paired tones with hippocampal electric-stimulation and measured auditory cortex activity by using the optical imaging technique described above. The stimulus-timing-dependent changes were observed spatiotemporally in auditory cortex and they changed from inhibitory to excitatory effects depending on the strength of hippocampal stimulation (Ide et al., 2006).


A theoretical model of hippocampal-cortical memory system

Based on the above physiological evidence, a theoretical model of the hippocampal-cortical memory system has been proposed by Pan and Tsukada (2006). The model consists of the following components: the sensory system, the hippocampus (short-term memory), and the association cortex (long-term memory).


Measurement systems

Development of fast multi-point uncaging system by galvano-mirror (slice, cells, networks and systems)

We developed the system for multi point rapid stimulation system using ultraviolet laser uncaging system combined with a conventional confocal laser microscope equipped with several laser sources including an infrared laser source. The use of a focused laser beam for uncaging provides fine spatial resolution for analyzing neural functions. However, most of the previous experiments have been carried out using either special locations or in a very scanning patterns. We developed the system for performing uncaging in an arbitrary pattern in order to emulate realistic neural activity (Kojima et al., 2006). Our system is capable of patterned photolysis of caged neurotransmitter at 100 locations per 200 ms with submicron resolution. Ultraviolet laser light is steered by galvanometer mirrors and projected onto the surface of preparations for uncaging the caged chemicals. Simultaneously, imaging of neurons is obtained by é-photon microscopy. Thus, the system allows us to study neuronal functions and investigate integration of synaptic signals at dendrite levels.


Human Investigations

Measurement of brain function

Our investigations focused on functional properties of sensory cortices and hippocampal regions in human episodic memory (Okuda et al., 2006)


The influence of semantics on the orienting of attention

In this project, we use reaction-time data from button press responses, and using eye tracking methods, we try to delineate the conditions under which we can exert voluntary or top-down control of visual attention (Lauwereyns et al., 2006; Lucas & Lauwereyns, 2007). Here also, we investigate the influence of semantics and consider the information processing in terms of perceptual sensitivity and responses.

Cross-Species

The anatomy of bias

This project is a continuation of work on the neural circuits for reward-oriented decision making on the basis of bias versus sensitivity (Lauwereyns et al., 2002a, b; Lauwereyns, 2006, 2008). This project uses converging methods of investigation, principally with behavioral and pharmacological techniques in rats (Lauwereyns & Wisnewski, 2006; Wisnewski & Lauwereyns, 2007) as they perform behavioural tasks with an asymmetric reward schedule, and with human experiments using electrophysiology and eye tracking on the topic of response bias (Weaver et al., 2007).

Main Findings

Hippocampus

Caracteristics of spatiotemporal pattern discrimination of the Spatio-temporal Learning Rule(STLR) by computer simulated model

Fig.1 The diagram and formula of the spatiotemporal learning rule.
Fig.2 The distributions of Hamming distances of output patterns for five learning rules. (a) Hebb+, (b) Extended Hebb (local), (c) Spatiotemporal learning rule.
Fig.3 The comparison of averaged HDs between two learning rules to learn three kinds of spatiotemporal patterns. The HDs between spatial patterns is 2 bits, 8 bits and 24 bits. The black columns represent the spatiotemporal learning rule (STLR), and the gray columns are the learning rule without coincidence (MSTLR).

Spatiotemporal learning rule (Tsukada and Pan, 2006)

The hippocampus plays an important role in the course of establishing long-term memory by associating short-term memory with spatial and temporal input information. Tsukada et al. (1996) proposed the spatiotemporal learning rule (Figure 1) based on differences observed in hippocampal long-term potentiation (LTP) induced by various spatiotemporal pattern stimuli. A key proposition of this learning rule is that the change of synaptic weight depends on both spatial coincidence and the temporal summation of input pulses. We applied this rule to a single-layered neural network and compared its ability to separate spatiotemporal patterns relative to other rules, including the Hebbian learning rule and various extensions of Hebbian learning rule. The simulation results showed that the spatiotemporal learning rule had the highest efficiency in discriminating spatiotemporal pattern sequences (Figure 2). Morevoer, the simulation results suggest that the spatiotemporal learning rule was sensitive to differences in temporal sequences whereas the Hebbian learning rule (including its extensions) was sensitive to differences in spatial patterns (Figure 3).


Experimental varification of the STLR in the CA1

The mechanism for inducing associative LTP in rat hippocampal CA1 area (Tsukada and Yamazaki 2006)

One characteristic feature of synaptic plasticity induced in the CA1 region of the hippocampus in relation to learning and memory is associativity of long-term potentiation (LTP). Using an extracellular electrophysiological recording technique with rat slice preparations together with pharmacological treatments, we investigated the role of dendritic active conductance in the heterosynaptic associative LTP induced by the activation of two independent sets of Schaffer collaterals. Both homo- and heterosynaptic LTP were induced at the conditioning pathway and test pathway by application of test pulses to the test pathway in temporal association with the conditioning bursts to the conditioning pathway (Figure 4; 155.5 ± 11.5 and 149.8 ± 9.6 % in the conditioning and test pathways, respectively; n = 9). The robust potentiation of the test pathway is a striking feature of the associative conditioning protocol because the test pulses alone produced no change in the synaptic strength (Figure 5; 103.4 ± 6.0 % at 40 min after 0.2 Hz single pulses; n = 6). However, we observed that the conductance inhibited by a low concentration of tetrodotoxin (low TTX; 10-20 nM) strongly influenced the induction of heterosynaptic LTP induced by weak synaptic input, whereas that of homosynaptic LTP induced by strong synaptic input was not affected strongly (Fig.6; 142.6 ± 4.8 and 122.1 ± 5.8 % in the conditioning and test pathways, respectively; n = 9). The present results suggest that the activation of Na+ channels in the dendritic membrane play a critical role in the induction of associative LTP in hippocampal CA1 pyramidal cells.


Requirement of back propagating actionpotentials for the induction of associative LTP in hippocampal CA1 pyramidal neurons.

It is unclear whether back propagation is necessary for induction of associative LTP by two independent dendritic inputs. We tried to induce associative LTP without back propagation in the hippocampal CA1 pyramidal neurons. By using field potential recording methods, Yamazaki et al. (2006) showed that it is possible to induce associative heterosynaptic LTP under weak back propagating conditions. Next, we attempted to induce heterosynaptic associative LTP under threshold conditions by using patch clamp recording methods. Our results suggest that LTP is inducible even under subthreshold conditions. Moreover, the size of LTP is smaller than those under normal back-propagating conditions.

Fig.4 Induction of associative LTP by use of a low-frequency pairing protocol.
Fig.5 Test pulses alone did not alter the synaptic strength.
Fig.6 Low TTX-sensitivity in the induction of heterosynaptic associative LTP.


Characteristics of spike timing dependent synaptic plasticity (STDP) (Hebb type)

Fig.7 The location dependency of STDP along the dendrite

Spatial analysis of STDP in the CA1 area of hippocampal slices using optical imaging (Tsukada et al. 2006).

We investigated spike-timing dependent long-term potentiation (LTP) and depression (LTD) in the CA1 area of hippocampal slices using optical imaging. A pair of electrical pulses were used to stimulate the Schaffer-commissural collateral and the stratum oriens with various sets of relative timing (τ) between the two stimuli. The profiles of these sets of LTP/LTD, whose induction was closely related to τ, were classified into two types depending on their layer specific location along the dendrite. One was characterized by a symmetric time window observed in the proximal region of the stratum radiatum (SR) and the other by an asymmetric time window in the distal region of the SR. The bath-application of bicuculline (GABA receptor antagonist) to hippocampal slices revealed that GABAergic interneuron projections were responsible for the symmetry of a time window. These results were further discussed in relation to memory functions, CA1 network structures and learning rules.

STDP was investigated spatially by using optical imaging with a voltage sensitive dye.The profiles of STDP could be classified into two types depending on location, a symmetric time window at the proximal dendrite (PD),an asymmetric time window at the distal dendrite (DD). Bicuculline application showed GABAergic interneuron projections were responsible for the symmetry of a time window.

Fig.8 The histogram of the average magnitude of LTPs calculated in three divided parts of area a1, a4, and a7. The mean magnitude of LTP induced proximal to the cell layer (PD; <100μm), distal to the cell layer (DD; 200-300μm) and in the middle of these two areas (MD; 100-200μm), are represented as VPD, VMD, and VDD, respectively.The white upper-surface and the black upper-surface of the histogram show LTP and LTD, respectively.

Spatio-Temporal Visualization of Long-Term Potentiation and Depression in the Hippocampal CA1 Area (Aihara et al. 2005).

Long-term potentiation (LTP) in the CA1 area of the hippocampus depends critically on the statistical characteristics of its stimulus. The ability of optical imaging to record spatial distribution has made it possible to systematically examine the effects of higher order statistical characteristics, such as the correlation between successive pairs of inter-stimulus intervals, on the induction of LTP. Accordingly, we investigated the effects of frequency (first order) and temporal pattern (second order) using this imaging technique. We investigated the effect of varying a stimulus` temporal structure using non-periodic stimuli presented at the same mean frequency (2Hz).

As the correlation of successive inter-stimulus intervals was increased from negative to positive, not only did the magnitude of LTP increase, there was also a statistically significant change in the spatial distribution of LTP. Interestingly, when a strong negatively-correlated stimulus was used, both LTP and long-term depression (LTD) were simultaneously observed in the CA1 area. Moreover, we also found that the magnitude of LTP 200~300 μm distal to the cellular layer was larger than that of the LTP induced proximal (< 100 μm) to that layer. These results support the hypothesis that the spatial distribution of LTP throughout the hippocampus relies principally on the temporal pattern of input stimulation. This insight into the structure of the CA1 neural network may reveal the importance of stimulus timing events in the spatial encoding of memories.

Fig.9
Fig.10 (P):Proximal Dendrite (D):Distal Dendrite (L):Lacunosum Moleculare

Analysis of Information Processing along a Dendrite (Aihara et al., 2006).

Recent research reported Spike-timing Dependent Synaptic Plasticity (STDP), that is, the relative timing between the pre- and post-synaptic spiking determines the direction and extent of synaptic change within a critical temporal window. This finding demonstrates the importance of the relation between the back-propagated action potential (BAP) and EPSP for the information processing at a dendrite. To investigate how the excitatory postsynaptic inputs of the proximal dendrite affect the information processing of synaptic inputs at the distal dendrite, we applied stimulation at the alveus and the proximal dendrite, respectively, to induce BAP and EPSP.

The resulting coincidence of magnitude of BAP and EPSP at the distal dendrite was enhanced when the BAP was delivered at timing (5 ms) to induce LTP. Furthermore, the magnitude of BAP at the distal dendrite was attenuated by the input from the proximal dendrite at a timing (20 ms) to induce LTD. These results suggest that the magnitude of BAP delivered to the distal dendrite can be amplified or attenuated depending on the relative timing between proximal input and BAP. In turn this mechanism may support novel learning in the brain.

