双方向性神経成熟度変化のメカニズム解明とその制御

2014 Fiscal Year Annual Research Report

• Project/Area Number: 25242078
• Research Institution: Fujita Health University
• Principal Investigator: 宮川 剛 藤田保健衛生大学, 総合医科学研究所, 教授 (10301780)
• Project Period (FY): 2013-10-21 – 2018-03-31
• Keywords: 遺伝学 / 脳神経疾患 / トランスレーショナルリサーチ / バイオテクノロジー / 脳・神経

Outline of Annual Research Achievements

前年度に引き続き以下の項目を進めた。
(1) 神経の双方向性成熟度変化の分子機序解明：「非成熟歯状回」を引き起こす必須のコモンパスウェイの検討のため、バイオインフォマティクス解析により複数の「非成熟歯状回」を示すマウス（iDGマウス）で共通して生じている分子変化を絞り込みをインフォマティクスツール・NextBio(米イルミナ社)を用い進めた。
(2) 神経成熟度を自在に制御する方法の探索と確立：部位特異的遺伝子改変による神経成熟度の制御方法の探索のため、iDG化を引き起こすことが知られているShn2遺伝子について前脳特異的ノックアウトマウスの作製を進めた。各種脳領域・細胞種特異的Creマウスとfloxedマウスの掛け合わせについても準備中。
(3) 神経細胞の双方向性成熟度変化の機能的意義の解明：Shn2 KOマウスについて3D電顕コネクトーム解析の準備を実施。前脳特異的Shn2 KOマウスについて網羅的行動解析を実施中。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

(1) 神経の双方向性成熟度変化の分子機序解明：iDGマウスで共通して生じている分子変化の候補（炎症関連パスウェイなど）を複数見出した。
(2) 神経成熟度を自在に制御する方法の探索と確立：Shn2遺伝子について前脳特異的ノックアウトマウスは作製済み。各種脳領域（歯状回、線条体）・細胞種（アストログリア）特異的Creマウスとfloxedマウスの掛け合わせについては、特異性などを確認中。
(3) 神経細胞の双方向性成熟度変化の機能的意義の解明：Shn2 KOマウスについて3D電顕コネクトーム解析の準備を実施中。データ解析前脳特異的Shn2 KOマウスについて網羅的行動解析を行っている。

Strategy for Future Research Activity

前年度に引き続き以下の項目を進める。
(1) 神経の双方向性成熟度変化の分子機序解明：バイオインフォマティクス解析により複数のiDGマウスで共通して生じている分子変化の探索を引き続き行い、絞り込みを実施する。
(2) 神経成熟度を自在に制御する方法の探索と確立：部位特異的遺伝子改変による神経成熟度の制御方法の探索のため、iDG化を引き起こすことが知られているShn2をはじめとした各種遺伝子について部位・細胞種特異的（歯状回、アストログリアなど）ノックアウトマウスの作製。各種脳領域・細胞種特異的Creマウスとfloxedマウスの掛け合わせと繁殖。
(3) 神経細胞の双方向性成熟度変化の機能的意義の解明：Shn2 KOマウス歯状回サンプルについて3D電顕コネクトーム解析を実施。上記(2)の部位特異的遺伝子改変マウスについて網羅的行動解析を行う。

