Hiroshi Kunugi

National Center of Neurology and Psychiatry, Кодаиры, Tōkyō, Japan

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Publications (356)1548.98 Total impact

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    ABSTRACT: Glucagon-like peptide-1 (GLP–1), an insulinotropic peptide secreted from enteroendocrine cells, has been known to have a neuroprotective effect. However, it is not fully understood the intracellular mediator of GLP–1 signaling in neuronal cells. In the present study, we examined the change in intracellular signaling of cortical neurons after GLP–1 application and luminal glucose stimulation in vitro and in vivo. GLP–1 receptor was highly expressed in cultured cortical neurons and brain tissues including the prefrontal cortex and hippocampus. The activation of GLP–1 receptor (5 min) significantly decreased levels of phosphorylated extracellular signal-regulated kinase (pERK), which is involved in neuronal cell survival and death, in cultured cortical neurons. Oral glucose administration also rapidly reduced pERK levels in the prefrontal cortex, while intraperitoneal glucose injection did not show such an effect. Further, GLP–1 attenuated hydrogen peroxide-induced cell death and hyperactivity of ERK in cultured cortical neurons. It is possible that increased GLP–1 by luminal glucose stimulation affects cortical system including the maintenance of neuronal cell survival.
    No preview · Article · Jan 2016 · Neuroscience Letters
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    ABSTRACT: Several microarray-based studies have investigated gene expression profiles in major depressive disorder (MDD), yet with highly variable findings. We examined blood-based genome-wide expression signatures of MDD, focusing on molecular pathways and networks underlying differentially expressed genes (DEGs) and behaviours of hypothesis-driven, evidence-based candidate genes for depression. Agilent human whole-genome arrays were used to measure gene expression in 14 medication-free outpatients with MDD who were at least moderately ill and 14 healthy controls matched pairwise for age and sex. After filtering, we compared expression of entire probes between patients and controls and identified DEGs. The DEGs were evaluated by pathway and network analyses. For the candidate gene analysis, we utilized 169 previously prioritized genes and examined their case-control separation efficiency and correlational co-expression network in patients relative to controls. The 317 screened DEGs mapped to a significantly over-represented pathway, the "synaptic transmission" pathway. The protein-protein interaction network was also significantly enriched, in which a number of key molecules for depression were included. The co-expression network of candidate genes was markedly disrupted in patients. This study provided evidence for an altered molecular network along with several key molecules in MDD and confirmed that the candidate genes are worthwhile targets for depression research.
    Preview · Article · Jan 2016 · Scientific Reports
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    Dataset: Matsuo