STLR non-Hebb and Hebb can coexist in the CA1 pyramidal cells of the hippocampus

See The mechanism for inducing associative LTP in rat hippocampal CA1 area (Tsukada & Yamazaki, 2006) in 2.


Experimental possibility of Cantor coding

Fig.11 Cluster index and nonlinear index by previous patterns of electrical stimulations.

The potentials of Cantor-like coding processing in hippocampal CA1 pyramidal neurons(Fukushima et al.2007a,2007b)

Tsuda and Kuroda (2001) proposed a mathematical model for the Cantor coding in the hippocampal CA1. The model predicts an attractor dynamics in the associative network as proposed by many other authors starting with Marr's theory of simple memory in the hippocampus (Marr, 1971). Motivated by Tsuda-Kuroda theory, we have tried to find Cantor-like patterns experimentally in the CA1 pyramidal neurons. We delivered temporally associated and non-associated electrical stimulations to Schaffer collaterals, and recorded membrane potentials using patch-clamp recording method. We concluded that at least two previous patterns of electrical stimulation affect the subsequent responses. The history of the response patterns depends on whether the sequential electrical stimulation was enough to induce action potentials or not. Our results suggest that pyramidal neurons in hippocampal CA1 have the potential to show Cantor-like coding of successive spatiotemporal information, and that this process has at least two modes which are dependent on the membrane potential. These property is also observerd when the neuron show many action potentials as in vivo coditions.


(a) Cluster index by previous patterns of electrical stimulation in "subthreshold" and "suprathreshold" conditions (see also materials and methods). Black solid and dotted lines indicate cluster index in "subthreshold" and "suprathreshold" conditions, respectively. Gray solid and dotted lines indicate randomized control of "subthreshold" and "suprathreshold" conditions respectively. X- and Y-axis indicates history of stimulating patterns and cluster index, respectively. Error bar indicates standard errors of the mean. *: p<0.05

(b) Nonlinear index of the neurons in "subthreshold" and "suprathreshold" conditions (See also materials and methods). X- and Y-axis indicates history of stimulating patterns and nonlinear index, respectively. Error bar indicates standard errors of the mean. *: p<0.05

(c) Mean standardized deviation in "subthreshold" and "suprathreshold conditions". X- and Y-axis indicates history of the stimulating patterns and mean of the neurons, respectively. Error bar indicates standard errors of the mean.


Phase shift of theta oscillation

Fig.12 Phase distribution of MPOs in response to the paired stimulations. The phase (ffilled circle) of MPOs indicate temporal differences of the positive peaks between MPO in response to a somatic current injection and the the paired-stimulation-induced MPO. The subtractive phase (fhopen square) analysis reveals a phase-shift property, depending on these MPO amplitudes (Vres) of each cycle in MPO. The phase shift courses are demonstrated by the linear summation model (dotted lines).

Phase shift of subthreshold theta oscillation in hippocampal CA1 pyramidal cell membrane by excitatory synaptic inputs. (Watanabe et al. 2006)

The theta rhythms and the activity of hippocampal neurons during theta rhythms could be fundamental for various operations of the hippocampus. Hippocampal CA1 neurons receive multiple rhythmical inputs with relatively independent phases during theta activity. However, it is unclear how these multiple rhythmical inputs affect oscillation properties in membrane potential of the CA1 pyramidal cell. To investigate oscillation properties in the subthreshold membrane potential, we generated oscillations in the membrane potential of the CA1 pyramidal cells in rat hippocampal slices in vitro with a sinusoidal current injection into the pyramidal soma at theta band frequencies (4–7 Hz) and analyzed the effect of rhythmically excitatory synaptic inputs. The Schaffer collaterals were stimulated using a cyclic Gaussian stimulation method with pulse intervals distributed with the mean set at 10 pulses/cycle (5 cycles/s). We found that the cyclic Gaussian stimulations induced membrane potential oscillations and their phase delays from the mean of the pulse distribution were dependent on membrane potential oscillation amplitude mean delay ( 27.5 ± 8.2 msec; n=10).

We applied four pairs of cyclic Gaussian stimulations and somatic sinusoidal current stimulations at the same frequency (5 Hz) with varying phase differences (-π/2, 0, π/2, π rad). The paired stimulations induced phase distributions of the oscillation in the membrane potential, which showed a dependency on an increasing membrane potential oscillation amplitude response to cyclic Gaussian stimulation. This membrane potential dynamic was exhibited by the mixture of the membrane potential oscillation-amplitude-dependent phase delay and the linear summation of the two sinusoidal waves (Figure 12). These findings suggest that phases of the membrane potential oscillation are modulated by excitatory synaptic inputs. In turn, this phase-modulation by excitatory synaptic inputs may play a crucial role for memory operation in the brain.


The basic mechanisms of synaptic transmission and its regulation

The transmitter release mechanisms from the presynaptic nerve terminal by electrophysiological and molecular biological experiments (Kojima et al.).

In this research, organotypic cultured slice preparations obtained from cerebellar cortex were used to investigate the transmitter release mechanisms and its regulation by tetanus neurotoxin (TeNT). Tetanus neurotoxin produced by Clostridium tetani specifically cleaves VAMP/synaptobrevin (VAMP) in central neurons, thereby causing inhibition of neurotransmitter release and ensuing spastic paralysis. Although polysialogangliosides act as components of the neurotoxin binding sites on neurons, the accumulated evidence suggests that a protein moiety is implicated as a receptor of TeNT. We have observed that treatment of cultured mouse neuronal cells with the phosphatidylinositol-specific phospholipase C (PIPLC) inhibited TeNT-induced cleavage of VAMP. Also, we have shown that the blocking effects of TeNT on neuroexocytosis can be prevented by incubation of Purkinje cell preparation with PIPLC. In addition, treatment of cultured mouse neuronal cells with cholesterol sequestrating agents such as nystatin and filipin (disrupting clustering of GPI-anchored proteins in lipid rafts) prevented intraneuronal VAMP cleavage by TeNT. Our results demonstrate that high sensitivity of neurons to TeNT requires rafts and one or more GPI-anchored protein(s) that act(s) as a pivotal receptor for the neurotoxin.(Kojima, Munro, & Poulain, 2001).

High sensitivity of mouse neuronal cells to tetanus toxin requires a GPI-anchored protein; this work has been investigated by measuring EPCSs obtained from buccal ganglion of Aplysia and applying non-stationary noise analysis to the amplitudes of these synaptic currents(Kojima et al.).

The role of small GTPases of the Rho family in synaptic functions has been addressed by analyzing the effects of lethal toxin (LT) from Clostridium sordellii strain IP82 (LT82) on neurotransmitter release at evoked identified synapses in the buccal ganglion of Aplysia. LT82 is a large monoglucosyltranferase that uses UDP-glucose as cofactor and glucosylates Rac (a small GTPase related to Rho), and Ras, Ral, and Rap (three GTPases of the Ras family). Intraneuronal application of LT (50 nm) rapidly inhibits evoked acetylcholine (ACh) release as monitored electrophysiologically. Injection of the catalytic domain of the toxin similarly blocked ACh release but not when key amino acids needed for glucosylation were mutated. Intraneuronal application of competitive nucleotide sugars that differentially prevent glucosylation of Rac- and Ras-related GTPases, and the use of a toxin variant that affects a different spectrum of small GTPases, established that glucosylation of Rac is responsible for the reduction in ACh release. To determine the quantal release parameters affected by Rac glucosylation, we developed a nonstationary analysis of the fluctuations in postsynaptic response amplitudes that was performed before and after the toxin had acted or during toxin action. The results indicate that neither the quantal size nor the average probability for release were affected by lethal toxin action. ACh release blockage by LT82 was only caused by a reduction in the number of functional release sites. This reveals that after docking of synaptic vesicles the vesicular Rac stimulates a membrane effector (or effectors) essential for the fusion competence of the exocytotic sites. (Kojima, Humeau and Poulain 2001)

The optical signal from hippocampal CA1 region of CaMKII-transgenic mouse was analyzed by using voltage-sensitive dye and photo-diode array recording system in order to investigate spatio-temporal pattern information processing.

The hippocampal system contributes to its information processing. However, the conventional techniques of electrical recording are restricted to the analysis from a few electrodes placed on a tissue. In order to overcome this limitation, optical recording from multi-sites of CA1 region has been carried out by using a photodiode array system. The optical signals of pre- and post-synaptic action potentials and synaptic responses by stimulation of Schaffer collaterals (SC) from CaMKII-transgenic mouse were pharmacologically identified and compared with electrical signals. Upon stimulation of SC, fluorescent optical signals of hippocampal slices stained with Di-4-Anepps were recorded from WT and CaMKII-transgenic mouse, respectively. Our findings suggest that the responses were larger in amplitude and extended to a wider region in transgenic mouse and that optical recording could be extended to the transgenic mouse (Kojima et al., 2004)


Behavioral experiments of the contextual formation

Fig.13 An example of error-related (outcome-mismatching correlates) unit. When the correct response to the nosepoke (upper histogram),, this unit shows slight increase of its firing rate after the responses, whereas in error responses, strong bursts can be observed (lower histogram).

Involvement of Hippocampal CA1 Neurons in Match-Mismatch Comparison of Memory Retrieval with Sensory Input in the Rat (Takahashi et al., 2006).

Computational studies of hippocampal functions suggest different properties for hippocampal subregions: dentate gyrus, CA3, and CA1. Several reports assume that CA1 performs match-mismatch comparisons of memory retrieval computed by CA3’s auto-associative neural networks, with sensory input originating from the entorhinal cortex. The detailed neurophysiological mechanism remains unclear however. Our study investigated this “CA1-Comparator” model using an ensemble recording technique with ~12 tetrodes in the rat. We employed directional memory-guided alternation and visual cue-guided discrimination tasks that contained a delay period in each trial for the same animal. After completion of training, the animals predicted the next direction according to the alternation paradigm even in the visual cue-guided discrimination task. Using the task prediction performance, we investigated the behavioral correlates of the unit activity in the dorsal hippocampal CA1 area when a match or mismatch between the prediction (i.e., waiting position) and the current situation (i.e., cue direction) occurred. Thus, comparison processes between memory retrieval based prediction and sensory input could occur in two stages of the task sequence: sensory-matching when the visual cue is presented or outcome-matching when the reward is presented.

We analyzed 140 well-isolated putative pyramidal cells and found 16 units with outcome-matching correlate units, 30 units firing during approach behavior to the nose pokes, but no sensory-matching correlates units as most of these units also tend to fire during approach behavior.

