Biomedical subjects

Masato Okada

Publications and source records attributed to Masato Okada.

At least 55 records · Page 3Linked to original sources

PubMed2004

A network model of perceptual suppression induced by transcranial magnetic stimulation.

We modeled the inhibitory effects of transcranial magnetic stimulation (TMS) on a neural population. TMS is a noninvasive technique, with high temporal resolution, that can stimulate the brain via a brief magnetic pulse from a coil placed on the scalp. Because of these advantages, TMS is extensively used as a powerful tool in experimental studies of motor, perception, and other functions in humans. However, the mechanisms by which TMS interferes with neural activities, especially in terms of theoretical aspects, are totally unknown. In this study, we focused on the temporal properties of TMS-induced perceptual suppression, and we computationally analyzed the response of a simple network model of a sensory feature detector system to a TMS-like perturbation. The perturbation caused the mean activity to transiently increase and then decrease for a long period, accompanied by a loss in the degree of activity localization. When the afferent input consisted of a dual phase, with a strong transient component and a weak sustained component, there was a critical latency period of the perturbation during which the network activity was completely suppressed and converged to the resting state. The range of the suppressive period increased with decreasing afferent input intensity and reached more than 10 times the time constant of the neuron. These results agree well with typical experimental data for occipital TMS and support the conclusion that dynamical interaction in a neural population plays an important role in TMS-induced perceptual suppression.

Afferent Pathways↗

PubMed2004

Investigation of possible neural architectures underlying information-geometric measures.

A novel analytical method based on information geometry was recently proposed, and this method may provide useful insights into the statistical interactions within neural groups. The link between informationgeometric measures and the structure of neural interactions has not yet been elucidated, however, because of the ill-posed nature of the problem. Here, possible neural architectures underlying information-geometric measures are investigated using an isolated pair and an isolated triplet of model neurons. By assuming the existence of equilibrium states, we derive analytically the relationship between the information-geometric parameters and these simple neural architectures. For symmetric networks, the first- and second-order information-geometric parameters represent, respectively, the external input and the underlying connections between the neurons provided that the number of neurons used in the parameter estimation in the log-linear model and the number of neurons in the network are the same. For asymmetric networks, however, these parameters are dependent on both the intrinsic connections and the external inputs to each neuron. In addition, we derive the relation between the information-geometric parameter corresponding to the two-neuron interaction and a conventional cross-correlation measure. We also show that the information-geometric parameters vary depending on the number of neurons assumed for parameter estimation in the log-linear model. This finding suggests a need to examine the information-geometric method carefully. A possible criterion for choosing an appropriate orthogonal coordinate is also discussed. This article points out the importance of a model-based approach and sheds light on the possible neural structure underlying the application of information geometry to neural network analysis.

Action Potentials↗

PubMed2003

Robustness of retrieval properties against imbalance between long-term potentiation and depression of spike-timing-dependent plasticity.

Spike-timing-dependent plasticity (STDP) has recently been shown in some physiological studies. STDP depends on the precise temporal relationship of presynaptic and postsynaptic spikes. Many authors have indicated that a precise balance between long-term potentiation (LTP) and long-term depression (LTD) of STDP is significant for a stable learning. However, a situation in which the balance is maintained precisely is inconceivable in the brain. Using a method of the statistical neurodynamics, we show robust retrieval properties of spatiotemporal patterns in an associative memory model against the imbalance between LTP and LTD. When the fluctuation of LTD is assumed to obey a Gaussian distribution with mean 0 and variance delta(2), the storage capacity takes a finite value even at large delta. This means that the balance between LTP and LTD of STDP need not be maintained precisely, but must be maintained on average. Furthermore, we found that the basin of attraction becomes smaller as delta increases while an initial critical overlap remains unchanged.

Animals↗

PubMed2003

Transmembrane phosphoprotein Cbp senses cell adhesion signaling mediated by Src family kinase in lipid rafts.