Research Products

• [Journal Article] Reply to Warren et al. and Shay et al.: Commonalities across species do exist and are potentially important. (2015)
  • Author(s): Takao K, Hagihara H, Miyakawa T.
  • Journal Title: Proc Natl Acad Sci USA Volume: 112(4) Pages: E347-8
  • DOI: 10.1073/pnas.1417369111
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive behavioral study of mGluR3 knockout mice: implication in schizophrenia related endophenotypes. (2014)
  • Author(s): Fujioka R, Nii T, Iwaki A, Shibata A, Ito I, Kitaichi K, Nomura M, Hattori S, Takao K, Miyakawa T, Fukumaki Y.
  • Journal Title: Mol Brain Volume: 7 Pages: 31
  • DOI: 10.1186/1756-6606-7-31
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hippocampal neurogenesis regulates forgetting during adulthood and infancy. (2014)
  • Author(s): Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang HL, Wheeler AL, Guskjolen A, Niibori Y, Shoji H, Ohira K, Richards BA, Miyakawa T, Josselyn SA, Frankland PW.
  • Journal Title: Science Volume: 344(6184) Pages: 598-602
  • DOI: 10.1126/science.1248903
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia. (2014)
  • Author(s): Hagihara H, Ohira K, Takao K, Miyakawa T.
  • Journal Title: Mol Brain Volume: 7 Pages: 41
  • DOI: 10.1186/1756-6606-7-41
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced stability of hippocampal place representation caused by reduced magnesium block of NMDA receptors in the dentate gyrus. (2014)
  • Author(s): Hayashi Y, Nabeshima Y, Kobayashi K, Miyakawa T, Tanda K, Takao K, Suzuki H, Esumi E, Noguchi S, Matsuda Y, Sasaoka T, Noda T, Miyazaki JI, Mishina M, Funabiki K, Nabeshima YI.
  • Journal Title: Mol Brain Volume: 7 Pages: 44
  • DOI: 10.1186/1756-6606-7-44
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms for interferon-α-induced depression and neural stem cell dysfunction. (2014)
  • Author(s): Zheng LS, Hitoshi S, Kaneko N, Takao K, Miyakawa T, Tanaka Y, Xia H, Kalinke U, Kudo K, Kanba S, Ikenaka K, Sawamoto K.
  • Journal Title: Stem cell Reports Volume: 3(1) Pages: 73-84
  • DOI: 10.1016/j.stemcr.2014.05.015
  • Peer Reviewed / Open Access
• [Journal Article] Genomic responses in mouse models greatly mimic human inflammatory diseases. (2014)
  • Author(s): Takao K, Miyakawa T.
  • Journal Title: Proc Natl Acad Sci USA. Volume: 112(4) Pages: 1167-72
  • DOI: 10.1073/pnas.1401965111
  • Peer Reviewed / Open Access
• [Journal Article] SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system. (2014)
  • Author(s): Watanabe S, Ageta-Ishihara N, Nagatsu S, Takao K, Komine O, Endo F, Miyakawa T, Misawa H, Takahashi R, Kinoshita M, Yamanaka K.
  • Journal Title: Mol Brain Volume: 7 Pages: 62
  • DOI: 10.1186/s13041-014-0062-1
  • Peer Reviewed / Open Access
• [Journal Article] IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours. (2014)
  • Author(s): Yasumura M, Yoshida T, Yamazaki M, Abe M, Natsume R, Kanno K, Uemura T, Takao K, Sakimura K, Kikusui T, Miyakawa T, Mishina M.
  • Journal Title: Sci Rep. Volume: 4 Pages: 6613
  • DOI: 10.1038/srep06613
  • Peer Reviewed / Open Access
• [Presentation] 精神疾患の中間表現型としての未成熟脳 (2015)
  • Author(s): 宮川剛
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] Transcriptomic effects of antidepressant treatment and glucocorticoid receptor-overexpression on the maturational status of brain cells in mice (2014)
  • Author(s): Tsuyoshi Miyakawa
  • Organizer: ACNP 53rd Annual Meeting
  • Place of Presentation: Phoenix, Arizona, USA
  • Year and Date: 2014-12-07 – 2014-12-11
  • Int'l Joint Research
• [Presentation] ranscriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia (2014)
  • Author(s): Hideo Hagihara, Koji Ohira, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
  • Int'l Joint Research
• [Presentation] Cohort removal induces hyperthermia, increased pain sensitivity, and decreased anxiety-like behavior. (2014)
  • Author(s): Keizo Takao, Satoko Hattori, Hirotaka Shoji, Tsuyoshi Miyakawa