In summary, we investigated the neuronal responses of the dorsal hippocampal CA1 area in situations when expectation and experience is matched or mismatched. Typical complex spike burst firing was observed primarily just after the rat performed correct nose poking to a specific site or during approach behaviors to the nose poke. Some units fired very specifically along the trajectory of their correcting performance (from wrong site to the correct one). These bursting activities might affect local hippocampus-EC circuits to maintain or refine the performance for goal-oriented behaviors.


Cortex

Classical conditioning in the sensory cortex

Optical Imaging of Plastic Changes Induced by Fear Conditioning in The Auditory Cortex(Ide et al. 2006)

Fear conditioning using sound and electric stimuli is frequently used in investigations of memory and emotion and many studies of plasticity in the auditory cortex using this paradigm have been carried out. Weinberger et al. (2004) reported that receptive fields in the auditory cortex are plastically changed by fear conditioning and that the best frequency strongly tunes to the frequency used for the conditioning. The information in the auditory cortex is spatially represented as a tonotopic map. Merzenich et al. (1998) reported that the response region to the training frequency in the monkey primary auditory cortex is enhanced after the frequency discrimination task. Specifically, they investigated the plastic change in the auditory cortex induced by fear conditioning with pairing of sound (Conditioned Stimulus, CS) and electric foot-shock (Unconditioned Stimulus, US) using an optical recording method with voltage sensitive dye. To investigate the effect of association learning, they recorded optical signals in the auditory cortex to CS (12 kHz pure tone) and non-CS (8 kHz and 16 kHz pure tone) before and after the conditioning. They found that the response area only to CS increased after the conditioning (Figure 14). To investigate whether auditory information could be retrieved by electric foot-shock after association learning, they examined auditory responses to foot-shock before and after the conditioning. The results showed that the optical response was not observed in the auditory cortex to only electric foot-shock without any sound stimulus before the conditioning but clearly appeared after the conditioning (Figure 15). Furthermore, a correlation between CS sound and electric foot-shock was found in the auditory response area (Figure 16).

Previous research revealed that acetylcholine (ACh) released from the basal forebrain to the cortex affects NMDA glutamate receptors in layer II/III of cortex during conditioning and promotes plastic changes in auditory cortex. Moreover, excitatory neuron activities based on NMDA glutamate receptor laterally exists beyond the iso-frequency band in tonotopic map of auditory cortex, suggesting that the increase of auditory response area for CS sound (12 kHz) after the conditioning based on NMDA glutamate receptor dependent LTP in the layer II/III. These findings suggest that LTP was induced in NMDA glutamate receptor dependent late-EPSP by CS sound and EPSP was induced by electric foot-shock in the same location in NMDA glutamate receptors where LTP was induced by conditioning. Furthermore, the correlation between auditory response area for CS sound and electric foot-shock implies that the acoustic information about CS sound was retrieved by electric foot-shock.

Fig.14 Auditory responses for CS (12 kHz) and non-CS (8, 16 kHz) recorded before and after conditioning.
Fig.15 Auditory response for electric foot-shock
Fig.16 Auditory responses for CS sound and electric foot-shock when CS sound was 12 kHz pure tone


Interaction between sensory and hippocampal information on the cortex.(Ide et al. 2006)

According to a widespread view, memory consists of both semantic memory (memory for facts) and episodic memory (memory for evens). Episodic memory is further subdivided into short-term memory mediated by the hippocampus and long-term memory mediated by association cortices. According to some views, short-term memories are initially stored in the hippocampus and then transferred to the cortex as long-term memories. From this perspective, it is necessary to investigate interactions between information processing in the hippocampus and cortex. While many studies have investigated memory mechanisms involving the hippocampus and the cortex, respectively, the mechanism of memory and learning and especially interactions between the hippocampus and cortical processing remains unclear. For this reason, we investigated the dynamic interaction between information processing in the cortex and hippocampus in the guinea pig auditory cortex induced by a combination of acoustic and hippocampal CA1 stimulation using the optical imaging method with the voltage sensitive dye (RH 795). We inserted a bipolar tungsten electrode into the hippocampal CA1 region and applied pulsed current stimulation (0.19 mA, 100 s) to it. The results showed that information representation in the auditory cortex induced by acoustic stimuli was strongly modified by hippocampal stimulation and further that this modification was inhibitory and depended on the timing of acoustic and hippocampal stimulation (Figure 17). Figure 18 shows the auditory response induced by compound acoustic-hippocampal simultaneous stimuli as a function of the current intensity of hippocampal stimulation. We investigated the auditory response by changing the current intensity of hippocampal stimulation from 0.19 mA to 0.76 mA. We found that hippocampal stimuli with a current intensity of less than 0.38 mA had an inhibitory effect on auditory response whereas hippocampal stimuli with a current intensity of over 0.57 mA had an excitatory effect on auditory response. In turn, these findings suggest that the auditory response induced by acoustic stimuli received excitatory or inhibitory influence from hippocampal activity depending on the magnitude of neuron activity of hippocampal CA1 region.

Fig.17 Inhibitory response of auditory cortex induced by hippocampal stimulation.
Fig.18 Auditory response induced by compound acoustic-hippocampal simultaneous stimulation as a function of current intensity of hippocampal stimulation.


A theoretical model of hippocampal-cortical memory system

Fig.19 The structure of the hippocampal-cortical memory system

Interactions between hippocampal and cortical memory systems (Pan and Tsukada, 2006)

It is commonly believed that the hippocampal-cortical network is a critical structure for storing and retrieving memory. The hippocampus works as a storage for short-term memory, while the cortical cortex is the storage for long-term memory. How is short-term memory in the hippocampus transferred into long-term memory in the cortex? Based on physiological evidence, we proposed a theoretical model of the hippocampal-cortical memory system (Fig.19). The model consists of the following components: the sensory system, the hippocampus (short-term memory) and the association cortex (long-term memory). A series of key codes (local information) is supplied from the sensory system, while context (global information) is inputted from the hippocampus. The two inputs interact dynamically in the association cortex. The interactive neurons work as a detector of coincidence. The cortical network learns the memory information through the coincidence window and, finally, stores it in the form of attractors. This local-global information works as an addressor to designate the stored location of the memory in the association cortex and accelerates the processing of storing and retrieving memory information (Fig.20 and Fig.21).

Fig 20.The capability of storing patterns in the associative cortex. (a) The memory system without hippocampus, and (b) the system with hippocampus. The three curves represent different learning rules: the Hebbian learning rule (the circle-curve), the global Hebbian learning rule (the square-curve) and the spatiotemporal learning rule (the triangle-line)
Fig 21.The courses of retrieving patterns from the cortex under the three learning rules. (a) The Hebbian learning rule, (b) the global Hebbian learning rule and (c) the spatiotemporal learning rule. In these figures, the triangle-curve is the result from the memory system without the hippocampus, while the square-curve is the data from the memory system with the hippocampus.


Measurement systems

Development of fast multi-point uncaging system by galvano-mirror(Kojima et al.2006)

Fig.23 Uncaging and Electrophysiology System

The system for multi point rapid stimulation system by ultraviolet laser uncaging system has been developed by combination of a conventional confocal laser microscope equipped with several laser sources including an infrared laser source. Neurons integrate many synaptic signals at the dendrite. Understanding these information processes is a central topic in experimental and computational neuroscience. The use of a focused laser beam for uncaging can provide fine spatial resolution to analysis of neural function. However, most experiments were carried out either at special locations or in a very scanning patterns. We developed a system for performing uncaging in an arbitrary pattern in order to emulate realistic neural activity. Our system is capable of patterned photolysis of caged neurotransmitters at 100 locations per 200 ms with submicron resolution. Ultraviolet laser light is steered by galvanometer mirrors and projected onto the surface of preparations for uncaging the caged chemicals. Simultaneously, imaging of neurons is obtained by é-photon microscopy. Figure shows the photo of the system used in Tamagawa University.

1. Deflector of UV-laser

2. UV-laser for uncaging

3. IR-laser (Chameleon-XR)

4. Visible light-lasers unit

5. Scanner of Imaging


Human Investigations

The measurement of Brain function

Fig.24 Activation patterns in auditory-related cortex (upper panels) and hippocampal region (lower panels). Graphs show fMRI signal change during true recognition (TR), correct rejection (CR), false recognition (FR), pretending not to know (PN), and pretending to know (PK). Filled bars indicate existence of actual auditory experiences (upper graph) and subjective feeling of recognition (lower graph).

Functional properties of sensory cortices and hippocampal regions in human episodic memory (Okuda, Sasaki, et al.2006)

One of the fundamental mechanisms underlying memory functions in animals and humans are contextual association between distinctive events (or stimuli) through experiences as demonstrated by behavioural and physiological experiments using classical conditioning (e.g., Ide et al., 2006, see previous section of this report). It is still unclear, however, how such mechanisms contribute to human episodic memory, a conscious and declarative form of memory that is thought to be unique to humans. We assumed reactivation of neural circuits that were recruited in the processing of experiences in the same context as a fundamental neural mechanism for the contextual association in mammalian brains and examined the role of this mechanism in human episodic memory with functional magnetic resonance imaging (fMRI). Specifically, we examined the functional properties of hippocampal regions and auditory-related cortices during visual recognition of auditorily encoded words with a false recognition task paradigm – a task designed to capitalize on subjective familiarity with not-experienced events.

Twenty-eight young healthy volunteers participated in the study. We prepared a number of word lists composed of semantically related words (e.g., candy, chocolate, pudding) designed to elicit false recognition (Deese, 1959; Roediger & McDermott, 1995) on a memory test. During the encoding phase, without fMRI scanning, participants were auditorily presented with 20 word lists of 15 words each (300 words in total) and asked to memorize them. During the retrieval phase with fMRI scanning, participants were visually presented with old words studied during the encoding phase (e.g., chocolate), new previously unstudied but semantically-related words (e.g., sweets), and new previously unstudied and unrelated words (e.g., car), and were asked to make old/new recognition judgments by using response buttons. To examine differences between conscious and unconscious processes during incorrect recognition to non-studied words (i.e., intentional lying or pretending to know, and false recognition based on subjective familiarity), participants were asked to make intentional deceptive responses to half of the trials. Participants were told the task context (lie or be honest) via a brief instruction period preceding each of the lying and honesty blocks (10-15 trials each) that alternated and repeated four times in one fMRI session. The pair of encoding-retrieval phases was repeated twice with different memory materials. The fMRI scanning was done using a 1.5 T MRI scanner (Magnetom Sonata, Siemens, Erlangen, Germany) and standard T2*-weighted gradient-echo echo-planner imaging sequence. The fMRI data were analyzed by SPM2 software (Wellcome Department of Imaging Neuroscience, UCL, London, UK) implemented in Matlab 6.5 (Natick, MA, USA).