Cbp, a C-terminal Src kinase (Csk)-binding protein, is a transmembrane phosphoprotein that has been implicated in the regulation of the Src family kinase (SFK) through recruiting Csk, a negative regulator of SFK, to a membrane microdomain of lipid rafts. To examine the contribution of Cbp to cell adhesion signaling mediated by SFK, we investigated the kinase responsible for phosphorylating Cbp and the mode of phosphorylation during the cell adhesion process. The results obtained by using mutant mice or cells that lack Csk and/or a member of SFK, Fyn, reveal that Cbp is phosphorylated predominantly by raft-localized Fyn in vivo. Upon cell adhesion onto fibronectin, Cbp becomes transiently phosphorylated (consistent with SFK activation) and recruits Csk to lipid rafts. These events are completed before the full activation of focal adhesion kinase, indicating that the transient activation and down-regulation of SFK in lipid rafts are earlier events in cell adhesion signaling. In Csk-deficient cells, continuous hyperactivation of SFK leads to continuous hyperphosphorylation of Cbp, accompanied by impaired cell spreading and migration. Silencing of Cbp by RNA interference also induced impaired cell spreading. These findings suggest that Cbp could serve as a sensor of SFK activity in early stages of cell adhesion signaling, and that Csk-mediated down-regulation of SFK is essential to allow dynamic cellular events involved in the regulation of cell spreading and migration.

Animals↗

PubMed2003

Mechanism of Csk-mediated down-regulation of Src family tyrosine kinases in epidermal growth factor signaling.

The Src family tyrosine kinases (SFKs) play pivotal roles as molecular switches that link a variety of extracellular cues to intracellular signaling pathway. The function of SFK is regulated by phosphorylation at the C-terminal regulatory site mediated by Csk. Recently a novel SFK target Cbp (or PAG) was identified as a membrane-anchored scaffold protein for Csk. To establish the mechanism of Csk/Cbp-mediated regulation of SFK in vivo, we observed dynamic changes in the interaction of Csk with Cbp by utilizing fusion proteins with modified green fluorescent proteins: cyan fluorescent protein (CFP) or yellow fluorescent protein (YFP). Upon SFK activation induced by epidermal growth factor stimulation, fluorescent resonance energy transfer (FRET) response was detected transiently at membrane ruffles in COS1 cells co-expressing CFP-Csk and Cbp-YFP and in cells expressing a single-molecule FRET indicator consisting of CskSH2 and Cbp. Suppression of SFK by PP2 or use of a mutant Cbp that lacks the Csk binding site abolished the FRET response, although a dominant-negative form of Csk enhanced and sustained the FRET response, demonstrating that the FRET response is dependent upon the SFK activity. These observations show that Csk/Cbp-mediated down-regulation of SFK takes place at membrane ruffles in an early stage of epidermal growth factor signaling and suggest that the Csk/Cbp-based FRET indicators are useful for monitoring the status of SFK in living cells.

Animals↗

PubMed2003

The neural computation of the aperture problem: an iterative process.

The aperture problem is defined as one of integrating motion information from inside and outside of the aperture, and determination of the true direction of motion of a line. Much is known about it and many models have been proposed for its neural mechanisms. However, it is still a matter of debate whether the brain solves the problem by using only feed-forward neural connections, also known as the one-shot algorithm, or by using the iterative algorithm while utilizing feedback as well as horizontal neural connections. Here we show unequivocal evidence for the latter model. The model was tested using critically designed psychophysical experiments and the results were perfectly in line with the psychophysical performance of the observers.

Algorithms↗

PubMed2003

Synapse efficiency diverges due to synaptic pruning following overgrowth.

In the development of the brain, it is known that synapses are pruned following overgrowth. This pruning following overgrowth seems to be a universal phenomenon that occurs in almost all areas-visual cortex, motor area, association area, and so on. It has been shown numerically that the synapse efficiency is increased by systematic deletion. We discuss the synapse efficiency to evaluate the effect of pruning following overgrowth, and analytically show that the synapse efficiency diverges as O(|ln c|) at the limit where connecting rate c is extremely small. Under a fixed synapse number criterion, the optimal connecting rate, which maximizes memory performance, exists.

Animals↗

PubMed2003

Identification of PSD-93 as a substrate for the Src family tyrosine kinase Fyn.

