Study on the neural mechanism controlling emotional behaviors

• Project/Area Number: 17H02220
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Basic / Social brain science
• Research Institution: Fujita Health University (2019); Nagoya University (2017-2018)
• Principal Investigator: Nagai Taku 藤田医科大学, その他部局等, 教授 (10377426)
• Co-Investigator(Kenkyū-buntansha): 伊藤 教道 名古屋大学, 医学部附属病院, 特任助教 (30726310)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: リン酸化シグナル / 情動 / ドーパミン / ドパミン

Outline of Final Research Achievements

The aim of present study is to propose the neural mechanism controlling emotional behaviors. To this end, we investigated signal transduction in dopamine D2 receptor-expressing mediumspiny neurons of mice. PKA/Rap1 signal in accumbal dopamine D2 receptor-expressing mediumspiny neurons promotes aversive behavior and results in a formation of aversive memory. With the cooperation of adenosine, dopamine concentration plays a role of switch in controlling active state shift between dopamine D1 and dopamine D2 receptor-expressing mediumspiny neurons in the neural circuit and thereby regulates emotional behaviors.

Academic Significance and Societal Importance of the Research Achievements

ドーパミン濃度の増減によりD1R-中型有棘神経細胞から D2R-中型有棘神経細胞への機能シフト、あるいはその逆が誘導され、情動行動が制御されるという新たなコンセプトを提唱することができた。また本研究成果は、これまで不明であったD2R拮抗作用を有する抗精神病薬がどのように細胞内シグナル調節しているのかを示唆しており、新規創薬標的を提示することに繋がる。