We analyzed fMRI data from 20 participants who showed better than chance behavioural performance (more than 20 trials) in all response categories of true recognition (correctly recognized old words as studied), correct rejection (correctly recognized new words as non-studied), false recognition (incorrectly recognized lure words as studied), pretending not to know (intentionally make a wrong response to old words), and pretending to know (intentionally make a wrong response to new words). Of these categories, auditory experiences at encoding were processed only for words in categories of true recognition and pretending not to know whereas subjective feeling of recognition was accompanied with true and false recognition and pretending not to know. We attempted to differentiate brain regions associated with the sensory signatures of physical experiences and subjective recognition by comparing fMRI signals across the 5 categories. We found that auditory-related cortex (middle temporal gyrus, upper right panel of Figure 1) was activated in parallel with the existence of physical auditory experiences (upper left panel of Figure 24) and that hippocampal regions (lower right panel of Figure 24) were activated depending on the subjective feeling of recognition (lower left panel of Figure 24).

The fact that the auditory-related cortex was activated during true recognition of visually presented words suggests that the auditory cortex may be automatically reactivated regardless of the testing modality (i.e., auditory vs. visual; Nyberg et al., 2000; Wheeler et al., 2000; Polyn et al., 2005). No activation of the auditory-related cortex during erroneous (false recognition for lure words) and intentionally wrong (pretending to know new words) recognition responses suggest that neural activation traces in the auditory cortex could be firmly maintained for several minutes or hours. In contrast, the activation pattern of hippocampal regions did not always correlate with the existence of actual auditory experiences but rather with subjective feeling of recognition (activation during true and false recognition but not during intentional wrong recognition response, i.e., pretending to know unstudied words). These results support a model that the auditory sensory cortex and hippocampus contribute differently to auditory episodic memory in humans, enabling sensory experiences, subjective recognition, and current task context to be integrated in a flexible and subjective processing of memory. This study was performed in collaboration with Tohoku University Graduate School of Medicine (Prof. T. Fujii, M. Suzuki, and N. Abe).


The influences of semantics on the orienting of attention

a)Stroop-Like Interference from a peripheral cue independent of spatial orienting

Previous research has suggested that semantic interference from an irrelevant peripheral cue can directly impact on the process of covert spatial orienting in visual detection and discrimination tasks. The present study sought to revisit this topic with careful eye position control and the application of the most archetypal of all paradigms of semantic interference – the Stroop test. Experiment 1 used words of colors as irrelevant peripheral cues and four types of color patches as targets for a two-choice visual discrimination task. The results indicated that the fastest responses occurred when the cue and target represented the same color (item priming), followed by when the cue and target represented different colors but the same response (response priming). The slowest responses occurred when the cue and target represented different colors and different responses. This pattern of semantic interference was obtained in the absence of any spatial influence from the peripheral cue. Experiment 2 used color patches as cues and words of colors as targets. The pattern of results was markedly different from Experiment 1, with no main effect of semantic information, nor any straightforward evidence of item or response priming, but an interaction between semantics and spatial orienting. The data were in agreement with the well-documented asymmetry in the Stroop test, showing stimulus-stimulus and stimulus-response compatibility effects from words on color patches, but not vice versa. This influence, however, appears to occur at a level of processing that does not interact with covert spatial orienting.


b) Selective working memory disables inhibition of visual features

Recent research suggests that information held in working memory can facilitate subsequent attentional processing. Here, we explore the negative corollary of this conception: Under which circumstances does information in working memory disrupt subsequent processing? Seventy participants performed visual discriminations in a dual-task paradigm. They were asked to judge colors or shapes in an online attention task under three different working-memory conditions: Same, Switch, or Unknown. In the Same condition, participants selectively maintained one visual feature in working memory, from the same dimension as in the online attention task. In the Switch condition, participants selectively maintained one visual feature in working memory, but had to focus on another visual dimension in the online attention task. In the Unknown condition, participants could not predict which visual feature would be relevant for the working-memory task. We found that irrelevant features in the online attention task were particularly difficult to ignore in the Switch condition, that is, when the irrelevant features belong to a visual dimension that is simultaneously prioritized in selective working memory. The findings are consistent with accounts in terms of neural overlap between working-memory and attention circuits, and suggest that mechanisms of selection, rather than resource limitations, critically determine the extent of visual interference.


Cross-Species

The anatomy of bias

a) Systemic dizocilpine (MK-801) facilitates performance in opposition to response bias

Previous research has established that dopamine signals are crucial in orienting behavior to reward. Less is known, however, about the psychopharmacology of task performance under small-reward conditions as compared to large-reward conditions. The current study examined the effects of the noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist dizocilpine (MK-801) on reaction time (RT) in a nose-poke task with rats completing an asymmetric reward schedule. In all trials, the rats were required to poke their nose in either the left or the right peripheral hole immediately adjacent to the centre hole when the corresponding light was illuminated. Depending on the stimulus-reward mapping, however, one position was associated with a large reward, while the alternative position was associated with a small reward. Correct performance was required in every trial; if the rat did not make a correct response within 20 s, the trial was aborted, and the same stimulus was presented again on the next trial. In this way, the rat was forced to perform the same visuo-spatial discrimination task under different reward conditions. Reaction times (ms) were faster for large-reward trials than for small-reward trials, replicating previous findings. At a dosage of MK-801 (0.04 mg/kg), there was no significant influence of on RT in large-reward trials. In contrast, the same dosage of MK-801 in small-reward trials produced a decrease in RT as compared to the control condition, implying an improvement of performance. Below 0.04 mg/kg of MK-801, a steady decrease of RT in small-trials was seen as a function of dosage. Above 0.04 mg/kg of MK-801, the majority of rats failed to perform the task at all, whereas the rats that did manage to perform the criterion of 80 correct trials in a session showed no difference in RT between largeand small-reward trials. These data indicate that the systemic administration of a relatively small dosage of MK-801 facilitates performance when reward is small. It is suggested that the facilitation may be due to the reinforcement of mechanisms that work in opposition to response bias. As a corollary, the study provides a useful paradigm to study the voluntary control of unavoidable action.


b) A reaction-time paradigm to measure reward-oriented bias in rats

We devised a nose-poke task with asymmetric position-reward mapping to distinguish between effects of bias and sensitivity in reaction times of rats. In all trials, the rats had to poke their noses into the hole to the left or to the right of center, corresponding to the side at which 4 lights were illuminated, while ignoring distracters on the other side. Reaction times were faster for large-reward trials than for small-reward trials. In large-reward trials, there was no influence of the number of distracters, whereas in small-reward trials, distracters produced an increase in reaction time. Analysis of reaction-time distributions according to a linear model of decision making suggests that most of the systematic variability was due to a reward-oriented bias.

Future Research Directions Learning and Memory

Our previous research revealed that STLR and Hebb mechanisms coexist in single pyramidal neurons of the hippocampal CA1 area. In STLR mechanism, synaptic weight changes are determined by the “synchrony“ level of input neurons (bottom-up) whereas in Hebb mechanism the soma fires by integrating dendritic local potentials or by top-down information such as environmental sensitivity, awareness, and consciousness (top-down). The coexistence of STLR (local information) and Hebb (global information) on the neuronal level may support this dynamic process that repeats itself until the internal model fits the external environment. The dendrite-soma interaction in pyramidal neurons of the hippocampal CA1 area can play an important role in the context formation of policy, reward, and value in reinforcement learning.


Our future research will address the following topics:

1.Dendrite-soma interactions in single pyramidal neurons of the hippocampal CA1 by using the system for multi-point rapid stimulation system by ultraviolet laser uncaging system developed by combination with a conventional confocal laser microscope (slice, system, laser uncaging system)

2.Context modulation in hippocampal-cortical memory system by using complex association memory tasks (in vivo, system, optical, and multi-units recording system)

3.Hippocampal functions related to formation of space and reward context using behavioral experiments

4.Multi-modal perceptual information processing and integration process, and cortical plasticity modulated by emotional information (reward/punishment) (in vivo, optical imaging, multi-units recording system and confocal laser microscope with laser uncaging system)


Creativity, Dynamics and Mutual Interaction

Our future research focus on how one individual or a group of individuals attains intelligence by mutually interacting with the environment. A breakthrough seems within reach by combining complex systems science, computational science, and mathematics. However, as yet undefined are the fundamental principles that underlie dynamic behaviors in irregularity produced by complex systems. Additionally, there is at present no satisfactory description of the mechanisms that produce new systems by mutual interaction among hetero-systems.

Judging from these developments, it would be a wise objective to open up and establish a new research field that deals with the mechanisms of creativity, by which new functions are created from preexisting stable and regular functions as a result of mutual interactions among hetero-systems.

Human intelligence is developed by creative evolution. When the brain plans specific actions, it builds several hypotheses and attempts to predict the future in those conditions. To verify these predictions, the body takes action in the physical world. If these actions do not fit, then a new hypothesis is formulated, new data are produced, and the internal model is amended. This dynamic process repeats until the internal model fits the outer environment. Thus, the human brain creates new functions from the previous functions as a result of mutual interaction between the outer environment and internal model. In this process, we can consider the following four functions to produce creativity. First is to make a new optimal combination from among the complexity of the fragmentary experience. Second is to develop a new global intelligence by stringing fragmentary events together. Third is to deduce a new idea by considering ideas that are opposed to each other. Fourth is to construct a new idea by a very important and noticeable change (paradigm shift) in the way of thinking when we reach a deadlock.


The BACH-PICASSO Project

How do things that mean things emerge in neural circuits? Most linguists and neuroscientist agree that this process of recursion, with information embedded in other information, forms the core faculty of language and consciousness. Yet surprisingly little is known about how the brain achieves this remarkable feat. The mystery of how the brain supports the mind, and especially the rich and complex human mind, is perhaps the last frontier in science. This is no hyperbole. Until recently great scientists such as Francis Crick and Roger Penrose remained sceptical about the power of science to address this question, but the flourishing field of cognitive neuroscience offers many exciting new insights that challenge the critics. The BACH-PICASSO project focuses directly on the core question of how semantic objects emerge through perceptual integration in neural circuits. Inspired by explorations in literary theory and philosophy, we developed an experimental paradigm to study the basic neural mechanisms that forge new units of thought. We address this question by integrating multiple neuroscience methods, from the very detailed (looking at single synapses, or connections, between individual neurons) to the global (brain waves measured with electrodes on the head of a human subject).

The project combines these techniques to address the dynamics of semantics in one and the same paradigm. The acronym BACH-PICASSO packs the theme in two ways: It describes the theme (Bivalent Adaptive Computational Headquarters for the Perceptual Integration of Compound Audiovisual Stimuli into Semantic Objects), and it also pays tribute to the aesthetic dimension that prompted the question, with two of the greatest artists in the auditory and the visual domain. This project combines operant and classical conditioning with compound auditory and visual stimuli – combinations that are neutral at first, but acquire a positive or negative meaning through conditioning. The key idea is that we use a single behavioral paradigm to move up and down in systems neuroscience, from experiments targeting single synapses, to recording of single neurons in task-performing animals, to measuring brain waves and cerebral blood flow in human subjects performing in analogous tasks.

