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Cytokine-Induced Neuropathologic Endophenotypes of Psychiatric Diseases

Planned Research

Project AreaUnraveling micro-endophenotypes of psychiatric disorders at the molecular, cellular and circuit levels.
Project/Area Number 24116010
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionNiigata University

Principal Investigator

Nawa Hiroyuki  新潟大学, 脳研究所, 教授 (50183083)

Co-Investigator(Renkei-kenkyūsha) NAMBA Hisaaki  新潟大学, 脳研究所, 助教 (90332650)
KAKITA Akiyoshi  新潟大学, 脳研究所, 教授 (80281012)
TAKEI Nobuyuki  新潟大学, 脳研究所, 准教授 (70221372)
Research Collaborator KIDA Satoshi  東京農業大学, 応用生物科学部, 教授 (80301547)
Project Period (FY) 2012-06-28 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥95,940,000 (Direct Cost: ¥73,800,000、Indirect Cost: ¥22,140,000)
Fiscal Year 2016: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2015: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2014: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2013: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000)
Fiscal Year 2012: ¥22,230,000 (Direct Cost: ¥17,100,000、Indirect Cost: ¥5,130,000)
Keywords統合失調症 / 幻聴 / サイトカイン / ドパミン / 上皮成長因子 / 神経栄養因子 / ニューレグリン / 脳波 / EGF / GDNF / 発声 / 精神疾患 / 動物モデル / 脳内炎症 / 聴覚機能 / OFF反応 / 非定型抗精神病薬 / セロトニン / 死後脳 / モデル動物 / 認知行動異常 / 依存薬物 / 中脳ドパミン神経
Outline of Final Research Achievements

The animals that had been exposed to cytokines as neonates later develop the abnormal behaviors relevant to schizophrenia. In the present investigation, we explored the cytokine animal model for schizophrenia, focusing on the monoaminergic pathways. Among various cytokines, epidermal growth factor (EGF) produced the most remarkable impact on animal behaviors. In the EGF model, dopaminergic neurons exhibited abnormal pallidal innervations and a postpubertal firing increase as well as their antipsychotic sensitivity. There were no significant influences on the other monoaminergic neurons in the EGF model. In addition, the EGF model in rats displayed the remarkable deficits particularly in the auditory system. These observations suggest that prenatal or perinatal cytokine exposure results in dopaminergic mal-development and deficits in auditory cognition.

Report

(6 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (38 results)

All 2016 2015 2014 2013 2012 Other

All Int'l Joint Research (1 results) Journal Article (18 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 16 results,  Open Access: 7 results,  Acknowledgement Compliant: 7 results) Presentation (17 results) (of which Int'l Joint Research: 4 results,  Invited: 14 results) Book (1 results) Remarks (1 results)

  • [Int'l Joint Research] University of Alabama/Dept of Psychiatry/Dr Kazu Nakazawa(米国)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] サルやマウスを使った統合失調症のモデル化とその課題2016

    • Author(s)
      那波宏之、斎藤摩美
    • Journal Title

      分子精神医学

      Volume: 16 Pages: 110-117

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Perinatal Exposure to Neuregulin-1 Results in Disinhibition of Adult Midbrain Dopaminergic Neurons: Implication in Schizophrenia Modeling2016

    • Author(s)
      Namba H, Okubo T, Nawa H
    • Journal Title

      Scientific Reports

      Volume: 6 Issue: 1 Pages: 22606-22606

    • DOI

      10.1038/srep22606

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Curr Top Behav Neurosci2015

    • Author(s)
      Nagano T, Mizuno M, Morita K, Nawa H
    • Journal Title

      Pathological Implications of Oxidative Stress in Patients and Animal Models with Schizophrenia: The Role of Epidermal Growth Factor Receptor Signaling.

