Development a translatable visual discrimination test in rodents to apply for drug discovery and development

• Project/Area Number: 17H04031
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Nagoya University
• Principal Investigator: Yamada Kiyofumi 名古屋大学, 医学部附属病院, 教授 (30303639)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: タッチパネル式視覚弁別試験 / 統合失調症 / 動物モデル / DISC1 / Npas4 / MHC1 / アストロサイト / 注意機能 / Reelin / DREADD / 薬理学 / 神経科学

Outline of Final Research Achievements

Cognitive function in mouse models of schizophrenia was evaluated by a touchscreen-based visual discrimination (VD) test, a rational assay that can be performed by rodents and humans, in order to provide translational validity. Genetic mouse models of schizophrenia, including mouse carrying DISC1 deletion, schizophrenia-associated RELN or ARHGAP10 gene mutation, all exhibited impairments in the VD test, which was accompanied by an increase in c-Fos expression in the prefrontal cortex and dorsomedial striatum. We also demonstrated that mitogen-activated protein kinase signaling in the dopamine D1 receptor expressing-medium spiny neurons of the nucleus accumbens plays an important role in stimulus-reward learning. Through the comprehensive behavioral and neurochemical analyses of genetic mouse models of neuropsychiatric disorders we have identified several new targets for novel drug discovery and development.

Academic Significance and Societal Importance of the Research Achievements

本研究において視覚弁別機能に関連する神経回路の一端が解明できたことにより、高次脳機能の理解が大きく進んだと考えられる。さらに、統合失調症の情動認知機能障害に関わる分子としてDISC1, リーリンおよびARHGAP10を同定した。これらの研究成果は、これまで治療困難であった統合失調症の新規治療薬や予防薬の開発に繋がるものと期待できる。実際、患者型遺伝子変異を有する動物モデルの研究から、ドーパミンD2受容体などの従来の創薬標的とは異なる新しい創薬標的候補分子を同定した。
以上、本研究成果は脳科学研究の発展に寄与するだけでなく、精神疾患の病態解明や新規治療薬の開発への応用展開が可能である。

