Neural mechanisms underlying stress vulnerability -involvement of neurogenesis in mood disorder

• Project/Area Number: 23591667
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Hokkaido University
• Principal Investigator: NAKAGAWA shin 北海道大学, 大学病院, 講師 (60360905)
• Co-Investigator(Kenkyū-buntansha): INOUE Takshi 北海道大学, 大学院医学研究科, 准教授 (70250438) ; BOKU Shuken 北海道大学, 大学院医学研究科, 助教 (60455665)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 神経細胞新生 / うつ病 / 抗うつ薬 / 気分安定薬 / ドパミン / グリア細胞 / CaMKIV / 気分障害 / 神経幹細胞 / 海馬 / DTI

Research Abstract

In this study we took particular note of neurogenesis in the adult hippocampus as molecular basis of stress vulnerability in the brain, and investigated the regulatory mechanisms of it. In vivo and vitro studies showed that dopamine increased neurogenesis via D1 receptors. Although antidepressants have been known to increase neurogenesis, we showed the new pathways including glia with FGF-2 and CaMKIV-CREB. In addition, anti-apoptotic effect and its mechanisms of mood stabilizers in the hippocampal progenitor cells were found. All these findings will contribute to make novel therapeutic drugs against mood disorder.

Research Products

• [Journal Article] The effect of dopamine on adult hippocampal neurogenesis (2014)
  • Author(s): Takamura N, Nakagawa S, Masuda T,Boku S, Kato A, Song N, An Y, Kitaichi Y, Inoue T, Koyama T, Kusumi I
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry Volume: 50 Pages: 116-124
  • DOI: 10.1016/j.pnpbp.2013.12.011
  • NAID: 120005411146
  • Peer Reviewed
• [Journal Article] Valproate recovers the inhibitory effect of dexamethasone on the proliferation of the adult dentate gyrus-derived neural precursor cells via GSK-3β and β-catenin pathway (2013)
  • Author(s): Boku S, Nakagawa S, Masuda T, Nishikawa H, Kato A, Takamura N, Omiya Y, Kitaichi Y, Inoue T, Kusuimi I
  • Journal Title: Eur J Pharmacol Volume: 723 Pages: 425-430
  • DOI: 10.1016/j.ejphar.2013.10.060
  • Peer Reviewed
• [Journal Article] Tricyclic antidepressant amitriptyline indirectly increases the proliferation of adult dentate gyrus-derived neural precursors : an involvement of astrocytes. (2013)
  • Author(s): Boku S, Hisaoka-Nahashima K, Nakagawa S, Kato A, Kaiitani N, Inoue T, Kusumi I, Takebayashi M
  • Journal Title: PLoS One Volume: 8 Issue: 11 Pages: 116-124
  • DOI: 10.1371/journal.pone.0079371
  • Peer Reviewed
• [Journal Article] GDNF facilitates differentiation of the adult dentate gyrus-derived neural precursor cells into astrocytes via STAT3 (2013)
  • Author(s): Boku S, Nakagawa S, Takamura N,Kato A, Takebayashi M, Hisaoka-Nakashima K, Omiya Y,Inoue T, Kusumi I
  • Journal Title: Biochem. Biophys Res Commun Volume: 434 Issue: 4 Pages: 779-784
  • DOI: 10.1016/j.bbrc.2013.04.011
  • NAID: 120005460238
  • Peer Reviewed
• [Journal Article] ROCK2 regulates bFGF-induced proliferation of SH-SY5Y cells through GSK-3β and β-catenin pathway. (2013)
  • Author(s): Boku S, Nakagawa S, Toda H, Kato A, Takamura N, Omiya Y, Inoue T, Koyama T
