Tokyo Institute of Psychiatry

Tokyo, Japan

Tokyo Institute of Psychiatry

Tokyo, Japan
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Iguchi Y.,Nagoya University | Katsuno M.,Nagoya University | Takagi S.,Nagoya University | Ishigaki S.,Nagoya University | And 6 more authors.
Neurobiology of Disease | Year: 2012

TAR DNA-binding protein 43 (TDP-43) is a major component of ubiquitin-positive inclusion of TDP-43 proteinopathies including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions, which is now referred to as FTLD-TDP. TDP-43 in the aberrant inclusion is known to be hyperphosphorylated at C-terminal sites, to be truncated at the N-terminal region, and to re-distribute from nucleus to cytoplasm or neurite. The pathogenic role of these modifications, however, has not been clarified. Furthermore, there is no evidence about the initial cause of these modifications. Herein we show that ethacrynic acid (EA), which is able to increase cellular oxidative stress through glutathione depletion, induces TDP-43 C-terminal phosphorylation at serine 403/404 and 409/410, insolubilization, C-terminal fragmentation, and cytoplasmic distribution in NSC34 cells and primary cortical neurons. In the investigation using a nonphosphorylable mutant of TDP-43, there was no evidence that C-terminal phosphorylation of TDP-43 contributes to its solubility or distribution under EA induction. Our findings suggest that oxidative stress induced by glutathione depletion is associated with the process of the pathological TDP-43 modifications and provide new insight for TDP-43 proteinopathies. © 2011 Elsevier Inc.


Kida I.,Tokyo Institute of Psychiatry | Iguchi Y.,Tokyo Institute of Psychiatry | Hoshi Y.,Tokyo Institute of Psychiatry
NeuroImage | Year: 2011

Evidence has suggested asymmetrical processing of taste in the human insular cortex, but this phenomenon has not been demonstrated in the rodent brain. Functional magnetic resonance imaging (fMRI) is a powerful tool for studying the functional organization of the brain. In this study, we established a blood oxygenation level-dependent (BOLD) fMRI method at 7 T to investigate the responses to gustatory stimulation in the insular cortex of anesthetized rats (220-310 g, n= 15). BOLD signals were observed in the insular cortex in response to 0.5 M sucrose solution as the tastant but not observed in response to distilled water as the control. The reproducibility of the BOLD signals in response to the tastant was confirmed between fMRI runs in the same animal and across animals. The signals were mainly located between 2.3 mm and 0.0 mm anterior to the bregma in the insular cortex. Interestingly, the signals were observed in the insular cortex of both hemispheres, but they were asymmetrical: the anterior and posterior regions to the intersection of the middle cerebral artery and the rhinal fissure as the landmark of the gustatory cortex were dominant in the left and right hemispheres of the insular cortex, respectively. These results suggest that activity in both hemispheres of the insular cortex should be considered to analyze taste processing. We think that BOLD fMRI of taste function in rodents will improve our understanding of taste information processing. © 2011 Elsevier Inc.


Scammell T.E.,Beth Israel Deaconess Medical Center | Matheson J.K.,Beth Israel Deaconess Medical Center | Honda M.,Tokyo Institute of Psychiatry | Thannickal T.C.,University of California at Los Angeles | Siegel J.M.,University of California at Los Angeles
Neurobiology of Aging | Year: 2012

A recent publication suggested that hypocretin (Hcrt, orexin) may mediate the neuropathological process leading to Alzheimer's disease (AD) and that antagonism of hypocretin receptors decreases this process. Narcoleptics have an approximately 90% loss of Hcrt neurons and commensurate reductions in the levels of Hcrt in their cerebrospinal fluid beginning at disease onset, usually before the age of 30. If Hcrt mediates the disease process, narcoleptics should be protected against AD. We examined the postmortem neuropathology and clinical records of 12 sequentially encountered cases of human narcolepsy. We found that AD was present in 4 of these narcoleptics, a prevalence that is similar to that of the general population. © 2012.