In order to study the role of tyrosine kinase signaling in the post-synaptic density (PSD), tyrosine-phosphorylated proteins associated with the PSD-95/NMDA receptor complex were analyzed. The NMDA receptor complex from the mouse brain was successfully solubilized with deoxycholate and immunopurified with anti-PSD-95 or anti-phosphotyrosine antibody. Immunoblot analyses revealed that the predominantly tyrosine-phosphorylated proteins in the NMDA receptor complex are the NR2A/B subunits and a novel 120 kDa protein. Purification and microsequencing analysis showed that the 120 kDa protein is mouse PSD-93/Chapsyn-110. Recombinant PSD-93 was phosphorylated by Fyn in vitro, and Tyr-384 was identified as a major phosphorylation site. Tyrosine phosphorylation of PSD-93 was greatly reduced in brain tissue from Fyn-deficient mice compared with wild-type mice. Furthermore, an N-terminal palmitoylation signal of PSD-93 was found to be essential for its anchoring to the membrane, where Fyn is also localized. In COS7 cells, exogenously expressed PSD-93 was phosphorylated, dependent on its membrane localization. In addition, tyrosine-phosphorylated PSD-93 was able to bind to Csk, a negative regulator of Src family kinases, in vitro as well as in a brain lysate. These results suggest that PSD-93 serves as a membrane-anchored substrate of Fyn and plays a role in the regulation of Fyn-mediated modification of NMDA receptor function.

Amino Acid Sequence↗

PubMed2003

Changes in L1 and NCAM expression in the rat suprachiasmatic nucleus during growth and after orbital enucleation.

Mammals possess a master circadian clock in the hypothalamic suprachiasmatic nucleus (SCN). In order to clarify the roles of the L1 adhesion molecule (L1) and neural cell adhesion molecule (NCAM), both members of the immunoglobulin superfamily, in the organization of the clock core, changes in the expression of these molecules in the SCN during the growth of rats were examined by immunohistochemistry. On postnatal day 7, L1 and NCAM were chiefly expressed in the region surrounding the SCN, but not in the SCN itself. In subsequent weeks, however, expression of both molecules shifted predominately to the SCN. This change seemed to parallel immunoreactivity increases in the SCN of synaptotagmin, a synapse marker, and of phosphotyrosine, a possible factor in the photic entrainment of the SCN clock. To further elucidate the roles of the L1 and NCAM adhesion molecules in the formation and maintenance of retinal neural projection into the SCN, the effects of orbital enucleation on their expression in the SCN were examined. L1 expression decreased on days 1 and 2 after the operation, in parallel with reductions in the tyrosine phosphorylation of several proteins, but recovered to the control level by the second week. In contrast, the expression of NCAM showed little change following orbital enucleation. These results suggest that L1 and NCAM are involved in the morphological organization of the SCN during the developmental stage, and that expression of L1 also contributes to the formation of the SCN network in a manner that is dependent on the retinal neural input to it.

Animals↗

PubMed2003

Identification of Fer tyrosine kinase localized on microtubules as a platelet endothelial cell adhesion molecule-1 phosphorylating kinase in vascular endothelial cells.

Platelet endothelial adhesion molecule-1 (PECAM-1) is a part of intercellular junctions and triggers intracellular signaling cascades upon homophilic binding. The intracellular domain of PECAM-1 is tyrosine phosphorylated upon homophilic engagement. However, it remains unclear which tyrosine kinase phosphorylates PECAM-1. We sought to isolate tyrosine kinases responsible for PECAM-1 phosphorylation and identified Fer as a candidate, based on expression cloning. Fer kinase specifically phosphorylated PECAM-1 at the immunoreceptor tyrosine-based inhibitory motif. Notably, Fer induced tyrosine phosphorylation of SHP-2, which is known to bind to the immunoreceptor tyrosine-based inhibitory motif of PECAM-1, and Fer also induced tyrosine phosphorylation of Gab1 (Grb2-associated binder-1). Engagement-dependent PECAM-1 phosphorylation was inhibited by the overexpression of a kinase-inactive mutant of Fer, suggesting that Fer is responsible for the tyrosine phosphorylation upon PECAM-1 engagement. Furthermore, by using green fluorescent protein-tagged Fer and a time-lapse fluorescent microscope, we found that Fer localized at microtubules in polarized and motile vascular endothelial cells. Fer was dynamically associated with growing microtubules in the direction of cell-cell contacts, where p120catenin, which is known to associate with Fer, colocalized with PECAM-1. These results suggest that Fer localized on microtubules may play an important role in phosphorylation of PECAM-1, possibly through its association with p120catenin at nascent cell-cell contacts.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Identification of the human IAI.3B promoter element and its use in the construction of a replication-selective adenovirus for ovarian cancer therapy.