This project aims to prove that the converging and multidisciplinary methods of cognitive neuroscience provide huge potential to study attention, consciousness, creative thought, and all of the mysterious aspects of the human experience. In addition to the exciting empirical data that are almost certain to derive from this project, we anticipate that it will provide us with plenty of fuel for one or more monographs that help shape new concepts in philosophy and literary theory.

Organization of the laboratory

Core members

Prof. Minoru Tsukada, Ph.D

Prof. Takeshi Aihara, Ph.D

Prof. Hiroshi Kojima, Ph.D

Assoc. Prof. Hiroshi Sasaki, Ph.D

Post-doctoral Staff

COE Researcher Yoshiyuki Yamazaki, Ph.D(2002~2007)

COE Researcher Hidenori Watanabe, Ph.D(2003~2008)

COE Researcher Yasuhiro Fukushima, Ph.D(2004~

COE Researcher Yoshinori Ide, Ph.D(2004~

COE Researcher Jiro Okuda, Ph.D

COE Researcher Muneyoshi Takahashi (2005~

COE Researcher Hiroki Fujiwara (2006~2008)


Internal and External Collaborators

Prof. Ichiro Tsuda, Ph.D ( Hokkaido University)

Prof. Sandner Guy, MD, Ph.D (Louis Pasteur University)

Prof. Makoto Nishiyama MD, Ph.D (NewYork University)

Assoc. Prof. Jan Lauwereyns, Ph.D. (Victoria University of Wellington)


Publications

Original Journal Papers

2009

Takahashi M, Lauwereyns J, Sakurai Y, Tsukada M. (in press) Behavioral state-dependent episodic representations in hippocampal CA1 neuronal activity during spatial alternation. Cognitive Neurodynamics.


2008

Abe N, Okuda J, Suzuki M, Sasaki H, Matsuda T, Mori E, Tsukada M, Fujii T. (2008) Neural correlates of true memory, false memory, and deception. Cerebral Cortex 18(12): 2811-2819. Link

Fukushima Y, Tsukada M, Tsuda I, Yamaguti Y, Kuroda S. (in press) Coding mechanisms in hippocampal networks for learning and memory. Lecture notes for INNS-NNN08 symposia. Link

Kaneki K, Araki O, Tsukada M. (in press) Dual Synaptic Plasticity in the Hippocampus: Hebbian and Spatiotemporal Learning Dynamics. Cognitive Neurodynamics. Link

Lauwereyns J. (2008). The contribution of dopamine to the implementation of reward value during the control of action. Central Nervous System Agents in Medicinal Chemistry 8(2): 72-84. Link

Pan X, Sawa K, Tsuda I, Tsukada M, Sakagami M. (2008) Reward prediction based on stimulus categorization in primate lateral prefrontal cortex. Nature Neuroscience 11(6): 703-712. Link


2007

Aihara T, Abiru Y, Yamazaki Y, Watanabe H, Fukushima Y, Tsukada M. (2007) The relation between spike-timing dependent plasticity and Ca2+ dynamics in the hippocampal CA1 network. Neuroscience 145: 80-87. Link

Fujiwara K, Fujiwara H, Tsukada M, Aihara, K. (2007) Reproducing Bursting Interspike Interval Statistics of the Gustatory Cortex. BioSystems 90: 442-448. Link

Fukushima Y, Tsukada M, Tsuda I, Yamaguti Y, Kuroda S. (2007) Spatial clustering property and its self-similarity in membrance potentials of hippocampal CA1 pyramidal neurons. Cognitive Neurodynamics 1: 305-316. Link

Lucas C, Lauwereyns J. (2007) Selective working memory disables inhibition of visual features. Experimental Psychology 54: 256-263. Link

Okuda J, Fujii T, Ohtake H, Tsukiura T, Yamadori A, Frith CD, Burgess PW. (2007) Differential involvement of regions of rostral prefrontal cortex (Brodmann area 10) in time- and event-based prospective memory. International Journal of Psychophysiology 64(3): 233-246. Link

Tsukada M, Yamazaki Y, Kojima H. (2007) Interaction between the Spatio-Temporal Learning Rule (STLR) and Hebb type (HEBB) in single pyramidal cells in the hippocampal CA1 Area. Cognitive Neurodynamics 1(2): 157-167. Link

Wisnewski RG, Lauwereyns J. (2007) Systemic dizocilpine (MK-801) facilitates performance in opposition to response bias. Behavioral and Brain Functions 3(48): 1-4. Link


2006

Okazaki, S. Kanoh, K. Takaura, M. Tsukada, K. Oka Change detection and difference detection of tone duration discrimination. Neuroreport 17(4),pp. 395-399, 2006 Link

H. Watamabe, T. Aihara, M. Tsukada Phase shift of subthreshold theta oscillation in hippocampal CA1 pyramidal cell membrane by excitatory synaptic inputs. Neuroscience Vol. 140(4),pp1189-1199, 2006 Link

Pan X, Tsukada M: A model of the hippocampal-cortical memory system.Biolgical Cybernetics  95, pp159-167, 2006. Link

Jiro Okuda, Toshikatsu Fujii, Hiroya Ohtake, Takashi Tsukiura, Atsushi Yamadori, Christopher D. Frith, Paul W. Burgess. Differential involvement of regions of rostral prefrontal cortex (Brodmann area 10) in time- and event-based prospective memory. International Journal of Psychophysiology (in press) Link

Paul W. Burgess, Iroise Dumontheil, Sam J. Gilbert, Jiro Okuda, Marieke Sholvinck.Burgess, Simons, J. S. On the role of rostral prefrontal cortex (area 10) in prospective memory. In: Prospective memory: Cognitive, neuroscience, developmental, and applied perspectives. Kliegel, M., McDaniel, M.A. & Einstein, G.O. (eds.) (Mahwah, Erlbaum, in press) [ Link]

Kojima, H., Simburger, E., Nakai. J., Boucsein, C., Maruo, T., Tsukada, M., Okabe, S., Aertsen, Ad. Development of a system for patterned rapid photolysis and 2-photon confocal microscopy. (in press) Nobember issue. IEEE Circuit and Device (Leos). [ Link]

Tsukada M, Yamazaki Y: Interaction between the Spatio-Temporal Learning Rule (STLR) and Hebb type (HEBB) in single pyramidal cells in the hippocampal CA1 Area. Cognitive Neurodynamics (in press) Link

Fujiwara K, Fujiwara H, Tsukada M, Aihara, K: Reproducing Bursting Interspike Interval Statistics of the Gustatory Cortex. BioSystems 2006 ( accepted). Link

Tsukada M, Yamazaki Y: Functional Differences between the Spatio-Temporal Learning Rule (STLR) and Hebb type (HEBB) in single pyramidal cells in the hippocampal CA1 Area. Lecture note in Computer Science, Springer, Vol. 4232/2006, p.72-81, 2006 Link

Tsukada M, Aihara T, Saito H, Kato H: A spatio-temporal learning rule based on the physiological data of LTP induction in the hippocampal CA1 network. Lecture Notes in Computer Science, Springer, Vol. 1112/1996, p.709-714, 2006 Link

Lauwereyns, J. & Wisnewski, R. G. (2006). A reaction-time paradigm to measure reward-oriented bias in rats. Journal of Experimental Psychology: Animal Behavior Processes, 32, 467-473. Link

Lauwereyns, J. (2006). Voluntary control of unavoidable action. Trends in Cognitive Sciences, 10, 47-49. Link

Lauwereyns, J., Wisnewski, R. G., Keown, K., & Govan, S. (2006). Crosstalk between on- and off-line processing of visual features. Psychological Research, 70, 170-179. Link


2006 (Submitted)

Kojima, H., Ileva, LV., Traynelis SF., and Tsukada, M. (2004) Nonstationary Noise Analysis and its Application to Synaptic Plasticity. Biological Cybernetics (Submitted).


2006 (In preparation)

Kojima, H., Ileva, V.L., and Santamaria, F. (2006). Mechanisms of glutamate receptor channels underlie long-term depression of cerebellar Purkinje cell of rat. Journal of Neuroscience (to be submitted)

Kojima, H. and Marshall, L.M. (2006) Change in properties of Nicotonic ACh Receptor Channels in B-cells of Bullfrog Sympathetic Ganglion during Development. NeuroReport (to be submitted).

Kojima, H., Katsumata, S., Sakai, K. (2006) Theoretical investigation of pyramidal cell information processing by computer simulation. The Journal of Neuroscience( to be submitted)

Ide Y, Miyazaki T, Lauwereyns J, Sandner G, Tsukada M: Phantom signals from fear conditioning in the guinea pig auditory cortex. Current Biology, 2006.


2005

Aihara T, Kobayashi Y, Tsukada M Spatiotemporal visualization of long-term potentiation and depression in the hippocampal CA1 area. Hippocampus 15: 68-78, 2005 Link

Tsukada M, Aihara T, Kobayashi Y, Shimazaki H Spatial analisis of spike-timing-dependent LTP and LTD in the CA1 area of hippocampal slices using optional imaging Hippocampus 15:104-109, 2005 [ Link]

Tsukada M, Pan X: The Spatiotemporal Learning Rule and Its Efficiency in separating spatiotemporal patterns. Biolgical Cybernetics 92, pp139-146, 2005 Link

Taufiq AM, Fujii S, Yamazaki Y, Sasaki H, Kaneko K, Li J, Kato H, Mikoshiba K, Involvement of IP3 receptors in LTP and LTD induction in guinea pig hippocampal CA1 neurons, Learn Mem 12(6), 594-600, 2005. Link


2004

Urakubo H, Aihara T, Kuroda S, Watanabe M, Kondo S. Spatial localization of synapses required for supralinear summation of action potentials and EPSPs. J. Computational Neuroscience 16(3) 251-65 Link

Toshikatsu Fujii, Maki Suzuki, Jiro Okuda, Hiroya Ohtake, Kazuyo Tanji, Keiichiro Yamaguchi, Masatoshi Itoh, Atsushi Yamadori. Neural correlates of context memory with real-world events, NeuroImage 2004, 21, 1596-1603. Link

Fujii S, Sasaki H, Mikoshiba K, Kuroda Y, Yamazaki Y, Mostafa Taufiq A, Kato H, A chemical LTP induced by co-activation of metabotropic and N-methyl-D-aspartate glutamate receptors in hippocampal CA1 neurons, Brain Res 999(1): 20-28,2004. Link