    Full-text · Dataset · Dec 2015
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    ABSTRACT: Altered tryptophan-kynurenine (KYN) metabolism has been implicated in major depressive disorder (MDD). The l-[1- 13 C]tryptophan breath test (13 C-TBT) is a noninvasive, stable-isotope tracer method in which exhaled 13 CO 2 is attributable to tryptophan catabolism via the KYN pathway. We included 18 patients with MDD (DSM-IV) and 24 age- and sex-matched controls. 13 C-tryptophan (150 mg) was orally administered and the 13 CO 2 / 12 CO 2 ratio in the breath was monitored for 180 min. The cumulative recovery rate during the 180-min test (CRR 0-180; %), area under the δ 13 CO 2 -time curve (AUC; %∗min), and the maximal δ 13 CO 2 (C max; %) were significantly higher in patients with MDD than in the controls (p = 0.004, p = 0.008, and p = 0.002, respectively). Plasma tryptophan concentrations correlated negatively with C max in both the patients and controls (p = 0.020 and p = 0.034, respectively). Our results suggest that the 13 C-TBT could be a novel biomarker for detecting a subgroup of MDD with increased tryptophan-KYN metabolism.
    Full-text · Article · Nov 2015 · Scientific Reports
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    ABSTRACT: Background: Neuromyelitis optica spectrum disorder (NMOSD) differs from multiple sclerosis (MS) by prognosis and approach to treatment, and it is thus important to distinguish NMOSD from MS. Objective: We evaluated the structural brain abnormalities in patients with NMOSD and with relapsing-remitting MS (RRMS) using with MRI. Methods: Twenty-one NMOSD patients with antibodies against aquaporin 4, 32 patients with RRMS, and current age- and sex- matched 39 healthy subjects underwent 3-T MRI. The differences in gray matter volume and fractional anisotropy (FA) value among the three groups were evaluated. Results: There were significant global gray matter volume reductions of NMOSD and RRMS groups, compared to the healthy subjects. Significant and diffuse decreases in FA values were observed in both the NMOSD and RRMS patients. Significant gray matter volume and FA value reductions of the RRMS patients in the bilateral thalami and some regions were observed compared to the NMOSD patients. Conclusion: Larger brain structural changes were seen in the RRMS group compared to the NMOSD group, and among them, the thalamus was revealed as the important region for the discrimination of these two diseases. MRI analyses of the brain may be helpful in differentiating NMOSD from RRMS patients.
    No preview · Article · Nov 2015 · Multiple Sclerosis and Related Disorders
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    ABSTRACT: Neuronal cell survival and synaptic plasticity are controlled through expression of various neurotrophic factors including brain-derived neurotrophic factor (BDNF). In the present study, we examined the mechanism behind BDNF-induced Bdnf mRNA production and the physiological role of its amplification system using cortical neurons. Exogenous BDNF was applied to the cultured cortical neurons at days in vitro (DIV) 3 and DIV 7 with or without inhibitors for intracellular signaling. Expression levels of total Bdnf and Bdnf variants (exon I, exon IV, and exon VI) were biphasically increased after the BDNF application in different developing stage of neurons. Inhibitor for extracellular signal-regulated kinase, calmodulin dependent protein kinase II, or protein kinase A repressed the BDNF-induced Bdnf mRNA expression. Furthermore, we found that application of TrkB-Fc, which scavenges produced endogenous BDNF, resulted in weakened BDNF/TrkB signaling and decreased expression of postsynaptic proteins, suggesting that newly synthesized BDNF induced by the self-amplification system contributes to the synaptic maturation and function.
    No preview · Article · Oct 2015 · Neurochemistry International
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    ABSTRACT: Rationale High-fat diet (HFD) has been recently reported to induce sensorimotor gating deficits, but the underlying mechanisms are not well understood. Objective The purpose of this study is to determine whether HFD induces long-lasting deficits in sensorimotor gating and to examine the involvement of altered dopamine (DA) function. Methods C57BL/6J mice were fed HFD for 10 weeks and then normal diet (ND) for 4 weeks. DA D2 receptor (D2R) knockout (KO) mice were also fed HFD for 10 weeks. The mice were evaluated for prepulse inhibition (PPI) of acoustic startle after HFD and the subsequent 4-week ND. We evaluated the effect of SCH23390, a D1 receptor (D1R) antagonist, on PPI and measured protein expression levels of D1R and D2R in the prefrontal cortex (PFC) in HFD mice. The concentrations of monoamines and their metabolites in the cortices of 10-week HFD or ND mice were measured using high performance liquid chromatography. Results Long-term HFD-induced PPI disruption in WT and D2R KO mice. Even after 4 weeks of subsequent ND, PPI remained to be disrupted. SCH23390 mitigated the PPI disruption. In HFD animals, D1R protein expression in the PFC was significantly decreased, while DA, homovanillic acid, and 3,4-dihydroxyphenylacetic acid levels in the cortex were increased. Conclusion This is the first evidence that HFD can induce long-lasting deficits in sensorimotor gating through alteration of cortical levels of DA and its metabolites. Our data suggest that HFD-induced PPI deficits are related to altered D1R signaling and that D1R antagonists may have therapeutic effects on the deficits.
    No preview · Article · Sep 2015 · Psychopharmacology
  • K. Hattori · M. Ota · S. Yoshida · Y. Goto · H. Kunugi