Research Products

• [Journal Article] Comprehensive analysis of a novel mouse model of the 22q11.2 deletion syndrome: a model with the most common 3.0-Mb deletion at the human 22q11.2 locus (2020)
  • Author(s): Saito Ryo、Koebis Michinori、Nagai Taku、Shimizu Kimiko、Liao Jingzhu、Wulaer Bolati、Sugaya Yuki、Nagahama Kenichiro、Uesaka Naofumi、Kushima Itaru、Mori Daisuke、Maruyama Kazuaki、Nakao Kazuki、Kurihara Hiroki、Yamada Kiyofumi、Kano Masanobu、Fukada Yoshitaka、Ozaki Norio、Aiba Atsu
  • Journal Title: Translational Psychiatry Volume: 10 Issue: 1 Pages: 35-35
  • DOI: 10.1038/s41398-020-0723-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia (2020)
  • Author(s): Masahito Sawahata, Daisuke Mori, Yuko Arioka, Hisako Kubo, Itaru Kushima, Kanako Kitagawa, Akira Sobue, Emiko Shishido, Mariko Sekiguchi, Akiko Kodama, Ryosuke Ikeda, Branko Aleksic, Hiroki Kimura, Kanako Ishizuka, Taku Nagai, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki
  • Journal Title: Psychiatry and clinical neurosciences Volume: 1 Issue: 5 Pages: 1-10
  • DOI: 10.1111/pcn.12993
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methamphetamine use causes cognitive impairment and altered decision-making. (2019)
  • Author(s): Mizoguchi H, Yamada K.
  • Journal Title: Neurochem Int. Volume: 124 Pages: 106-113
  • DOI: 10.1016/j.neuint.2018.12.019
  • Peer Reviewed / Open Access
• [Journal Article] Nicotine and varenicline ameliorate changes in reward-based choice strategy and altered decision-making in methamphetamine-treated rats. (2019)
  • Author(s): Mizoguchi H, Wang T, Kusaba M, Fukumoto K, Yamada K.
  • Journal Title: Behav Brain Res. Volume: 359 Pages: 935-941
  • DOI: 10.1016/j.bbr.2018.06.016
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacological and proteomic analyses of neonatal polyI:C-treated adult mice. (2018)
  • Author(s): Kitagawa, K., Nagai, T., Yamada, K.
  • Journal Title: Neurosci. Res. Volume: - Pages: 39-47
  • DOI: 10.1016/j.neures.2018.10.007
  • Peer Reviewed / Open Access
• [Journal Article] Astroglial major histocompatibility complex class I following immune activation leads to behavioral and neuropathological changes. (2018)
  • Author(s): A Sobue, N Ito, T Nagai, W Shan, K Hada, Nakajima A, Y Murakami, A Mouri, Y Yamamoto, T Nabeshima, K Saito, K Yamada
  • Journal Title: Glia Volume: 66 Issue: 5 Pages: 1034-52
  • DOI: 10.1002/glia.23299
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Juvenile social defeat stress exposure persistently impairs social behaviors and neurogenesis. (2018)
  • Author(s): Mouri A, Ukai M, Uchida M, Hasegawa S, Taniguchi M, Ito T, Hida H, Yoshimi A, Yamada K, Kunimoto S, Ozaki N, Nabeshima T, Noda Y.
  • Journal Title: Neuropharmacology. Volume: 133 Pages: 23-37
  • DOI: 10.1016/j.neuropharm.2018.01.016
  • Peer Reviewed / Open Access
• [Journal Article] Repetitive and compulsive-like behaviors lead to cognitive dysfunction in Disc1Δ2-3/Δ2-3 mice (2018)
  • Author(s): Wulaer B, Nagai T, Sobue A, Itoh N, Kuroda K, Kaibuchi K, Nabeshima T, Yamada K
  • Journal Title: Genes Brain Behav Volume: 印刷中 Issue: 8
  • DOI: 10.1111/gbb.12478
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell type-specific activation of mitogen-activated protein kinase in D1 receptor-expressing neurons of the nucleus accumbens potentiates stimulus-reward learning in mice (2018)
  • Author(s): Bin Saifullah Md. Ali、Nagai Taku、Kuroda Keisuke、Wulaer Bolati、Nabeshima Toshitaka、Kaibuchi Kozo、Yamada Kiyofumi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 14413-14413
  • DOI: 10.1038/s41598-018-32840-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia. (2018)
  • Author(s): Sobue A, Kushima I, Nagai T, Shan W, Kohno T, Aleksic B, Aoyama Y, Mori D, Arioka Y, Kawano N, Yamamoto M, Hattori M, Nabeshima T, Yamada K, Ozaki N.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 13046-13046
  • DOI: 10.1038/s41598-018-31390-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Innate immune activation of astrocytes impairs neurodevelopment via upregulation of follistatin-like 1 and interferon-induced transmembrane protein 3. (2018)
  • Author(s): Yamada, S., Itoh, N., Nagai, T., Nakai, T., Ibi, D., Nakajima, A., Nabeshima, T., Yamada, K.
  • Journal Title: J. Neuroinflammation. Volume: 15 Issue: 1 Pages: 295-295
  • DOI: 10.1186/s12974-018-1332-0
  • Peer Reviewed / Open Access
• [Journal Article] Valocin-containing protein (VCP) is a novel IQ motif containing GTPase activating protein 1 (IQGAP1) interacting protein. (2017)
  • Author(s): Itoh, N., Nagai, T,, Watanabe, T., Taki, K., Nabeshima, N., Kaibuchi, K., Yamada, K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 493 Issue: 4 Pages: 1384-1389
  • DOI: 10.1016/j.bbrc.2017.09.159
  • Peer Reviewed / Open Access
• [Journal Article] Neuronal PAS domain protein 4 (Npas4) controls neuronal homeostasis in pentylenetetrazole-induced epilepsy through the induction of Homer1a. (2017)