Little is known concerning promoters or gene therapy specific for ovarian cancer. To explore the potential use of IAI.3B isolated from ovarian cancer cells in gene therapy for ovarian cancer, we identified the promoter region of the IAI.3B gene and created a replication-selective adenovirus, AdE3-IAI.3B, driven by the promoter. Transient transfection experiments showed that the DNA segment located between -1816 and -1 bp resulted in preferential expression in ovarian cancer cells with negligible expression in squamous cell carcinoma and normal cells. The promoter activity of IAI.3B was almost the same as that of cytomegalovirus and an order of magnitude higher than those of midkine and cyclooxygenase-2 in ovarian cancer cells. AdE3-IAI.3B replicated as efficiently as the wild-type adenovirus and caused extensive cell killing in a panel of ovarian cancer cells in vitro. In contrast, squamous cell carcinoma and normal cells were not able to support AdE3-IAI.3B replication. In animal studies, AdE3-IAI.3B administered to flank and i.p. xenografts of ovarian cancer cells led to a significant therapeutic effect. These results demonstrate the usefulness of the IAI.3B promoter for generation of ovarian cancer-specific adenoviral vectors and provide a potential for the development of ovarian cancer-specific oncolytic viral therapies.

Adenoviridae↗

PubMed2003

Csk regulates integrin-mediated signals: involvement of differential activation of ERK and Akt.

Csk phosphorylates Src family tyrosine kinases and down-regulates their activities in vitro and in vivo. To gain insight into the integrin-mediated cellular functions of this negative regulator of the Src family, we examined integrin-mediated signals in Csk-deficient fibroblasts (Csk(-) cells) and their stable transfectants expressing re-introduced Csk (Csk(-)/Csk cells). Integrin-mediated activation of extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase in Csk(-)/Csk cells upon adhesion to fibronectin or laminin-10/11 was down-regulated, whereas Akt activation increased. Interestingly, the suppression of ERK-MAP kinase activation in Csk(-)/Csk cells was restored by overexpression of a dominant-negative Akt. In agreement with these results, Csk(-)/Csk cells were more resistant to apoptosis induced by serum depletion, but were less proliferative, compared with Csk(-) cells. These results, taken together, demonstrate that Csk is an important regulator of integrin-mediated signaling and cellular behavior.

Animals↗

PubMed2003

Molecular cloning and characterization of TPP36 and its isoform TPP32, novel substrates of Abl tyrosine kinase.

We have molecularly cloned TPP36, a novel 36 kDa protein with 281 amino acids that was identified as a protein phosphorylated in B progenitor cells following stimulation with pervanadate/H(2)O(2). Analysis with anti-TPP36 antiserum revealed that TPP36 was expressed ubiquitously and had an isoform with 236 amino acids, designated TPP32. TPP36/32 were localized mainly in cytoplasm despite the presence of a typical nuclear localization signal sequence. These proteins were phosphorylated preferentially by Abl among a panel of tyrosine kinases examined. Phosphorylation of tyrosine 120 in TPP36/32 led to an apparent mobility shift in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, suggesting conformational change in the phosphorylated protein. Thus, TPP36/32 appear to be novel substrates of Abl tyrosine kinase.

Amino Acid Sequence↗

PubMed2003

Suprachiasmatic nucleus circadian oscillatory protein, a novel binding partner of K-Ras in the membrane rafts, negatively regulates MAPK pathway.