    No preview · Article · Sep 2015
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and functions in the central nervous system (CNS). Because BDNF protein is sorted into secretory vesicles at the trans-Golgi network in the cell body after translation, transport of BDNF-containing vesicles to the secretion sites is an important process for its function. Here we examined the effect of dexamethasone (DEX), a synthetic glucocorticoid, on BDNF-containing vesicle transport and found that DEX decreased the proportion of stationary vesicles and increased velocity of the microtubule-based vesicle transport in dendrites of cortical neurons. Furthermore, DEX increased huntingtin (Htt) protein levels via glucocorticoid receptor (GR) activation, and reduction in the amount of Htt by a specific shRNA reversed the action of DEX on BDNF vesicle transport. Given that Htt protein is a positive regulator for the microtubule-dependent vesicular transport in neurons, our data suggest that glucocorticoid stimulates BDNF vesicle transport through upregulation of Htt protein levels.
    Preview · Article · Aug 2015 · Scientific Reports
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    ABSTRACT: Although the clinical efficacy of electroconvulsive therapy (ECT) is well established, the underlying mechanisms of action remain elusive. The aim of this study was to elucidate structural changes of the brain following ECT in patients with major depressive disorder (MDD). Fifteen patients with MDD underwent magnetic resonance imaging scanning before and after ECT. Their gray matter volumes were compared between pre- and post-ECT. There were significant volume increases after ECT in the bilateral medial temporal cortices, inferior temporal cortices, and right anterior cingulate. Further, the increase ratio was correlated with the clinical improvement measured by the Hamilton Depression Rating scale. All subjects were treated with antidepressants that could have a neurotoxic or neuroprotective effect on the brain. We found that there were significant increases of gray matter volume in medial temporal lobes following ECT, suggesting that a neurotrophic effect of ECT could play a role in its therapeutic effect. Copyright © 2015 Elsevier B.V. All rights reserved.
    No preview · Article · Jul 2015 · Journal of Affective Disorders
  • Miho Ota · Shintaro Ogawa · Koichi Kato · Chiaki Masuda · Hiroshi Kunugi
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    ABSTRACT: Previous studies have demonstrated that patients with schizophrenia show greater sensitivity to psychostimulants than healthy subjects. Sensitization to psychostimulants and resultant alteration of dopaminergic neurotransmission in rodents has been suggested as a useful model of schizophrenia. This study sought to examine the use of methylphenidate as a psychostimulant to induce dopamine release and that of [(18)F]fallypride as a radioligand to quantify the release in a primate model of schizophrenia. Four common marmosets were scanned by positron emission tomography twice, before and after methylphenidate challenge, to evaluate dopamine release. Four other marmosets were sensitized by repeated methamphetamine (MAP) administration. Then, they were scanned twice, before and after methylphenidate challenge, to evaluate whether MAP-sensitization induced greater sensitivity to methylphenidate. We revealed a main effect of the methylphenidate challenge but not the MAP pretreatment on the striatal binding potential. These results suggest that methylphenidate-induced striatal dopamine release in the common marmoset could be evaluated by [(18)F]fallypride. Copyright © 2015. Published by Elsevier Ireland Ltd.
    No preview · Article · Jul 2015 · Neuroscience Research
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    ABSTRACT: Major depressive disorder (MDD) presumably includes heterogeneous subgroups with differing pathologies. To obtain a marker reflecting such a subgroup, we analyzed the cerebrospinal fluid (CSF) levels of fibrinogen, which has been reported to be elevated in the plasma of patients with MDD. Three fibrinogen-related proteins were measured using aptamer-based analyses and CSF samples of 30 patients with MDD and 30 controls. The numbers of patients with an excessively high level (>99 percentile of the controls) was significantly increased (17 to 23%). Measurement reproducibility of these results was confirmed by an ELISA for fibrinogen (Pearson's r = 0.77). In an independent sample set from 36 patients and 30 controls, using the ELISA, results were similar (22%). When these two sample sets were combined, the number of patients with a high fibrinogen level was significantly increased (15/66; odds ratio 8.53; 95% confidence interval 1.9-39.1, p = 0.0011). By using diffusion tensor imaging, we found white matter tracts abnormalities in patients with a high fibrinogen level but not those patients with a normal fibrinogen level, compared with controls. Plasma fibrinogen levels were similar among the diagnostic groups. Our results point to a subgroup of MDD represented by increased CSF fibrinogen and white matter tract abnormalities.
    Preview · Article · Jun 2015 · Scientific Reports
  • Shintaro Ogawa · Hiroshi Kunugi