  • Journal Title: Brain research Volume: 1492 Pages: 7-17
  • DOI: 10.1016/j.brainres.2012.11.034
  • NAID: 120005228253
  • Peer Reviewed
• [Journal Article] Involvement of CaMKIV in neurogenic effect with chronic fluoxetine treatment (2013)
  • Author(s): Song N, Nakagawa S, Izumi T, Toda H, Kato A, Boku S, Inoue T, Sakagami H, Li X, Koyama T
  • Journal Title: Int J Neuropsychopharmacol Volume: 16(4) Issue: 4 Pages: 803-812
  • DOI: 10.1017/s1461145712000570
  • Peer Reviewed
• [Journal Article] Anxiolytic-like effect of mirtazapine mediates its effect in the median raphe nucleus (2013)
  • Author(s): An Y, Inoue T, Kitaichi Y, Izumi T, Nakagawa S, Song N, Chen C, Li X, Koyama T, Kusumi I
  • Journal Title: Eur J Pharmacol Volume: 720 Issue: 1-3 Pages: 192-197
  • DOI: 10.1016/j.ejphar.2013.09.078
  • NAID: 120005367409
  • Peer Reviewed
• [Journal Article] Selegiline remarkably improved stage 5 treatment-resistant major depressive disorder: a case report. (2013)
  • Author(s): Kitaichi Y, Inoue T, Mitsui N, Nakagawa S, Kameyama R, Hayashishita Y, Shiga T, Kusumi I, Koyama T
  • Journal Title: Neuropsychiatr Dis Treat Volume: 9 Pages: 1591-1594
  • DOI: 10.2147/ndt.s49261
  • Peer Reviewed
• [Journal Article] Differences between bipolar and unipolar depression on Rorshach testing (2013)
  • Author(s): Kimura H, Osaki A, Kawashima R, Inoue T, Nakagawa S, Suzuki K, Asakura S, Tanaka T, Kitaichi Y, Masui T, Kitagawa N, Kako Y, Abekawa T, Kusumi I, Yamanaka H, Denda K, Koyama T
  • Journal Title: Neuropsychiatr Dis Treat Volume: 9 Pages: 619-627
  • DOI: 10.2147/ndt.s42702
  • Peer Reviewed
• [Journal Article] Development and validation of a screening quationnaire for present ora past (hypo) minic episodes based on DSM-IV criteria (2013)
  • Author(s): Kameyama R, Inoue T, Uchida M, Tanaka T, Kitaichi Y, Nakato Y, Hayashishita Y, Nakai Y, Nakagawa S, Kusumi I, Koyama T
  • Journal Title: J Affect Disord Volume: 150 Issue: 2 Pages: 546-550
  • DOI: 10.1016/j.jad.2013.01.034
  • Peer Reviewed
• [Journal Article] Impaired integrity of the brain parenchyma in non-geriatric patients with major depressive disorder revealed by diffusion tensor imaging (2013)
  • Author(s): Tha KK, Terae S, Nakagawa S, Inoue T, Kitagawa N, Kako Y, Nakato Y, Popy KA, Fujima N, Zaitsu Y, Yoshida D, Ito YM, Miyamato T, Koyama T, Shirato H
  • Journal Title: Psychiatry Res Volume: 212 Issue: 3 Pages: 208-215
  • DOI: 10.1016/j.pscychresns.2012.07.004
  • NAID: 120005322419
  • Peer Reviewed
• [Journal Article] Mood stabilizers commonly restore staurosporine-induced increase of p53 expression and following decrease of Bcl-2 expression in SH-SY5Y cells (2012)
  • Author(s): Song N, et al.
  • Journal Title: Prog Neuropsychophamacol Biol Psychiatry Volume: (in press) Issue: 2 Pages: 183-189
  • DOI: 10.1016/j.pnpbp.2012.03.006
  • Peer Reviewed
• [Journal Article] Noradrenaline increases neural precursor cells derived from adult rat dentate gyrus through beta2 receptor (2012)
  • Author(s): Masuda T, et al.