Suprachiasmatic nucleus circadian oscillatory protein (SCOP) is a member of the leucine-rich repeat (LRR)-containing protein family. In addition to circadian expression in the rat hypothalamic suprachiasmatic nucleus, SCOP is constitutively expressed in neurons throughout the rat brain. Here we found that a substantial amount of SCOP was localized in the brain membrane rafts, in which only K-Ras was abundant among Ras isoforms. SCOP interacted directly through its LRR domain with a subset of K-Ras in the guanine nucleotide-free form that was present in the raft fraction. This interaction interfered with the binding of added guanine nucleotide to K-Ras in vitro. A negative regulatory role of SCOP for K-Ras function was examined in PC12 cell lines stably overexpressing SCOP or its deletion mutants. Overexpression of full-length SCOP markedly down-regulated ERK1/ERK2 activation induced by depolarization or phorbol ester stimulation, and this inhibitory effect of overexpressed SCOP was dependent on its LRR domain. These results strongly suggest that SCOP negatively regulates K-Ras signaling in the membrane rafts, identifying a novel mechanism for regulation of the Ras-MAPK pathway.

Animals↗

PubMed2003

Distinct roles of the Src family kinases, SRC-1 and KIN-22, that are negatively regulated by CSK-1 in C. elegans.

To elucidate the primitive roles of the Src family kinases (SFKs), here we characterized Caenorhabditis elegans orthologues of SFKs (src-1 and kin-22) and their regulator kinase Csk (csk-1). SRC-1 and KIN-22 possess the C-terminal regulatory tyrosines characteristic of SFKs, and their activities are negatively regulated by CSK-1 in a yeast expression system. The src-1 and csk-1 genes are co-expressed in some head neurons, the anchor cell and the tail region, while kin-22 and csk-1 genes are co-expressed in pharyngeal muscles and tail region. Expression of KIN-22 induced morphological defects in the pharynx, whereas expression of SRC-1 did not show any overt phenotype in adult. RNA interference of src-1, but not that of kin-22, caused a developmental arrest in early development. These results suggest that SRC-1 and KIN-22 play distinct roles under the control of CSK-1.

Animals↗

PubMed2003

Spatio-temporal dynamics of depth propagation on uniform region.

The depth of each point on a binocularly presented untextured horizontal bar is physically ambiguous except for the two vertical edges at both ends, since the correspondence between left and right images is not unique on such a uniform region. These depths, however, are unambiguously perceived, and this suggests the existence of some mechanism that interpolates the depth information from the two ends toward the center. Temporal properties of this integration process were examined by a phase-matching task, which allowed us to measure the phase of the perceived depth at the center of a horizontal bar when disparities at the ends were sinusoidally oscillated. We found that the perceived depth at the center of the bar was slightly temporally delayed for 7-60 ms relative to the physical depth at the ends. The difference increased with the length of the bar, decreased as the vertical position of the bar became farther from the fixation point, and increased in the presence of occluders. This finding indicates that depth information is propagated over an object to solve this ambiguity by using a time-consuming process. Accordingly, we suggest that depth propagation is accomplished by spatially local diffusion-like interactions of locally represented depth information.

Analysis of Variance↗

PubMed2003

Two-level hierarchy with sparsely and temporally coded patterns and its possible functional role in information processing.

We study the stability of two types of mixed states in an oscillator neural network model. Patterns to be stored are represented by complex variables whose amplitudes are either 0 (silent state) or 1 (firing state) and whose phases represent the timing of firing. The mixed states are defined in terms of a certain type of average over some specified number s of memory patterns. We define two types of such mixed states, each of which corresponds to a different type of restriction placed on this set of s memory patterns. The stability of each type is investigated both theoretically and numerically. We find that only one type of a mixed state, which consists of temporally correlated patterns, is stable. Finally, we discuss a possible functional role of such mixed states in information processing.

Mental Processes↗

PubMed2002

Statistical mechanics of the Bayesian image restoration under spatially correlated noise.

We investigated the use of the Bayesian inference to restore noise-degraded images under conditions of spatially correlated noise. The generative statistical models used for the original image and the noise were assumed to obey multidimensional Gaussian distributions, whose covariance matrices are translational invariant. We derived an exact description to be used as the expectation for the restored image by the Fourier transformation and restored an image distorted by spatially correlated noise by using a spatially uncorrelated noise model. We found that the resulting hyperparameter estimations for the minimum error and maximal posterior marginal criteria did not coincide when the generative probabilistic model and the model used for restoration were in different classes, while they did coincide when they were in the same class.

Journal Article↗