    No preview · Article · Jun 2015 · Current Neuropharmacology
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    ABSTRACT: Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · May 2015 · Neuroscience Letters
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    Dataset: fetchObject

    Full-text · Dataset · May 2015
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    ABSTRACT: Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. Previous studies suggested that l-theanine affects the glutamatergic neurotransmission and ameliorates symptoms in patients with schizophrenia. The aims of the present study were twofold: to examine the possible effects of l-theanine on symptoms in chronic schizophrenia patients and to evaluate the changes in chemical mediators, including glutamate + glutamine (Glx), in the brain by using 1H magnetic resonance spectroscopy (MRS). The subjects were 17 patients with schizophrenia and 22 age- and sex-matched healthy subjects. l-Theanine (250 mg/day) was added to the patients' ongoing antipsychotic treatment for 8 weeks. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), Pittsburgh Sleep Quality Index scores and MRS results. There were significant improvements in the PANSS positive scale and sleep quality after the l-theanine treatment. As for MRS, we found no significant differences in Glx levels before and after the 8 week l-theanine treatment. However, significant correlations were observed between baseline density of Glx and change in Glx density by l-theanine. Our results suggest that l-theanine is effective in ameliorating positive symptoms and sleep quality in schizophrenia. The MRS findings suggest that l-theanine stabilises the glutamatergic concentration in the brain, which is a possible mechanism underlying the therapeutic effect.
    No preview · Article · Apr 2015 · Acta Neuropsychiatrica
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    ABSTRACT: Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipo-lar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of evaluating autistic like traits/symptoms underlying adult-onset psychiatric disorders for the best-suited treatment. Further studies with a prospective design and larger samples are needed.
    Full-text · Article · Apr 2015 · PLoS ONE
  • Hiroshi Kunugi · Hiroaki Hori · Shintaro Ogawa
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    ABSTRACT: The pathophysiology of major depressive disorder (MDD) remains elusive, and there is no established biochemical marker used in the daily clinical setting. This situation may result in part from the heterogeneity of MDD which might include heterogeneous subgroups with different biological mechanisms. In this review, we discuss three promising biological systems/markers to potentially subtype MDD, that is, dopamine system, hypothalamic-pituitary-adrenal (HPA) axis, and chronic inflammatory markers. Several lines of evidence suggest that a portion of MDD is a dopamine agonist-responsive subtype. Focusing on the HPA axis, depressive spectrum disorders show hypercortisolism to hypocortisolism which could be detected by hormonal challenge tests such as the dexamethasone/corticotropin releasing hormone test. Finally, accumulating evidence suggests that at least a portion of MDD patients show characteristics similar to those of chronic inflammatory diseases including neuroinflammatory markers and reduced tryptophan due to the increased activation of the tryptophan-kynureline pathway. Future studies should examine the inter-relationships between these systems/markers to subtype and integrate the pathophysiology of MDD. This article is protected by copyright. All rights reserved.
    No preview · Article · Mar 2015 · Psychiatry and Clinical Neurosciences
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    ABSTRACT: Intrauterine growth restriction (IUGR) is a risk factor for memory impairment and emotional disturbance during growth and adulthood. However, this risk might be modulated by environmental factors during development. Here we examined whether exposing adolescent male and female rats with thromboxane A2-induced IUGR to social defeat stress (SDS) affected their working memory and anxiety-like behavior in adulthood. We also used BrdU staining to investigate hippocampal cellular proliferation and BrdU and NeuN double staining to investigate neural differentiation in female IUGR rats. In the absence of adolescent stress, IUGR female rats, but not male rats, scored significantly lower in the T-maze test of working memory and exhibited higher anxiety-like behavior in the elevated-plus maze test compared with controls. Adolescent exposure to SDS abolished these behavioral impairments in IUGR females. In the absence of adolescent stress, hippocampal cellular proliferation was significantly higher in IUGR females than in non-IUGR female controls and was not influenced by adolescent exposure to SDS. Hippocampal neural differentiation was equivalent in non-stressed control and IUGR females. Neural differentiation was significantly increased by adolescent exposure to SDS in controls but not in IUGR females. There was no significant difference in the serum corticosterone concentrations between non-stressed control and IUGR females; however, adolescent exposure to SDS significantly increased serum corticosterone concentration in control females but not in IUGR females. These results demonstrate that adolescent exposure to SDS improves behavioral impairment independent of hippocampal neurogenesis in adult rats with IUGR. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Feb 2015 · Hormones and Behavior
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    ABSTRACT: Previous studies demonstrated that patients with schizophrenia show greater sensitivity to psychostimulants than healthy subjects. Sensitization to psychostimulants and resultant alteration of dopaminergic neurotransmission in rodents have been suggested as a useful model of schizophrenia. This study was aimed to examine the use of methylphenidate as a psychostimulant to induce dopamine release and that of [(18)F]fallypride as a radioligand to estimate the release in a rat model of schizophrenia. Six rats were scanned by positron emission tomography (PET) twice before and after methylphenidate challenge to evaluate dopamine release. After the scans, these rats were sensitized by using repeated methamphetamine (MAP) administration. Then, they were re-scanned twice again before and after methylphenidate challenge to evaluate whether MAP-sensitized rats show greater sensitivity to methylphenidate. We revealed a main effect of MAP-pretreatment and that of metylphenidate challenge. We found that % change of distribution volume ratio after repeated administration of MAP was greater than that before sensitization. These results suggest that methylphenidate-induced striatal dopamine release increased after sensitization to MAP. PET scan using [(18)F]fallypride at methylphenidate-challenge may provide a biological marker for schizophrenia and be useful to diagnose schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · Feb 2015 · Psychiatry Research: Neuroimaging