Kojima, H., Humeua, Y., Poulain, B. and Tsukada, M., Application of modified non-stationary analysis for the inhibitory synapstic transmission in Aplysia. Tamagawa University Research Review. Vol.10, p1-18, 2004 [ Link]


2003

Jiro Okuda, Toshikatsu Fujii, Hiroya Ohtake, Takashi Tsukiura, Kazuyo Tanji, Kyoko Suzuki, Ryuta Kawashima, Hiroshi Fukuda, Masatoshi Itoh, Atsushi Yamadori. Thinking of the future and past: the roles of the frontal pole and the medial temporal lobes, NeuroImage 2003, 19, 1369-1380. Link

Kazuyo Tanji, Kyoko Suzuki, Jiro Okuda, Shimizu, H., Seki, H., Kimura, I., Keiko Endo, Kazumi Hirayama, Toshikatsu Fujii, Atsushi Yamadori. Formant interaction as a cue to vowel perception: a case report, Neurocase 2003, 9, 350-355. Link

Hyun-Suk Lee, Toshikatsu Fujii, Jiro Okuda, Takashi Tsukiura, Atsushi Umetsu, Maki Suzuki, Tatsuo Nagasaka, Shoki Takahashi, Atsushi Yamadori. Changes in brain activation patterns associated with learning of Korean words by Japanese: An fMRI study, NeuroImage 2003, 20, 1-11. Link

Watanabe, K., Lauwereyns, J., & Hikosaka, O. (2003). Neural correlates of rewarded and unrewarded eye movements in primate caudate nucleus. Journal of Neuroscience, 23, 10052-10057. Link

Watanabe, K., Lauwereyns, J., & Hikosaka, O. (2003). Effects of motivational conflicts on visually elicited saccades in monkeys. Experimental Brain Research, 152, 361-367. Link


2002

Takahashi S, Sakurai Y, Tsukada M, Anzai Y, Classification of neuronal activities form tetrode recordings using independent component analysis. Neurocomputing 49, 289-298, 2002 Link

Humeau, Y., Popoff, M., Kojima, H., Doussau, F., Poulain, B. Rac GTPase Plays an Essential Role in Exocytosis by Controlling the Fusion Competence of Release Sites. The Journal of Neuroscience vol. 22(18) p7968-7981, 2002 Link

Maki Suzuki, Toshikatsu Fujii, Takashi Tsukiura, Jiro Okuda, Atsushi Umetsu, Tatsuo Nagasaka, Shunji Mugikura, Isao Yanagawa, Shoki Takahashi, Atsushi Yamadori. Neural basis of temporal context memory: a functional MRI study, NeuroImage 2002, 17, 1790-1796. Link

Takashi Tsukiura, Toshikatsu Fujii, Jiro Okuda, Hiroya Ohtake, Ryuta Kawashima, Masatoshi Itoh, Hiroshi Fukuda, Atsushi Yamadori. Time-dependent contribution of the hippocampal complex when remembering the past: a PET study, NeuroReport 2002, 13, 2319-2323. Link

Toshikatsu Fujii, Jiro Okuda, Takashi Tsukiura, Hiroya Ohtake, Maki Suzuki, Ryuta Kawashima, Masatoshi Itoh, Hiroshi Fukuda, Atsushi Yamadori. Encoding-related brain activity during deep processing of verbal materials: a PET study, Neuroscience Research 2002, 44, 429-438. Link

Takashi Tsukiura, Toshikatsu Fujii, Toshimitsu Takahashi, Xiao, R., Motoaki Sugiura, Jiro Okuda, Toshio Iijima, Atsushi Yamadori. Medial temporal lobe activation during context-dependent relational processes in episodic retrieval: an fMRI study. Human Brain Mapping 2002, 17, 203-213. Link

Atsushi Umetsu, Jiro Okuda, Toshikatsu Fujii, Takashi Tsukiura, Tatsuo Nagasaka, Isao Yanagawa, Motoaki Sugiura, Kentaro Inoue, Ryuta Kawashima, Kyoko Suzuki, Michio Tabuchi, Murata, T., Shunji Mugikura, Higano, S., Shoki Takahashi, Hiroshi Fukuda, Atsushi Yamadori. Brain activation during the fist-edge-palm test: a functional MRI study, NeuroImage 2002, 17, 385-392. Link

Toshikatsu Fujii, Jiro Okuda, Takashi Tsukiura, Hiroya Ohtake, Rina Miura, Reiko Fukatsu, Kyoko Suzuki, Ryuta Kawashima, Masatoshi Itoh, Hiroshi Fukuda, Atsushi Yamadori. The role of the basal forebrain in episodic memory retrieval: a positron emission tomography study, NeuroImage 2002, 15, 501-508. Link

Takashi Tsukiura, Toshikatsu Fujii, Reiko Fukatsu, Taisuke Otsuki, Jiro Okuda, Atsushi Umetsu, Kyoko Suzuki, Michio Tabuchi, Isao Yanagawa, Tatsuo Nagasaka, Ryuta Kawashima, Hiroshi Fukuda, Shoki Takahashi, Atsushi Yamadori. Neural basis of the retrieval of people's names: evidence from brain-damaged patients and fMRI, Journal of Cognitive Neuroscience 2002, 14, 922-937. Link

Fujii S, Sasaki H, Ito K-I, Kaneko K, Kato H, Temperature dependence of synaptic responses in guinea pig hippocampal CA1 neurons in vitro, Cell Mol Neurobiol 22: 379-391, 2002. Link

Fujii S, Igarashi K, Sasaki H, Furuse H, Ito K-I, Kaneko K, Kato H, Inokuchi J, Waki H, Ando S, Effects of the mono- and tetrasialogangliosides GM1 and GQ1b on ATP-induced long-term potentiation in hippocampal CA1 neurons, Glycobiology 12: 339-344, 2002. Link

He B, Zhang X, Lian J, Sasaki H, Wu D, Towle VL, Boundary element method-based cortical potential imaging of somatosensory evoked potentials using subjects' magnetic resonance images, Neuroimage 16: 564-576, 2002. Link

Jiro Okuda, Toshikatsu Fujii, Hiroya Ohtake, Takashi Tsukiura, Atsushi Umetsu, Maki Suzuki, Atsushi Yamadori. Brain mechanisms underlying human prospective memory. In: Frontiers of Human Memory. Atsushi Yamadori, Ryuta Kawashima, Toshikatsu Fujii, Kyoko Suzuki (eds.), pp. 79-95 (Tohoku University Press, Sendai, Japan, 2002). [ Link]

Toshikatsu Fujii, Jiro Okuda, Takashi Tsukiura, Hiroya Ohtake, Maki Suzuki, Atsushi Yamadori. Episodic memory encoding and the medial temporal lobe. In: Frontiers of Human Memory. Atsushi Yamadori, Ryuta Kawashima, Toshikatsu Fujii, Kyoko Suzuki (eds.), pp. 253-262 (Tohoku University Press, Sendai, Japan, 2002). [ Link]

Kyoko Suzuki, Yuji Otuska, Akira Sugawara, Jiro Okuda, Nobukazu Nakasato, Atsushi Yamadori. Effects of memory on the judgement of incongruity: A magnetoencephalographic study. In: Frontiers of Human Memory. Atsushi Yamadori, Ryuta Kawashima, Toshikatsu Fujii, Kyoko Suzuki (eds.), pp. 97-104 (Tohoku University Press, Sendai, Japan, 2002). [ Link]

Lammertyn, J., Fias, W., & Lauwereyns, J. (2002). Semantic influences on feature-based attention due to the overlap of neural circuits. Cortex, 38, 878-882. Link

Lauwereyns, J., Watanabe, K., Coe, B., & Hikosaka, O. (2002). A neural correlate of response bias in monkey caudate nucleus. Nature, 418, 413-417. Link

Kobayashi, S., Lauwereyns, J., Koizumi, M., Sakagami, M., & Hikosaka, O. (2002). Influence of reward expectation on visuospatial processing in macaque lateral prefrontal cortex. Journal of Neurophysiology, 87, 1488-1498. Link

Lauwereyns, J., Takikawa, Y., Kawagoe, R., Kobayashi, S., Koizumi, M., Coe, B., Sakagami, M., & Hikosaka, O. (2002). Feature-based anticipation of cues that predict reward in monkey caudate nucleus. Neuron, 33, 463-473. Link

Conference Presentations (International)

2008

Fukushima Y, Kiryu S, Tsukada M, Aihara T. (2008) The effect of the proximal dendritic input on the information processing at the distal dendrite by means of back-propagating action potential in the hippocampal CA1 neuron. Annual Meeting of the

Fukushima Y, Tsukada M, Tsuda I, Yamaguti Y, Kuroda S. (2008) Possibility of Cantor coding by spatial input patterns. 15th International Conference on Neural Information Processing of the Asia-Pacific Neural Network Assembly (ICONIP-2008) November 25-28, Auckland, New Zealand

Ide Y, Lauwereyns J, Tsukada M. 'Optical imaging of plastic changes induced by fear conditioning in the auditory cortex of guinea pig. 15th International Conference on Neural Information Processing of the Asia-Pacific Neural Network Assembly (ICONIP-2008) November 25-28, 2008, Auckland, New Zealand

Kojima H. (2008) Gulutamate receptor channel kinetics models and synaptic plasticity: future application of 2-thoton laser photolysis. 1st International Symposium, INNS-NNN 2008, Auckland, New Zealand.

Miyamoto A, Toujoh S, Sakai K, Katsumata S, Kojima H. (2008) An analysis of synaptic transmission and its plasticity by glutamate receptor channel kinetics models and 2-photon laser photolysis. 1st International Symposium, INNS-NNN 2008, Auckland, New Zealand.

Tsukada M. (2008) Coding mechanisms in hippocampal networks for learning and memory. 1st International Symposium, INNS-NNN 2008, Auckland, New Zealand.

Tsukada M, Fukushima Y, Tsuda I, Yamaguti Y, Kuroda S. (2008) Cantor coding mechanisms in hippocampal networks for learning and memory. 1st International Symposium, INNS-NNN 2008, Auckland, New Zealand.

Weaver M, Lauwereyns J. (2008, November) Semantic influences on overt and covert attention. Annual Meeting of the American Society for Neuroscience, Washington, DC, U.S.A.

Weaver M, Lauwereyns J. (2008, August) Semantic influences on overt and covert attention. 26th International Australasian Winter Conference on Brain Research, Queenstown, New Zealand.


2007

Derom D, Lauwereyns J. (2007, November) Integrating past, present and future data sets: Using ANEVA for data synthesis. Annual Meeting of the American Society for Neuroscience, San Diego, CA, U.S.A.