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry Volume: 36 Issue: 1 Pages: 44-51
  • DOI: 10.1016/j.pnpbp.2011.08.019
  • Peer Reviewed
• [Journal Article] The effects of the co-administration of the α1-adrenoreceptor antagonist prazosin on the anxiolytic effect of citalopram in conditioned fear stress in the rat. (2012)
  • Author(s): Takamura N, Masuda T, Inoue T, Nakagawa S, Koyama T
  • Journal Title: Progress in neuro-psychopharmacology & biological psychiatry Volume: 39 Issue: 1 Pages: 107-111
  • DOI: 10.1016/j.pnpbp.2012.05.017
  • Peer Reviewed
• [Journal Article] Effect of triiodothyronine (T(3)) augmentation of acute milnacipran administration on monoamine levels: an in vivo microdialysis study in rats. (2012)
  • Author(s): Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kato A, Kusumi I, Koyama T
  • Journal Title: Neuropsychiatric disease and treatment Volume: 8 Pages: 501-507
  • DOI: 10.2147/ndt.s36906
  • NAID: 120004979568
  • Peer Reviewed
• [Journal Article] Social Anxiety/Taijin-Kyofu Scale (SATS): Development and Psychometric Evaluation of a New Instrument. (2012)
  • Author(s): Asakura S, Inoue T, Kitagawa N, Hasegawa M, Fujii Y, Kako Y, Nakato Y, Hashimoto N, Ito K, Tanaka T, Nakagawa S, Kusumi I, Koyama T
  • Journal Title: Psychopathology Volume: 45 Issue: 2 Pages: 67-72
  • DOI: 10.1159/000329741
  • NAID: 120003898278
  • Peer Reviewed
• [Journal Article] Effects of mood stabilizers on adult dentate gyrus-derived neural precursor cells (2011)
  • Author(s): Boku S, Nakagawa S, Masuda T,Nishikawa H, Kato A, Toda H, Song N, Kitaichi Y, Inoue T, Koyama T
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry Volume: 35 Issue: 1 Pages: 111-117
  • DOI: 10.1016/j.pnpbp.2010.09.019
  • NAID: 120004856983
  • Peer Reviewed
• [Journal Article] Long-term naturalistic follow-up of lithium augmentation : Relevance to bipolarity (2011)
  • Author(s): Inoue T, Abekawa T, Nakagawa S, Suzuki K, Tanaka T, Kitaichi Y, Boku S, Nakato Y, Toda H, Koyama T
  • Journal Title: J Affect Disord Volume: 129 Issue: 1-3 Pages: 64-67
  • DOI: 10.1016/j.jad.2010.08.022
  • Peer Reviewed
• [Journal Article] Effects of aripiprazole and haloperidol on progression to schizophrenia-like behavioural abnormalities and apoptosis in rodents. (2011)
  • Author(s): Abekawa T, Ito K, Nakagawa S, Nakato Y, Koyama T
  • Journal Title: Schizophr Res Volume: 125 Issue: 1 Pages: 77-87
  • DOI: 10.1016/j.schres.2010.08.011
  • Peer Reviewed
• [Presentation] Involvement of CaMKIV in antidepressant action (2013)
  • Author(s): Nakagawa. S, Song. N, Takamura. N,Kato. A, An. Y, Inoue. T, Li. X, Kusumi. I
  • Organizer: 43th Annual Meeting Society for Neuroscience
  • Place of Presentation: Convention Center (San Diego, USA)
• [Presentation] Effect of dopamine on adulthippocampal neurogenesis (2013)
  • Author(s): Nakagawa. S, Takamura. N, Boku. S,Song. N, Kato. A, Inoue. T, Kusumi. I
  • Organizer: 第11回世界生物学的精神医学会国際会議
  • Place of Presentation: 国立京都国際会館(京都市)
• [Presentation] Effect of dopamine on adult hippocampal neurogenesis. (2013)
  • Author(s): Nakagawa S, Takamura N, Boku S, Song N, Inoue T, Kusumi I
  • Organizer: 第11回世界生物学的精神医学会国際会議