      Volume: Epub ahead of print

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Schisandrin B Ameliorates ICV-Infused Amyloid β Induced Oxidative stress and Neuronal Dysfunction through Inhibiting RAGE/NF-κB/MAPK and Up-regulating HSP/beclin Expression.2015

    • Author(s)
      Vijayasree V. Giridharan, Rajarajan A. Thandavarayan, Somasundaram Arumugam, Makoto Mizuno, Hiroyuki Nawa, Kenji Suzuki, Kam M. Ko, Prasanna Krishnamurthy, Kenichi Watanabe, T Konish.
    • Journal Title

      Pros One

      Volume: 15 Issue: 11 Pages: 1-17

    • DOI

      10.1371/journal.pone.0142483

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Curr Mol Med2015

    • Author(s)
      Kato T, Abe Y, Hirokawa S, Iwakura Y, Mizuno M, Namba H, Nawa H.
    • Journal Title

      Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801.

      Volume: 15 Pages: 222-236

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Assessment of Copy Number Variations in the Brain Genome of Schizophrenia Patients2015

    • Author(s)
      Miwako Sakai et al.
    • Journal Title

      Molecular Cytogenetics

      Volume: n/a

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A possible link between BDNF and mTOR in control of food intake.2014

    • Author(s)
      Takei N, Furukawa K, Hanyu O, Sone H, Nawa H.
    • Journal Title

      Front Psychol

      Volume: 5 Pages: 1093-1093

    • DOI

      10.3389/fpsyg.2014.01093

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Neuropathologic implication of peripheral neuregulin-1 and EGF signals in dopaminergic dysfunction and behavioral deficits relevant to schizophrenia: their target cells and time window.2014

    • Author(s)
      Nawa H, Sotoyama H, Iwakura Y, Takei N, Namba H.
    • Journal Title

      Biomed Res Int.

      Volume: n/a Pages: 697935-697935

    • DOI

      10.1155/2014/697935

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Elevated postmortem striatal t-DARPP expression in schizophrenia and associations with DRD2/ANKK1 polymorphism2014

    • Author(s)
      Kunii Y, Miura I, Matsumoto J, Hino M, Wada A, Niwa SI, Nawa H, Sakai M, Someya T, Takahashi H, Kakita A, Yabe H.
    • Journal Title

      Prog Neuropsychopharmacol Biol Psychiatry

      Volume: 5846(14)(Epub ahead of print) Pages: 123-128

    • DOI

      10.1016/j.pnpbp.2014.03.014

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased l1 retrotransposition in the neuroral genome in schizophrenia.2014

    • Author(s)
      Miki Bundo, Manabu Toyoshima, Yohei Okada, Wado Akamatsu, Junko Ueda, Taeko Nemoto-Miyauchi, Fumiko Sunaga, Michihiro Toritsuka, Daisuke Ikawa, Akiyoshi Kakita, Motoichiro Kato, Kiyoto Kasai, Toshifumi Kishimoto, Hiroyuki Nawa, Hideyuki Okano, Takeo Yoshikawa, Tadafumi Katoemail, Kazuya Iwamoto
    • Journal Title

      Neuron

      Volume: 81 Issue: 2 Pages: 306-313

    • DOI

      10.1016/j.neuron.2013.10.053

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An Attempt of Non-human Primate Modeling of Schizophrenia with Neonatal Challenges of Epidermal Growth Factor2014

    • Author(s)
      Sakai M, Kashiwahara M, Kakita A, Nawa H
    • Journal Title

      J Addict Res Ther

      Volume: 5 Issue: 01 Pages: 170-170

    • DOI

      10.4172/2155-6105.1000170

    • NAID

      120006749407

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] mTOR signaling and its roles in normal and abnormal brain development2014

    • Author(s)
      Takei N, Nawa H
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 未定

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 統合失調症と炎症性サイトカイン2014

    • Author(s)
      那波宏之 、湯川尊行
    • Journal Title

      生命の科学

      Volume: 65 Pages: 43-47

    • Related Report
      2013 Annual Research Report
  • [Journal Article] Neurobehavioral deficits of epidermal growth factor-overexpressing transgenic mice: impact on dopamine metabolism2013