Fukushima Y, Tsukada M, Tsuda I, Yamaguti Y, Kuroda S. (2007) Physiological evidence for Cantor coding output in hippocampal CA1 neurons. The 1st International conference on cognitive neurodynamics, Shanghai, China

Fukushima Y, Tsukada M, Tsuda I, Yamaguti Y, Kuroda S. (2007) The potentials of Cantor coding in hippocampal CA1 pyramidal neurons. 39th Annual General Meeting European Brain and Behaviour Society, Trieste, Italy

Ide Y, Lauwereyns J, Sandner G, Tsukada M. (2007, November) Optical imaging of plastic changes induced by fear conditioning in the auditory cortex of guinea pig. The 1st International Conference on Cognitive Neurodynamics, Shanghai, P.R. China.

Kuroda S, Yamaguti Y, Fukushima Y, Tsukada M, Tsuda I. (2007) Iterated function systems in hippocampal CA1 neurons. The 1st International conference on cognitive neurodynamics, Shanghai, China

Takahashi M, Lauwereyns, J, Sakurai Y, Tsukada M. (2007, November). Hippocampal code for alternation sequence during fixation. 7th International Neural Coding Workshop (Neural Coding 2007), Montevideo, Uruguay.

Takahashi M, Lauwereyns J, Sakurai Y, Tsukada M. (2007, November). Sequential coding of spatial response bias in hippocampal CA1 neurons. Annual Meeting of the American Society for Neuroscience, San Diego, CA, U.S.A.

Tsukada M, Fukushima Y, Kojima H, Tsuda I, Yamaguti Y, Kuroda S. (2007) A spatiotemporal coding in the hippocampal CA3-CA1 networks. 7th International Neural Coding Workshop (Neural Coding 2007), Montevideo, Uruguay.

Weaver M, Yim J, Carpenter RHS, Lauwereyns J. (2007, November) The expression of response bias in manual single versus double choice tasks: An ERP study. Annual Meeting of the American Society for Neuroscience, San Diego, CA, U.S.A.

Weaver M, Yim J, Carpenter RHS, Lauwereyns J. (2007, November) The expression of response bias in manual single versus double choice tasks: An ERP study. 69th Meeting of the Wellington Health and Biomedical Research Society, Wellington, New Zealand.

Yamaguti Y, Kuroda S, Tsuda I, Tsukada M, Fukushima Y. (2007) Cantor coding of temporal sequences in hippocampal CA1 model. 39th Annual General Meeting European Brain and Behaviour Society, Trieste, Italy


2006

Kojima, H., Nakazato, Y., Toujou, M., Yoneyama, M., Tsukada, M. Multi-point synaptic activation by UV-laser uncaging system. Society for Neuroscience in the USA. 479, 2006

Kojima, H., Yoneyama, M., Kamijou, M., Yamazaki, Y., Tsukada, M. (2006) Imaging analysis of associative LTP in rat hippocampus CA1 region. O66, 1O-04F7. The Journal of Physiological Sciences S84, vol. 56 Suppl. April. 

Kojima, H. (2006) A system for rapid uncaging in defined patterns and its application. Neuroscience Research S67 OS3P-2-04.

Uchikune Y, Shiun D, Urakubo H, Kitajima T, Tsukada M, Aihara T. The relation of information processing at the proximal and distal dendrite in the hippobcanpal CA1 network. Society for Neuroscience 2006. 63, 2006

Kiatajima S, Sawai Y, Nishiyama M, Hong K, Aihara T. Modeling approach for the bi-directional turning of axon growth cone. Society for Neuroscience 2006, 2006

Masahiro Kawasaki, Masataka Watanabe, Jiro Okuda, Masamichi Sakagami, Kazuyuki Aihara. 36th Annual Meeting of the Society for Neuroscience, Atlanta, Georgia, October 14-18, 2006.

Yosuke Morishima, Rei Akaishi, Jiro Okuda, Tetsuya Matsuda, Hiroshi Sasaki, Keiichiro Toma, Katsuyuki Sakai. Temporal dynamics of effective connectivity in attentional network. 36th Annual Meeting of the Society for Neuroscience, Atlanta, Georgia, October 14-18, 2006.

Paul W. Burgess, Jiro Okuda, Marieke Sholvinck, Jon S. Simons, Sam J. Gilbert, Iroise Dumontheil, Angela Costello, Sally Zlotowitz, Shelley Channon, Catrin Forbes. The role of rostral prefrontal cortex (Area 10) in prospective memory. 4th International Conference on Memory (Symposium), Sydney, Australia, July 16-21, 2006.

Nobuhito Abe, Jiro Okuda, Maki Suzuki, Hiroshi Sasaki, Tetsuya Matsuda, Etsuro Mori, Minoru Tsukada, Toshikatsu Fujii. Brain activities associated with false memory and deception: an fMRI investigation. 4th International Conference on Memory, Sydney, Australia, July 16-21, 2006.

Sayuri Takahira, Torsten Wustenberg, Tetsuya Matsuda, Kirsten Jordan, Hans Strasburger, Jiro Okuda. Contribution of eye movements to neural network activation in mental rotation. 12th Annual Meeting of the Organization for Human Brain Mapping, Florence, Italy, June 11-15, 2006.

Masahiro Kawasaki, Masataka Watanabe, Jiro Okuda, Masamichi Sakagami. SFS for feature selective maintenance, IPS for simple maintenance in visual working memory. 5th Annual Meeting of the Vision Sciences Society, Sarasota, Florida, May 5-10, 2006.

Masahiro Kawasaki, Masataka Watanabe, Jiro Okuda, Masamichi Sakagami. Feature integration in visual working memory: An fMRI study. CNS (Cognitive Neuroscience Society) 2006 Annual Meeting, San Francisco, CA, April 8-11, 2006.

Lauwereyns, J. (2006, August). Neural circuits for executive control of sensitivity and bias in vision. Invited talk, Symposium on “Brain area interaction” (Convener: Koki Kawamura), 29th European Conference on Visual Perception, St Petersburg, Russia.


2005

H.Wtanabe, T.Aihara, M.Tsukada Phase shift of theta oscillation in hippocampal CA1 pyramidal call membrane Proc. of 35nd Annual Meeting, Society for Neuroscience 971.14 (2005)

T.Aihara, M.Uchida, Y.Uchikune, D.Shiun, Y.Fukushima, M.Tsukada The characteristics of information processing in the proximal and the distal dendrite in the hippocampal CA1 network Proc. of 35nd Annual Meeting, Society for Neuroscience 384.14 (2005)

Y.Sawai, T.Kitajima, T. Aihara, M Nishiyma, K. Hong Cytosolic calcium oscillation in a model cell by reciplocal interactions between ER Ca release/uptake and plasmalemmal Ca entry/extrusion, Proc. of 35nd Annual Meeting, Society for Neuroscience 688.14 , 2005

Kojima, H., Humeau, Y., Tsukada, M. and Poulain, B. (2005) A graphical analysis of synaptic transmission in Aplysia. Japanese Journal of Physiology Suppl. S152,

Fukushima, Y., Yamazaki. Y., Aihara, T., Kojima, H. and Tsukada, M. (2005) The requirement of back-propagating action potentials to the induction of associative LTP in hippocampal CA1 pyramidal neurons. Neuroscience Research Suppl.

Jiro Okuda. Cognitive neuroscience of prospective memory. 2nd International Conference on Prospective Memory (Discussant of Neuroscience Session), Zurich, Switzerland, July 25-27, 2005.

Jiro Okuda, Jon S. Simons, Sam J. Gilbert, Christopher D. Frith, Paul W. Burgess. Target probability effects in prospective memory: a trade-off between ongoing- and target-related activities as revealed by functional magnetic resonance imaging. 2nd International Conference on Prospective Memory, Zurich, Switzerland, July 25-27, 2005.

Jiro Okuda, Hiroshi Sasaki, Ryosuke Soga, Tetsuya Matsuda, Manabu Tsumoto, Katsuyuki Sakai, Minoru Tsukada. Covert sensation of time in the left hippocampal region. 11th Annual Meeting of The Organization for Human Brain Mapping, Toronto, Canada, June 13-16, 2005.

Tetsuya Matsuda, Katsuyuki Sakai, Jiro Okuda, Hiroshi Sasaki, Masato Matsuura, Minoru Tsukada1. Integration of auditory and visual information with attention shift. 11th Annual Meeting of The Organization for Human Brain Mapping, Toronto, Canada, June 13-16, 2005.

Paul W. Burgess, Jiro Okuda, Marieke Sholvinck, Jon S. Simons, Sam J. Gilbert, Iroise Dumontheil, Angela Costello, Sally Zlotowitz, Shelley Channon, Catrin Forbes. The role of rostral prefrontal cortex (Area 10) in prospective memory. 2nd International Conference on Prospective Memory, Zurich, Switzerland, July 25-27, 2005.

Paul W. Burgess, Iroise Dumontheil, Catrin Forbes, Sam J. Gilbert, Jiro Okuda, Marieke Sholvinck. The role of rostral prefrontal cortex in prospective memory. Annual Meeting for International Neuropsychological Society (Symposium: The functional and neural basis of prospective memory), Dublin, Ireland, July 6-9, 2005.

Tetsuya Matsuda, Katsuyuki Sakai, Jiro Okuda, Hiroshi Sasaki, Minoru Tsukada. Cue-related activity during visual and auditory target detection task. 35th Annual Meeting of the Society for Neuroscience, Washington D.C., November 12-16, 2005.

Keiichiro Toma, Hiroshi Sasaki, Manabu Tsumoto, Jiro Okuda, Tetsuya Matsuda, Katsuyuki Sakai. Neural substrates for detecting the distinctiveness of targets presented at variable local sequence probability. 35th Annual Meeting of the Society for Neuroscience, Washington D.C., November 12-16, 2005.

Manabu Tsumoto, Hiroshi Sasaki, Jiro Okuda, Tetsuya Matsuda, Katsuyuki Sakai. Modulation of fusiform activity during explicit and implicit categorization of ambiguous face images. 35th Annual Meeting of the Society for Neuroscience, Washington D.C., November 12-16, 2005.

Wisnewski, R. G., Harper, D. N., Schenk, S., & Lauwereyns, J. (2005, November). Effects of NMDA versus dopamine antagonists on reward-oriented spatial bias in rats. NIDA minisymposium, Washington, D.C., U.S.A.

Wisnewski, R. G., Harper, D. N., Schenk, S., & Lauwereyns, J. (2005, November). Effects of NMDA versus dopamine antagonists on reward-oriented spatial bias in rats. Annual Meeting of the American Society for Neuroscience, Washington, D.C., U.S.A.