Publication Stats

8k Citations
1,548.98 Total Impact Points


  • 1970-2016
    • National Center of Neurology and Psychiatry
      • Department of Mental Disorder Research
      Кодаиры, Tōkyō, Japan
  • 2015
    • University of Yamanashi
      • Interdisciplinary Graduate School of Medicine and Engineering
      Kōhu, Yamanashi, Japan
  • 2010-2015
    • Japan Science and Technology Agency (JST)
      Edo, Tokyo, Japan
  • 2011
    • St. Marianna University School of Medicine
      • Department of Physiology
      Kawasaki Si, Kanagawa, Japan
  • 2006
    • Shukutoku University
      Koromo, Aichi, Japan
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan
  • 1994-2004
    • Teikyo University
      • Department of Medicine
      Edo, Tōkyō, Japan
  • 1996-2003
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
    • New South Wales Institute of Psychiatry
      Sydney, New South Wales, Australia
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
    • Juntendo University
      • Department of Psychiatry
      Edo, Tōkyō, Japan
    • Zhejiang University
      • Department of Physics
      Hangzhou, Zhejiang Sheng, China
  • 1998
    • Tokyo Metropolitan Geriatric Medical Center
      Edo, Tōkyō, Japan
  • 1995
    • King's College London
      • Institute of Psychiatry
      Londinium, England, United Kingdom