  • Place of Presentation: 国立京都国際会議場（京都）
• [Presentation] Involvement of CaMKIV in antidepressant action (2013)
  • Author(s): Nakagawa S, Song N, Takamura N, Kato A, An Y, Inoue T, Li X, Kusumi I
  • Organizer: 43th Annual Meeting Society for Neuroscience
  • Place of Presentation: San Diego Convention Center (San Diego, USA)
• [Presentation] Effect of dopamine on adult hippocampal neurogenesis (2012)
  • Author(s): Nakagawa. S, Takamura. N, Boku. S,Song. N, Kato. A, Inoue. T
  • Organizer: 42th Annual Meeting Society for Neuroscience
  • Place of Presentation: New Orleans Convention Center (New Orleans,USA)
• [Presentation] セロトニンと海馬の神経新生 (2012)
  • Author(s): 中川 伸
  • Organizer: 第18回「性と生殖」公開シンポジウム、第5回早稲田大学―日本歯科大学合同シンポジウム
  • Place of Presentation: 東京
  • Invited
• [Presentation] Effect of dopamine on adult hippocampal neurogenesis. (2012)
  • Author(s): Nakagawa S, Takamura N, Boku S, Song N, Kato A, Inoue T
  • Organizer: 42th Annual Meeting Society for Neuroscience
  • Place of Presentation: New Orleans, USA
• [Presentation] Involvement of CaM kinase IV in the action of antidepressant treatment (2011)
  • Author(s): Nakagawa. S, Song. N, Izumi. T,Boku. S, Toda. H, Kato. A, Li. X, Inoue.T, Sakagami. H, Koyama. T
  • Organizer: 41th Annual Meeting Society for Neuroscience
  • Place of Presentation: Washington DCConvention Center (Washington DC,USA)
• [Presentation] 抗うつ薬未服用のうつ病患者における脳拡散テンソル画像 (2011)
  • Author(s): 中川 伸、Khin Khin Tha、井上 猛、仲唐安哉、北川信樹、賀古勇輝、戸田裕之、朴秀賢、亀山梨絵、寺江 聡、小山 司
  • Organizer: 第30回躁うつ病の薬理・生化学的研究懇話会
  • Place of Presentation: 京都ガーデンパレス(京都府）
• [Presentation] Involvement of CaM kinase IV in the action of antidepressant treatment (2011)
  • Author(s): Shin Nakagawa, Ning Song, Takeshi Izumi, Shuken Boku, Hiroyuki Toda, Akiko Kato, Xiaobai Li, Takeshi Inoue, Hiroyuki Sakagami, Tsukasa Koyama
  • Organizer: 41th Annual Meeting Society for Neuroscience
  • Place of Presentation: Washington Convention Center (Washington DC, USA)
• [Book] うつ病—治療・研究の最前線 医学のあゆみ 別冊 (2014)
  • Author(s): 中川 伸、井上 猛、橋本謙二、功刀 浩
  • Total Pages: 512
  • Publisher: 医歯薬出版株式会社
• [Book] うつ病ー治療・研究の最前線 医学のあゆみ、別冊 (2014)
  • Author(s): 中川 伸、井上 猛、橋本謙二、功刀 浩
  • Total Pages: 512
  • Publisher: 医歯薬出版株式会社
• [Book] 精神・神経の治療薬辞典 専門医からのアドバイス (2013)
  • Author(s): 中川 伸、井上 猛、北市雄士、仲唐安哉、樋口輝彦
  • Total Pages: 369
  • Publisher: 総合医学社
• [Book] 抗うつ薬と躁転.130-134,今日の精神疾患.治療指針 (2012)
  • Author(s): 中川 伸
  • Publisher: 医学書院
• [Book] ラット母子分離ストレスによる成獣後の不安行動への脆弱性の分子メカニズム. 気分障害の薬理・生化学 (2012)
  • Author(s): 戸田裕之、朴 秀賢、中川 伸、小山 司
  • Publisher: 医薬ジャーナル誌
• [Book] うつ病における脳拡散テンソル画像. 気分障害の薬理・生化学 (2012)
  • Author(s): 中川 伸、Tha KK、小山 司
  • Publisher: 医薬ジャーナル誌
• [Book] 専門医のための精神科リュミエール (2011)
  • Author(s): 中川 伸、小山 司
  • Total Pages: 345
  • Publisher: 中山書店 (27)
• [Book] Depression. Neurogenesis in the adult brain II (2011)
  • Author(s): Nakagawa S and Duman RS (Edited by Seki T, Sawamoto K, Parent JM and Alvarez-Buylla A)
  • Total Pages: 210
  • Publisher: Springer, Tokyo
• [Book] Depression. Neurogenesis in the adult brain II (2011)
  • Author(s): Nakagawa S and Duman RS
  • Publisher: Springer
• [Book] 1.ストレスと心身医学の基礎.A.心身相関の生物学的基礎研究領域. II. 精神科が得意とする心身医学の領域. 専門医のための精神科リュミエール 27 (2011)
  • Author(s): 中川 伸、小山 司
  • Publisher: 中山書店