  • Author(s): 2.Shan W, Nagai T, Tanaka M, Itoh N, Furukawa-Hibi Y, Nabeshima T, Sokabe M, Yamada K.
  • Journal Title: J Neurochem. Volume: - Issue: 1 Pages: 19-33
  • DOI: 10.1111/jnc.14274
  • Peer Reviewed / Open Access
• [Presentation] Evaluation of cognitive function in preclinical animal models of schizophrenia using touchscreen-based visual discrimination tasks. (2019)
  • Author(s): Jingzhu Liao,Taku Nagai,Daisuke Mori,Bolati Wulaer,Toshitaka Nabeshima,Norio Ozaki,Kiyofumi Yamada
  • Organizer: The7th China-Japan Joint Meeting of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Roots of decision-making in addiction:the insular cortex,nucleus accumbens,striatum. (2019)
  • Author(s): Hiroyuki Mizoguchi,Kiyofumi Yamada
  • Organizer: 7TH INTERNATIONAL DRUG ABUSE RESEARCH SOCIETY
  • Int'l Joint Research
• [Presentation] Reelin supplementation therapy in preclinical models of schizophrenia. (2019)
  • Author(s): Kiyofumi Yamada,Masahito Sawahata,Taku Nagai,Daisuke Ibi,Masayuki Hiramatsu
  • Organizer: 6th Congress of AsCNP
  • Int'l Joint Research
• [Presentation] A novel animal model of schizophrenia based on copy-number variations. (2019)
  • Author(s): Taku Nagai,Akira Sobue,Daisuke Mori,Kazuhiro Hada,Jingzhu LIAO,Bolati Wulaer,Toshitaka Nabeshima,Norio Ozaki,Kiyofumi Yamada.
  • Organizer: 6th Congress of AsCNP
  • Int'l Joint Research
• [Presentation] Acute administration of methamphetamine impairs higher cognitive function in C57BL/6J mice through cortico-striatal circuits. (2019)
  • Author(s): Jingzhu Liao,Taku Nagai,Bolati Wulaer,Toshitaka Nabeshima,Kiyofumi Yamada
  • Organizer: Society for Neuroscience (SfN) Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] In vivo imaging for the effect of cocaine. (2018)
  • Author(s): Youyun Zhu,Norimichi ito,Taku Nagai,Keisuke Kuroda,Kozo Kaibuchi,Toshitaka Nabeshima,Kiyofumi Yamada
  • Organizer: 19th Congress of the International Society for Biomedical Research on Alcoholism (ISBRA2018)
  • Int'l Joint Research
• [Presentation] Acute methamphetamine administration impairs cognitive function in a touchscreen-based visual discrimination task in C57BL/6 mice. (2018)
  • Author(s): Liao Jingzhu,Wulaer Bolati,Nagai Taku,Yamada Kiyofumi
  • Organizer: 19th Congress of the International Society for Biomedical Research on Alcoholism (ISBRA2018)
  • Int'l Joint Research
• [Presentation] An operant task for testing risky decision-making in mice. (2018)
  • Author(s): Tian Wang,Kazuya Fukumoto,Hiroyuki Mizoguchi,Kiyofumi Yamada
  • Organizer: 19th Congress of the International Society for Biomedical Research on Alcoholism (ISBRA2018)
  • Int'l Joint Research
• [Presentation] Specific MHCI overexpression in astrocytes induces behavioral and neuropathological abnormalities in mice (2018)
  • Author(s): Kazuhiro Hada,Akira Sobue,Bolati Wulaer,Norimichi Itoh,Akira Nakajima,Takatoshi Nabeshima,Taku Nagai,Kiyofumi Yamada
  • Organizer: Society for Neuroscience 48th Annual Meeting(NEUROSCIENCE2018)
  • Int'l Joint Research
• [Presentation] The pathophusiological role of astroglial MHCI following systemic immune activation (2018)
  • Author(s): Akira Sobue,NorimichiIto,Kazuhiro Hada,Akira Nakajima,Murakami Yuki,Mouri Akihiro,Yamamoto Yasuko,Toshitaka Nabeshima,Kuniaki Saito,Taku Nagai,Kiyofumi Yamada
  • Organizer: 第41回日本神経科学大会
• [Presentation] 統合失調症モデル側坐核ニューロンの形態学的およびメタンフェタミン反応性の変化 (2018)
  • Author(s): 羽田和弘、永井拓、伊藤教道、祖父江顕、Bolati Wulaer、森大輔、久島周、鍋島俊隆、尾崎紀夫、山田清文
  • Organizer: 第40回日本生物学的精神医学会・第61回日本神経化学会大会合同年会
• [Presentation] Disruption of exons 2 and 3 of the Disc1 gene in the mouse is associated with elevated repetitive behavior. (2017)
  • Author(s): Bolati Wulaer, Taku Nagai, Keisuke Kuroda, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada.
  • Organizer: 5th Congress Of Asian College of Neuropsychopharmacology, AsCNP2017
  • Int'l Joint Research
• [Presentation] Impaired visual discrimination learning in Disc1-knockout mice,reversed by clozapine treatment. (2017)
  • Author(s): Bolati Wulaer, Taku Nagai, Akira Sobue, Keisuke Kuroda, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada.
  • Organizer: IBNS2017Annual Meeting
  • Int'l Joint Research
• [Presentation] Cognitive deficit correlated with changes in neuronal activity in Disc1 mice in touchscreen-based visual discrimination task. (2017)
  • Author(s): Bolati Wulaer, Taku Nagai, Akira Sobue, Norimichi Itoh, Keisuke Kuroda, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada.
  • Organizer: NEUROSCIENCE2017
  • Int'l Joint Research
• [Presentation] タッチパネル式視覚弁別試験を用いた精神疾患モデルマウスの認知機能解析 (2017)
  • Author(s): 山田清文
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会合同年会
• [Remarks] 名古屋大学大学院医学系研究科・附属病院薬剤部
  • URL: http://www.nagoya-u.ac.jp/pharmacy/
• [Remarks] 名古屋大学大学院医学系研究科医療薬学・附属病院薬剤部
  • URL: http://www.med.nagoya-u.ac.jp/pharmacy/