It is essential to elucidate the relationship between blood oxygenation level-dependent (BOLD) signals and neuronal activity for the interpretation of the functional magnetic resonance imaging (fMRI) signals; this relationship has been quantitatively investigated by animal studies measuring evoked potentials as indices of neuronal activity. Although most human fMRI studies employ the event-related task design, in which the stimulus duration is short, few studies have investigated the relationship between BOLD signals and evoked potentials at short stimulus durations. The present study investigated this relationship in the somatosensory cortex of anesthetized rats by using electrical forepaw stimulation at a short duration of 4 s and comprehensively analyzed it at different frequencies (1-10 Hz) and currents (0.5-2.0 mA). Somatosensory evoked potential (SEP) responses were measured at the scalp using silver ball electrodes. The sum of the peak-to-peak amplitude (ΣSEP) and average SEP (avg. SEP) responses were calculated. BOLD signals were obtained using a spin-echo echo-planar imaging sequence at 7 T. The relationship between the avg. SEP and BOLD signals varied with frequency, whereas that between ΣSEP and BOLD signals showed a significant correlation at varying frequencies and currents. In particular, the relationship between ΣSEP and ΣBOLD, which is the sum of the BOLD signals obtained at each time point reflecting the area under the BOLD response curves, mostly converged, irrespective of the frequency. Our results suggest that ΣBOLD obtained using a spin-echo sequence reflects the neural activity as quantified by ΣSEP, which was determined at different frequencies and currents. © 2009 Elsevier B.V. All rights reserved.


Nishizawa D.,Tokyo Institute of Psychiatry
Methods in molecular biology (Clifton, N.J.) | Year: 2010

Opioid analgesics are commonly used for the treatment of acute as well as chronic, moderate to severe pain. Well-known, however, is the wide interindividual variability in sensitivity to opioids that exists, which has often been a critical problem in pain treatment. To date, only a limited number of studies have addressed the relationship between human genetic variations and sensitivity to opioids, and such studies are still in their early stages. Therefore, revealing the relationship between genetic variations in many candidate genes and individual differences in sensitivity to opioids will provide valuable information for appropriate individualization of opioid doses required for adequate pain control. Although the methodologies for such association studies can be diverse, here we summarize protocols for investigating the association between genetic polymorphisms and sensitivity to opioids in human volunteers and patients undergoing painful surgery.


Nonaka T.,Tokyo Institute of Psychiatry | Watanabe S.T.,Tokyo Institute of Psychiatry | Watanabe S.T.,University of Tokyo | Iwatsubo T.,University of Tokyo | Hasegawa M.,Tokyo Institute of Psychiatry
Journal of Biological Chemistry | Year: 2010

The deposition of amyloid-like filaments in the brain is the central event in the pathogenesis of neurodegenerative diseases. Here we report cellular models of intracytoplasmic inclusions of α-synuclein, generated by introducing nucleation seeds into SH-SY5Y cells with a transfection reagent. Upon introduction of preformed seeds into cells overexpressing α-synuclein, abundant, highly filamentous α-synuclein-positive inclusions, which are extensively phosphorylated and ubiquitinated and partially thioflavin-positive, were formed within the cells. SH-SY5Y cells that formed such inclusions underwent cell death, which was blocked by small molecular compounds that inhibit β-sheet formation. Similar seed-dependent aggregation was observed in cells expressing four-repeat Tau by introducing four-repeat Tau fibrils but not three-repeat Tau fibrils or α-synuclein fibrils. No aggregate formation was observed in cells overexpressing three-repeat Tau upon treatment with four-repeat Tau fibrils. Our cellular models thus provide evidence of nucleation-dependent and protein-specific polymerization of intracellular amyloid-like proteins in cultured cells. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Sae-Ung K.,Srinakharinwirot University | Ueda K.,Tokyo Institute of Psychiatry | Govitrapong P.,Mahidol University | Phansuwan-Pujito P.,Srinakharinwirot University
Journal of Pineal Research | Year: 2012

Alpha-synuclein (α-syn) is a neuronal protein that is involved in various degenerative disorders such as Parkinson's disease. It is found in the presynaptic terminals and perinuclear zones of many brain regions. Amphetamine (AMPH), a psychostimulant drug abused progressively more commonly in recent years, has been known to induce neurotoxicity in the central dopaminergic pathway, which is associated with increased oxidative stress. Recently, AMPH has been shown to significantly increase the level of α-syn in dopaminergic neuroblastoma cell cultures. Melatonin is recognized as an antioxidant for the nervous system. This study tested whether melatonin can attenuate the effect of AMPH on the expression of α-syn in the dopaminergic pathway of the neonatal rat. Four-day old postnatal rats (P4) were injected subcutaneously with either AMPH (increasing dose, 5-10 mg/kg daily) alone or AMPH with melatonin (2 mg/kg) daily at 10:00 AM for 7 consecutive days. As determined using Western blot, the level of α-syn was significantly increased in the substantia nigra, dorsal striatum, nucleus accumbens, and prefrontal cortex of the AMPH-treated group, while melatonin treatment either prior to AMPH or alone decreased the accumulation of the protein to 77%, 96%, 78%, and 77% of the control value, respectively. Furthermore, an immunofluorescent study showed that the α-syn-immunoreactivity increased noticeably in the nuclei of cell bodies and nerve terminals of the AMPH-treated group. Again, melatonin lowered this immunoreactivity. These results indicate that melatonin has a direct or indirect effect in reducing the expression of α-syn in the postnatal rat. The exact mechanism of this mitigation should be further investigated. © 2011 John Wiley & Sons A/S.