    • Author(s)
      Eda T, Mizuno M, Araki K, Iwakura Y, Namba H, Sotoyama H, Kakita A, Takahashi H, Satoh H, Chan SY, Nawa H
    • Journal Title

      Neurobehavioral deficits of epidermal growth factor-overexpressing transgenic mice: impact on dopamine metabolism

      Volume: 547 Pages: 21-25

    • DOI

      10.1016/j.neulet.2013.04.055

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ErbB inhibitors ameliorate behavioral impairments of an animal model for schizophrenia: implication of their dopamine-modulatory actions.2013

    • Author(s)
      Mizuno M, Sotoyama H, Namba H, Shibuya M, Eda T, Wang R, Okubo T, Nagata K, Iwakura Y, Nawa H.
    • Journal Title

      Transl Psychiatry.

      Volume: 3 Issue: 4 Pages: e252-e252

    • DOI

      10.1038/tp.2013.29

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Exposure to the cytokine EGF leads to abnormal hyperactivity of pallidal GABA neurons: implications for schizophrenia and its modeling.2013

    • Author(s)
      Sotoyama H
    • Journal Title

      J Neurochem

      Volume: 未定 Issue: 4 Pages: 518-528

    • DOI

      10.1111/jnc.12223

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson's disease.2013

    • Author(s)
      Iwakura Y
    • Journal Title

      Front Cell Neurosci

      Volume: 7 Pages: 4-4

    • DOI

      10.3389/fncel.2013.00004

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ErbB2 dephosphorylation and anti-proliferative effects of neuregulin-1 in ErbB2-overexpressing cell lines; re-evaluation of their low-affinity interaction.2013

    • Author(s)
      Wang, R., Iwakura, Y., Araki, K., Keino-Masu, K., Masu, M., Wang, X., Takei, N., Higashiyama, S. and Nawa, H.
    • Journal Title

      Scientific reports

      Volume: 3 Issue: 1 Pages: 1402-1402

    • DOI

      10.1038/srep01402

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] 思春期以降に幻聴・幻覚を発病するかもしれないモデル動物2016

    • Author(s)
      那波宏之
    • Organizer
      第59回日本神経化学会大会
    • Place of Presentation
      福岡国際会議場(福岡県福岡市)
    • Year and Date
      2016-09-08
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Abnormal firing activity of midbrain dopaminergic neurons of a schizophrenia animal model established by perinatal EGF treatment2016

    • Author(s)
      Hidekazu Sotoyama, Hiroyuki Nawa
    • Organizer
      DOPAMINE2016
    • Place of Presentation
      Vienna Austria
    • Year and Date
      2016-09-05
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 統合失調症のサイトカインモデにおける大脳基底核間接路の変調2016

    • Author(s)
      Hiroyuki NAWA
    • Organizer
      Basal Ganglia in Health and Disease
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-07-10
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Postpubertal impairments of auditory processing in a cytokine-induced schizophrenia model2016

    • Author(s)
      Hisaaki Namba, Takeshi Okubo, Hiroyuki Nawa
    • Organizer
      DOPAMINE2016
    • Place of Presentation
      Vienna Austria
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Postpubertal impairments of auditory processing in a cytokine-induced schizophrenia model2016

    • Author(s)
      Hiroyuki NAWA
    • Organizer
      International Symposium on Microendophenotype on psychiatric disorders
    • Place of Presentation
      横浜ワールドポータース(神奈川県横浜市)
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] サイトカインを用いた統合失調症モデリングとその課題2015

    • Author(s)
      那波宏之
    • Organizer
      JSTさきがけシンポジウム「脳情報の解読と制御」
    • Place of Presentation
      新潟大学 (新潟県、新潟市)
    • Year and Date
      2015-11-10
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Neuroinflammatory features of the cytokine-induced animal model for schizophrenia; implication of the regional specificity2015