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
  • Int'l Joint Research
• [Presentation] Transcriptomic evidence for immaturity in the frontal cortex and dentate gyrus of mice treated with antidepressants (2014)
  • Author(s): Koji Ohira, Hideo Hagihara, Rika Takeuchi, Tsuyoshi Miyakawa
  • Organizer: Neuroscience 2014
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
  • Int'l Joint Research
• [Presentation] Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia (2014)
  • Author(s): Hideo Hagihara, Koji Ohira, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: Molecular and Cellular Cognition Society
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-14
  • Int'l Joint Research
• [Presentation] Contrasting expression patterns for immaturity and maturity marker genes in the dentate gyrus between mouse line with ‘immature dentate gyrus’ and mice overexpressing glucocorticoid receptor (2014)
  • Author(s): Hisatsugu Koshimizu, Hideo Hagihara, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: Molecular and Cellular Cognition Society
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-14
  • Int'l Joint Research
• [Presentation] 遺伝子改変マウスの行動解析を起点とする精神疾患の研究―マウスはモデルになりますー (2014)
  • Author(s): 宮川剛
  • Organizer: 第36回日本生物学的精神医学会・第57回日本神経化学会大会
  • Place of Presentation: 奈良
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] Bidirectional change of maturation status of cells in the brain: Relevance to neuropsychiatric disorder (2014)
  • Author(s): Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Genomic responses in mouse models greatly mimic human inflammatory diseases: In defense of mouse models for studying human disorders (2014)
  • Author(s): Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Comprehensive behavioral analysis of forebrain and dentate gyrus-specific Schnurri-2 knockout mice (2014)
  • Author(s): Satoko Hattori, Keizo Takao, Maya Yamazaki, Keiko Toyama, Juzoh Umemori, Kenji Sakimura, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia (2014)
  • Author(s): Hideo Hagihara, Koji Ohira, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Transcriptomic evidence for the immaturity in the frontal cortex of mice treated with antidepressants (2014)
  • Author(s): Koji Ohira, Hideo Hagihara, Rika Takeuchi, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Contrasting expression pattern for immaturity and maturity marker genes in the dentate gyrus between mouse lines with “immature dentate gyrus” and mice overexpressing glucocorticoid receptor (2014)
  • Author(s): Hisatsugu Koshimizu, Hideo Hagihara, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Remote memory deficit in three strains of mutant mice immature dentate gyrus phenotype (2014)
  • Author(s): Hirotaka Shoji, Tsuyoshi Takagi, Shunsuke Ishii, Isabella A Graef, Gerald R Crabtree, Paul W Frankland, Tsuyoshi Miyakawa
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Bidirectional change of maturation status of cells in the brain: relevant to neuropsychiatric disorders (2014)
  • Author(s): Tsuyoshi Miyakawa
  • Organizer: 9th International Conference for Neurons and Brain Disease
  • Place of Presentation: マドリッド、スペイン
  • Year and Date: 2014-07-11 – 2014-07-16
  • Int'l Joint Research
• [Presentation] 精神疾患の中間表現型としての未成熟脳 (2014)
  • Author(s): 宮川剛
  • Organizer: 第110回日本精神神経学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-06-26 – 2014-06-28
• [Presentation] Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia (2014)
  • Author(s): Hideo Hagihara, Koji Ohira, Keizo Takao, Tsuyoshi Miyakawa
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-22 – 2014-06-26
  • Int'l Joint Research
• [Presentation] Retrospective prediction of behavioral state by hippocampal transcriptomes (2014)
  • Author(s): Hideo Hagihara, Tomoyasu Horikawa, Hironori K. Nakamura, Hirotaka Shoji, Yukiyasu Kamitani, Tsuyoshi Miyakawa
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-22 – 2014-06-26
  • Int'l Joint Research