Kobayashi T.,Niigata University | Washiyama K.,Niigata University | Ikeda K.,Tokyo Institute of Psychiatry
Neuropsychopharmacology | Year: 2010

Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attention-deficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K+ (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentration-dependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A 1 adenosine receptors or by intracellularly applied GTPγS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain-and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function. © 2010 Nature Publishing Group All rights reserved.


Tanaka S.,Tokyo Institute of Psychiatry | Honda M.,Tokyo Institute of Psychiatry
PLoS ONE | Year: 2010

Background: A close association between narcolepsy and the Human Leukocyte Antigen (HLA)-DQB1*0602 allele suggests the involvement of the immune system, or possibly an autoimmune process. We investigated serum IgG levels in narcolepsy. Methodology/Principal Findings: We measured the serum total IgG levels in 159 Japanese narcolepsy-cataplexy patients positive for the HLA-DQB1*0602 allele, 28 idiopathic hypersomnia patients with long sleep time, and 123 healthy controls (the HLA-DQB1*0602 allele present in 45 subjects). The serum levels of each IgG subclass were subsequently measured. The distribution of serum IgG was significantly different among healthy controls negative for the HLA-DQB1*0602 allele (11.66±3.55 mg/ml), healthy controls positive for the HLA-DQB1*0602 allele (11.45±3.43), narcolepsy patients (9.67±3.38), and idiopathic hypersomnia patients (13.81±3.80). None of the following clinical variables, age, disease duration, Epworth Sleepiness Scale, smoking habit and BMI at the time of blood sampling, were associated with IgG levels in narcolepsy or idiopathic hypersomnia. Furthermore we found the decrease in IgG1 and IgG2 levels, stable expression of IgG3, and the increase in the proportion of IgG4 in narcolepsy patients with abnormally low IgG levels. The increase in the proportion of IgG4 levels was also found in narcolepsy patients with normal serum total IgG levels. Idiopathic hypersomnia patients showed a different pattern of IgG subclass distribution with high IgG3 and IgG4 level, low IgG2 level, and IgG1/IgG2 imbalance. Conclusions/Significance: Our study is the first to determine IgG abnormalities in narcolepsy and idiopathic hypersomnia by measuring the serum IgG levels in a large number of hypersomnia patients. The observed IgG abnormalities indicate humoral immune alterations in narcolepsy and idiopathic hypersomnia. Different IgG profiles suggest immunological differences between narcolepsy and idiopathic hypersomnia. © 2010 Tanaka, Honda.


Bandoh H.,Hokkaido University | Kida I.,Tokyo Institute of Psychiatry | Ueda H.,Hokkaido University
PLoS ONE | Year: 2011

Many studies have shown that juvenile salmon imprint olfactory memory of natal stream odors during downstream migration, and adults recall this stream-specific odor information to discriminate their natal stream during upstream migration for spawning. The odor information processing of the natal stream in the salmon brain, however, has not been clarified. We applied blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging to investigate the odor information processing of the natal stream in the olfactory bulb and telencephalon of lacustrine sockeye salmon (Oncorhynchus nerka). The strong responses to the natal stream water were mainly observed in the lateral area of dorsal telencephalon (Dl), which are homologous to the medial pallium (hippocampus) in terrestrial vertebrates. Although the concentration of L-serine (1 mM) in the control water was 20,000-times higher than that of total amino acid in the natal stream water (47.5 nM), the BOLD signals resulting from the natal stream water were stronger than those by L-serine in the Dl. We concluded that sockeye salmon could process the odor information of the natal stream by integrating information in the Dl area of the telencephalon. © 2011 Bandoh et al.

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