    • Author(s)
      Hiroyuki Nawa, Hiroaki Tsukano, Katsuei Shibuki, Akiyoshi Kakita, Hidekazu Sotoyama, Hisaaki Namba
    • Organizer
      第58回日本神経化学大会 シンポジウム
    • Place of Presentation
      ソニック大宮 (埼玉県、大宮市)
    • Year and Date
      2015-09-10
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] サイトカインモデルを使った非定型抗精神病薬の作用 機序の解明2015

    • Author(s)
      那波宏之、難波寿明、外山英和
    • Organizer
      応用薬理学学会
    • Place of Presentation
      新潟大学 (新潟県、新潟市)
    • Year and Date
      2015-09-04
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Impact of circulating neuregulin-1 and EGF on brain circuit development and maintenance; Implication in schizophrenia2015

    • Author(s)
      Hiroyuki Nawa
    • Organizer
      第1回Neuroscience Network in Kobe
    • Place of Presentation
      神戸大学
    • Year and Date
      2015-02-06
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] サイトカインによる脳神経マイクロエンドフェノタイプ変換;統合失調症とそのモデル研究より2014

    • Author(s)
      那波宏之
    • Organizer
      包括脳ネットワーク 5領域合同シンポジウム
    • Place of Presentation
      東京医歯科大学
    • Year and Date
      2014-12-11 – 2014-12-13
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 統合失調症の現状と課題2014

    • Author(s)
      那波宏之
    • Organizer
      平成26年度 新潟精神医学会 総会
    • Place of Presentation
      新潟市 ANAクラウンプラザホテル
    • Year and Date
      2014-10-25
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Perinatal exposure to the cytokine EGF produces pallidal hyperinnervation of dopaminergic neurons and the indirect pathway dysfunction in the schizophrenia animal model2013

    • Author(s)
      Nawa H, Sotoyama H, Namba H
    • Organizer
      DOPAMINE 2013
    • Place of Presentation
      アルゲーロ、イタリア
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Pallidal hyperdopaminergic innervation induced by neonatal exposure to epidermal growth factor; implication in schizophrenia2012

    • Author(s)
      Nawa H
    • Organizer
      Asian-Pacific Society for Neurochemistry
    • Place of Presentation
      Kobe, JAPAN
    • Year and Date
      2012-09-29
    • Related Report
      2012 Annual Research Report
  • [Presentation] Impact of circulating neuregulin-1 and EGF on brain circuit development and maintenance; Implication in schizophrenia

    • Author(s)
      Nawa H
    • Organizer
      The 5th Nagasaki-Hallym Joint Meeting on Neurobiology adn Brain Aging
    • Place of Presentation
      長崎
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Animal modeling of schizophrenia with cytokines; its application to drug development

    • Author(s)
      Nawa H, Mizuno M
    • Organizer
      Neuro2013 公開シンポジウム
    • Place of Presentation
      京都
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Impact of circulating neuregulin-1 and EGF on brain circuit development and maintenance; Implication in schizophrenia

    • Author(s)
      Nawa H
    • Organizer
      WFSBP-Neuro2013 Joint Symposium
    • Place of Presentation
      京都
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Vulnerability of dopaminergic development to cytokines and its implication of the D2R-dependent indirect pathway in schizophrenia

    • Author(s)
      Nawa H, Namba H, Sotoyama H,
    • Organizer
      WFSBP
    • Place of Presentation
      京都
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Book] 統合失調症2013

    • Author(s)
      那波宏之(分筆)
    • Total Pages
      768
    • Publisher
      医学書院
    • Related Report
      2013 Annual Research Report
  • [Remarks] C. サイトカイン病態生理学

    • URL

      http://www.bri.niigata-u.ac.jp/~molecular/results/

    • Related Report
      2016 Annual Research Report

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Published: 2012-11-27   Modified: 2022-06-09  

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