2004

AiharaT, Kashiwagi Y, Tsukada M The Ca2+ mobility during the induction of spike-timing-dependent plasticity in the hippocampal CA1 network. NOLTA2004, 215-218, 2004

AiharaT, Kashiwagi Y, Watanabe H, Fukushima Y, Tsukada M The relation between STDP and Ca2+ influx in the hippocampal CA1 network analyzed using optical imaging. Society for Neuroscience, 57(3) 16, 2004

S. Okazaki, S. Kanoh, K. Shisbuya, K. Takaura, K. Takeda, M. Tsukada, K. Oka Duration Mismatch Negativity in Hippocampus of Anesthetized Guinea Pigs. Society for Neuroscience 2004/10/23-27

Kojima, H., Munro, P., Dupon, J-L., Bossu, J-L., Poulain, B., Boquet, P and Tsukada., M. (2004) High sensitivity of Mouse neuronal cells to Tetanus Toxin requires a GPI-anchored protein. Japanese Journal of Physiology vol. 54, Suppl, 306 S142

Kojima, H., Satoh, M., Magamune, Y and Tsukada, M. (2004) Enhancement of optical signals recorded from CA1 of CaMKII-transgenic mouse during long-term potentiation. Neuroscience Research Suppl. 1, vol. 50, OG3-10

Kojima, H., Munro, P., Dupont, J-L., Bossu, J-L, Poulain, B. and Tsukada, M. Important role of rafts and GPI-anchored proteins in neuron sensitivity to TeNT. (2004) 144.9. Oral session of Presynaptic Mechanisms. Society for Neuroscience USA, 2004.

Tsukada, M., Yamazaki, Y. and Kojima, H., (2004) Experimental investigation of dynamical model of learning and memory. Proceedings of the Sentan-nou. P159

Jiro Okuda, Christopher D. Frith, Paul W. Burgess. Organisation of time- and event-based intentions in the rostral prefrontal cortex. 10th Annual Meeting of the Organization for Human Brain Mapping, Budapest, Hungary, June, 2004.

Wisnewski, R. G., Harper, D. N., Schenk, S., & Lauwereyns, J. (2004, October). Dopamine receptor contributions to reward-oriented visuo-spatial processing in rats. Annual Meeting of the American Society for Neuroscience, San Diego, U.S.A.

Wisnewski, R. G., Harper, D. N., Schenk, S., & Lauwereyns, J. (2004, August). Dopamine receptor contributions to reward-oriented visuo-spatial processing in rats. 22nd International Australasian Winter Conference on Brain Research, Queenstown, New Zealand.

Lauwereyns, J. (2004, April). The reward factor in the control of action: A neurophysiological theory. 31st Australasian Experimental Psychology Conference, Dunedin, New Zealand.

Wisnewski, R. G., Keown, K., & Lauwereyns, J. (2004, April). Crosstalk between on- and off-line processing of visual features. 31st Australasian Experimental Psychology Conference, Dunedin, New Zealand.

Lauwereyns, J., Sakagami, M., Tsutsui, K., Kobayashi, S., Koizumi, M., & Hikosaka, O. (2004, January). Competition between relevant and irrelevant stimulus-response codes in prefrontal cortex. 22nd European Workshop on Cognitive Neuropsychology, Bressanone, Italy.


2003

M.Tsukada, T.Aihara, and Y.Kobayashi Spike timing LTP and LTD in the CA1 area of hippocampal slices by the optical imaging. Annual Computational Neuroscience meeting 2003 (2003) 7/5

T. Miyazaki, K. Takeda, S. Okazaki, R. Suzuki, Y. Usui, H. Sasaki, M. Mizuno, M. Tsukada, Y. Anzai Optical imaging of the response to two-tone sequences in the guinea pig auditory cortex. International Brain Research Organization 2003/7/10-15

S. Okazaki, K. Takeda, T. Miyazaki, T. Matsuda, Y. Kitamura, M. Tsukada, K. Oka Late Response Properties in Primary Auditory Cortex Cells of the Anesthetized Guinea Pig. Auditory Cortex Meeting 2003/9/13-17

S. Okazaki, K. Takeda, T. Miyazaki, T. Matsuda, Y. Kitamura, M. Tsukada, K. Oka Neuronal Mechanisms of Late Response in Primary Auditory Cortex of the Anesthetized Guinea Pig. Society for Neuroscience 2003/11/8-13

Shunji Mugikura, Toshikatsu Fujii, Maki Suzuki, Jiro Okuda, Hyung-suk Lee, Tatsuo Nagasaka, Yoshiyuki Hosokai, Shoki Takahashi. Retrieving contextual information about person and time in episodic memory. 9th Annual Meeting of the Organization for Human Brain Mapping, New York, NY, June 18-22, 2003.

Jiro Okuda. Imaging our future: From studies into prospective memory and future thinking. COE Lecture, Tamagawa University, Tokyo, Japan, June, 2003.

Jiro Okuda. Prospective memory and thoughts about the future. ICN Seminar, Institute of Cognitive Neuroscience, University College London, London, UK, June, 2003.

Koizumi, M., Kobayashi, S., Noritake, A., Lauwereyns, J., Sakagami, M., & Hikosaka, O. (2003, November). Role of lateral prefrontal cortex in speed of discrimination during a go/no-go task under selective attention. Annual Meeting of the American Society for Neuroscience, New Orleans, U.S.A.

Watanabe, K., Lauwereyns, J., & Hikosaka, O. (2003, August). Role of primate caudate nucleus in goal-oriented saccadic eye movement. The 12th European Conference on Eye Movements, Dundee, United Kingdom.


2002

Takashi S, Sakurai Y, Tsukada M, Anzai Y, Classification of neuronal activities form tetrode recordings using independent component analysis. Neurocomputing 49, 289-298, 2002

T. Miyazaki, K. Takeda, S. Okazaki, R. Suzuki, Y. Usui, H. Sasaki, M. Mizuno, M. Tsukada, Y. Anzai Inhibition and facilitation of the response to two tone sequences in the guinea pig auditory cortex using optical imaging method. Proc. of 32nd Annual Meeting, Society for Neuroscience, 354.16 (2002)

S. Okazaki, K. Takeda, T. Miyazaki, H. Sasaki, M. Tsukada Cross Correlation of Neuronal Activity in the Auditory Cortex of Guinea Pig -Reconsideration of Cross-Correlogram Method Application- The Society of Instrument and Control Engineers Annual Conference 2002/8/6

K. Takeda, S. Okazaki, J. Ushiba, T. Miyazaki, H. Sasaki, M. Tsukada, Y. Tomita The Change of Neuronal Response in Guinea-pig Auditory Cortex by Hippocampal Modulation -Application of Bootstrap Method- The Society of Instrument and Control Engineers Annual Conference 2002/8/6

M.Takahashi, M.Kawai, T.Aihara, M.Tsukada, Y.Anzai Dynamics of neuronal ensembles in rat hippocampus during serial-pattern tasks. Proc. of 32nd Annual Meeting, Society for Neuroscience (2002)

Y.Abiru, T. Aihara, H.Asai, H. Matsuda, M. Tsukada Spatial analysis of CA2+ infulux depending on the spike timing in the hippocanpal CA1 neurons. Proc. of 32nd Annual Meeting, Society for Neuroscience 152.9 p.70 (2002)

M. Takahashi, M Kawai, T. Aihara, M. Tsukada, Y. Anzai Dynamis of neuronal ensembles in rat hippocampus during serial-pattern tasks. Proc. of 32nd Annual Meeting, Society for Neuroscience 477.9 P.31 (2002)

T. Aihara, M. Tsukada, Y. kobayashi, H. Shimazaki Spike-timing dependent LTP and LTD in the CA1 area of Hippocampal slices using optical imaging methods.DBF-2001 proceedings p.15(2002)

Y.Abiru, T. Aihara, H.Asai, H. Matsuda, M. Tsukada Spatial analysis of CA2+ infulux depending on the spike timing in the hippocanpal CA1 neurons. Proc. of 32nd Annual Meeting, Society for Neuroscience 152.9 p.70 (2002)

K.Togashi, T. Kitajima, T. Aihara, K. Hong, M. Poo, M. Nishiyama Gating of activity-dependent long-term depression by GABAergic activity in the hippocampus. Proc. of 33nd Annual Meeting, Society for Neuroscience 123.4 ,2003

M. Takahashi, M Kawai, T. Aihara, M. Tsukada, Y. Anzai Dynamis of neuronal ensembles in rat hippocampus during serial-pattern tasks. Proc. of 32nd Annual Meeting, Society for Neuroscience 477.9 P.31 November, 2002

T. Aihara, M. Tsukada, Y. kobayashi, H. Shimazaki Spike-timing dependent LTP and LTD in the CA1 area of Hippocampal slices using optical imaging methods. DBF-2001 proceedings p.15, 2002

Jiro Okuda, Toshikatsu Fujii, Hiroya Ohtake, Takashi Tsukiura, Kazuyo Tanji, Kyoko Suzuki, Ryuta Kawashima, Hiroshi Fukuda, Masatoshi Itoh, Atsushi Yamadori. Thinking of the future and past: the roles of the frontal pole and the medial temporal lobes. 8th Annual Meeting of the Organization for Human Brain Mapping, Sendai, Japan, June 3-6, 2002.

Toshikatsu Fujii, Jiro Okuda, Maki Suzuki, Kazuyo Tanji, Hiroya Ohtake, Keiichiro Yamaguchi, Masatoshi Itoh, Ryuta Kawashima, Hiroshi Fukuda, Atsushi Yamadori. Neural networks for retrieving contextual information of real-world events: A PET study. 8th Annual Meeting of the Organization for Human Brain Mapping, Sendai, Japan, June 3-6, 2002.

Yuji Otsuka, Kyoko Suzuki, Nobukazu Nakasato, Jiro Okuda, Akitake Kanno, Keisaku Hatanaka, Atsushi Yamadori. Event-related magnetic responses elicited by phonological incongruency. 8th Annual Meeting of the Organization for Human Brain Mapping, Sendai, Japan, June 3-6, 2002.

Lauwereyns, J., Watanabe, K., & Hikosaka, O. (2002, November). The dynamics of reward-oriented response bias in monkey caudate nucleus. Annual Meeting of the American Society for Neuroscience, Orlando, U.S.A.

Watanabe, K., Lauwereyns, J., & Hikosaka, O. (2002, November). Neural activity for reluctant saccades in monkey caudate nucleus. Annual Meeting of the American Society for Neuroscience, Orlando, U.S.A.

Kobayashi, S., Lauwereyns, J., Koizumi, M., Sakagami, M., Kawagoe, R., Takikawa, Y., Coe, B. & Hikosaka, O. (2002, November). Motivational influence on visuospatial processing: Comparison between caudate and lateral prefrontal cortex. Annual Meeting of the American Society for Neuroscience, Orlando, U.S.A.

Lammertyn, J., Fias, W., & Lauwereyns, J., (2002, February). Semantic influences on feature-based attention due to overlap of neural circuits. 20th European Workshop on Cognitive Neuropsychology, Bressanone, Italy.