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
  • URL: https://pure.teikyo.jp/en/publications/ffaf265c-5861-4ce2-beba-82ea8b69cfa5
  • 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] Balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in striatal medium spiny neurons. (2019)
  • Author(s): Zhang, X., Nagai, T., Ahammadm, R.D., Kuroda, K., Nakamuta, S., Nakano, T., Yukinawa, N., Funahashi, Y., Yamahashi, Y., Amano, M., Yoshimoto, J., Yamada, K., Kaibuchi, K.
  • Journal Title: Neurochem. Int. Volume: 122 Pages: 8-18
  • Peer Reviewed
• [Journal Article] Pharmacological and proteomic analyses of neonatal polyI:C-treated adult mice. (2019)
  • Author(s): Kitagawa, K., Nagai, T., Yamada, K.
  • Journal Title: Neurosci. Res. Volume: 147 Pages: 39-47
  • Peer Reviewed
• [Journal Article] Proteomic analysis of lymphoblastoid cell lines from schizophrenic patients (2019)
  • Author(s): Yoshimi A, Yamada S, Kunimoto S, Aleksic B, Hirakawa A, Ohashi MS, Matsumoto A, Hada K, Itoh N, Arioka Y, Kimura H, Kushima I, Nakamura Y, Shiino T, Mori D, Tanaka S, Hamada S, Noda Y, Nagai T, Yamada K, Ozaki N
  • Journal Title: Translational Psychiatry Volume: 9 Issue: 1 Pages: 126-126
  • DOI: 10.1038/s41398-019-0461-2
  • Peer Reviewed / Open Access
• [Journal Article] Methylation analysis for postpartum depression : a case control study. (2019)
  • Author(s): Nakamura Y, Nakatochi M, Kunimoto S, Okada T, Aleksic B, Toyama M, Shiino T, Morikawa M, Yamauchi A, Yoshimi A, Furukawa-Hibi Y, Nagai T, Ohara M, Kubota C, Yamada K, Ando M, Ozaki N.
  • Journal Title: BMC Psychiatry. Volume: 19 Issue: 1 Pages: 190-199
  • DOI: 10.1186/s12888-019-2172-x
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors (2019)
  • Author(s): Funahashi Yasuhiro、Ariza Anthony、Emi Ryosuke、Xu Yifan、Shan Wei、Suzuki Ko、Kozawa Sachi、Ahammad Rijwan Uddin、Wu Mengya、Takano Tetsuya、Yura Yoshimitsu、Kuroda Keisuke、Nagai Taku、Amano Mutsuki、Yamada Kiyofumi、Kaibuchi Kozo
  • Journal Title: Cell Reports Volume: 29 Issue: 10 Pages: 3235-3252.e9
  • DOI: 10.1016/j.celrep.2019.10.116
  • NAID: 130007812598
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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] 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] Administration of molecular hydrogen during pregnancy improves behavioral abnormalities of offspring in a maternal immune activation model. (2018)
  • Author(s): Imai, K., Kotani, T., Tsuda, H., Nakano, T., Ushida, T., Iwase, A., Nagai T,, Toyokuni, S., Suzumura, A., Kikkawa, F.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 9221-9221
  • DOI: 10.1038/s41598-018-27626-4
  • 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] 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] 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: Gene Brain Behav Volume: -
  • Peer Reviewed
• [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
• [Journal Article] Exposure to diphtheria toxin during the juvenile period impairs both inner and outer hair cells in C57BL/6 mice (2017)
  • Author(s): Konishi H, Ohgami N, Matsushita A, Kondo Y, Aoyama Y, Kobayashi M, Nagai T, Ugawa S, Yamada K, Kato M, Kiyama H
  • Journal Title: Neuroscience Volume: 印刷中 Pages: 15-23
  • DOI: 10.1016/j.neuroscience.2017.03.028
  • NAID: 120006331816
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of impaired neuronal migration with cognitive deficits in extremely preterm infants. (2017)
  • Author(s): Kubo, K.I., Deguchi, K., Nagai, T,, Ito, Y., Yoshida, K., Endo, T., Benner, S., Shan, W., Kitazawa, A., Aramaki, M., Ishii, K., Shin, M., Matsunaga, Y., Hayashi, K., Kakeyama, M., Tohyama, C., Tanaka, K.F., Tanaka, K., Takashima, S., Nakayama, M.
  • Journal Title: JCI Insight. Volume: 2 Issue: 10 Pages: 88609-88609
  • DOI: 10.1172/jci.insight.88609
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] 統合失調症の克服に向けた薬理学的アプローチ (2020)
  • Author(s): 永井拓.
  • Organizer: 第93回日本薬理学会年会
  • Invited
• [Presentation] 情動行動を司る細胞内シグナルの探索 (2020)
  • Author(s): 永井拓.
  • Organizer: 第68回脳の医学・生物学研究会
  • Invited
• [Presentation] Phosphoroteomic analysis in orleans reeler mice identified TWF1 as a novel reelin-associated phosphorylation signal. (2019)
  • Author(s): Nagai Taku, Matsui Takaaki, Sato Ayato, Itoh, Norimichi, Yamada Kiyofumi.
  • Organizer: NEURO2019 第42回日本神経科学大会 第62回日本神経化学大会
• [Presentation] 快・不快情動の細胞内シグナル (2019)
  • Author(s): 永井拓
  • Organizer: 第49回日本神経精神薬理学会・第29回日本臨床神経精神薬理学会合同年会
  • Invited
• [Presentation] ゲノムのコピー数変化から統合失調症の診断治療標的を探る. (シンポジウム). (2019)
  • Author(s): 永井拓, 尾崎紀夫, 山田清文.
  • Organizer: 第92回日本薬理学会年会.
  • Invited
• [Presentation] Striatal phosphorylation signals regulating reward and aversive behaviors. (Symposium). (2019)
  • Author(s): Nagai T.
  • Organizer: The 22nd Japan-Korea Joint Seminar on Pharmacology.
  • Int'l Joint Research
• [Presentation] ホメオスタシスの観点から考えるてんかん治療の標的分子. (シンポジウム). (2018)
  • Author(s): 永井拓, Shan Wei, 山田清文.
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] Npas4-Homer1a pathway regulates neuronal homeostasis in animal model of epilepsy. (2018)
  • Author(s): Nagai, T., Shan, W., Tanaka, M., Itoh, N., Furukawa-Hibi, Y., Nabeshima, T., Sokabe, M., Yamada, K.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology.
  • Int'l Joint Research
• [Presentation] 免疫活性化によって誘導されるアストロサイト由来MHC class Iの病態生理学的役割. (シンポジウム). (2018)
  • Author(s): 永井拓.
  • Organizer: 第61回日本神経化学会大会・第40回日本生物学的精神医学会.
• [Presentation] 自然免疫系の過剰な活性化はアストロサイト由来主要組織適合抗原I型を介して異常行動を引き起こす. (シンポジウム). (2018)
  • Author(s): 永井拓, 祖父江顕, 山田清文.
  • Organizer: 第34回日本ストレス学会学術総会.
  • Invited
• [Presentation] 統合失調症患者から同定されたReelin遺伝子変異の病態生理学的意義. (シンポジウム). (2018)
  • Author(s): 永井拓, 祖父江顕, 久島周, 尾崎紀夫, 山田清文.
  • Organizer: 第28回日本臨床精神神経薬理学会・第48回日本神経精神薬理学会 合同年会.
  • Invited
• [Presentation] 統合失調症の克服を目指したリバーストランスレーショナルリサーチ. (シンポジウム). (2018)
  • Author(s): 永井拓, 尾崎紀夫, 山田清文.
  • Organizer: 第28回日本医療薬学会年会.
  • Invited
• [Presentation] Role of striatal phosphorylation signaling in emotional behaviors. (ワークショップ). (2018)
  • Author(s): 永井拓, 貝淵弘三.
  • Organizer: 第41回日本分子生物学会年会.
  • Invited
• [Presentation] ホメオスタシスの観点から考えるてんかん治療の標的分子. (2018)
  • Author(s): 永井拓, Shan Wei, 山田清文.
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] ドパミン神経伝達により引き起こされる神経興奮と報酬関連行動の細胞内シグナル. (2017)
  • Author(s): 永井拓, 黒田啓介, 貝淵弘三.
  • Organizer: 第40回日本神経科学会大会
  • Invited
• [Presentation] Npas4 mediates pentylenetetrazole-induced Homer1a expression in the hippocampus. (2017)
  • Author(s): 永井拓, Shan Wei, 田中基樹, 鍋島俊隆, 曽我部正博, 山田清文
  • Organizer: 第60回日本神経化学会大会
• [Presentation] 脳機能を制御するリン酸化シグナルの解明に関する研究. (2017)
  • Author(s): 永井拓.
  • Organizer: 第60回日本神経化学会大会
  • Invited
• [Presentation] ペンチレンテトラゾール誘発てんかん発作におけるNpas4の役割. (2017)
  • Author(s): 永井拓, Shan Wei, 田中基樹, 鍋島俊隆, 曽我部正博, 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.
• [Presentation] Phosphorylation signals in reward-motivated behaviors. (2017)
  • Author(s): 永井拓, 貝淵弘三.
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Invited
• [Remarks] 名古屋大学大学院医学系研究科医療薬学研究室
  • URL: https://www.med.nagoya-u.ac.jp/medical_J/laboratory/clinical-pharma/clinical-pharma/neuropsycho-pharmacology/
• [Remarks] 医療薬学研究室ホームページ
  • URL: https://www.med.nagoya-u.ac.jp/medical_J/laboratory/clinical-pharma/clinical-pharma/neuropsycho-pharmacology/