Elucidation of regulation mechanism of gene expression and emotional memory by dopamine signal

• Project/Area Number: 16K18393
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Nagoya University
• Principal Investigator: Funahashi Yasuhiro 名古屋大学, 医学系研究科, 助教 (00749913)
• Research Collaborator: Kaibuchi Kozo ; Nagai Taku ; Amano Mutsuki ; Nishioka Tomoki ; Kuroda Keisuke
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: ドーパミン / リン酸化 / プロテオミクス解析 / 情動 / 報酬 / 記憶・学習 / 転写因子 / 遺伝子発現 / 学習・記憶 / 細胞種特異的 / MAPK / 学習 / 記憶 / 情動記憶

Outline of Final Research Achievements

How dopamine regulates reward-related learning and memory through gene expression is poorly understood. Here, to identify the relevant transcriptional factors, we performed proteomic analysis using affinity beads coated with CREB-binding protein (CBP), a transcriptional coactivator involved in reward-related behavior. We identified more than 100 CBP-interacting proteins, including Neuronal Per-Arnt-Sim domain protein 4 (Npas4). We also found that MAPK phosphorylated Npas4 downstream of PKA, increasing Npas4-CBP interaction and the transcriptional activity of Npas4 at the brain-derived neurotrophic factor (BDNF) promoter. Deletion of Npas4 in the D1R-expressing MSNs impaired cocaine-induced place preference, which was rescued by Npas4-WT but not by a phospho-deficient Npas4 mutant. These observations suggest that MAPK phosphorylates Npas4 in D1R-MSNs and increases its transcriptional activity to enhance reward-related learning and memory.

Academic Significance and Societal Importance of the Research Achievements

ドーパミンの下流で働くリン酸化酵素により、リン酸化される主要な転写因子が明らかになり、ドーパミンによる遺伝子発現の制御機構、並びに、情動記憶形成の制御機構の一端が解明された。これらの成果は、基礎神経科学において重要というだけでなく、統合失調症やうつ病、薬物依存症、パーキンソン病などの精神・神経疾患の病因・病態解明や診断・治療法の確立等の医学分野に貢献する可能性が高い。

Research Products

• [Journal Article] In Vivo Identification of Protein Kinase Substrates by Kinase-Oriented Substrate Screening (KIOSS) (2019)
  • Author(s): Nishioka Tomoki、Amano Mutsuki、Funahashi Yasuhiro、Tsuboi Daisuke、Yamahashi Yukie、Kaibuchi Kozo
  • Journal Title: Current Protocols in Chemical Biology Volume: 11 Issue: 1
  • DOI: 10.1002/cpch.60
  • Peer Reviewed / Open Access
• [Journal Article] Balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in striatal medium spiny neurons (2018)
  • Author(s): Zhang XJ, Nagai T, Ahammad RU, Kuroda K, Nakamuta S, Nakano T, Yukinawa N, Funahashi Y, Yamahashi Y, Amano M, Yoshimoto J, Yamada K, and Kaibuchi K.
  • Journal Title: Neurochemistry International Volume: 122 Pages: 8-18
  • DOI: 10.1016/j.neuint.2018.10.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive analysis of kinase-oriented phospho-signalling pathways (2018)
  • Author(s): Amano Mutsuki、Nishioka Tomoki、Tsuboi Daisuke、Kuroda Keisuke、Funahashi Yasuhiro、Yamahashi Yukie、Kaibuchi Kozo
  • Journal Title: The Journal of Biochemistry Volume: 165 Issue: 4 Pages: 301-307
  • DOI: 10.1093/jb/mvy115
  • Peer Reviewed / Open Access
• [Journal Article] Focused Proteomics Revealed a Novel Rho-kinase Signaling Pathway in the Heart (2016)
  • Author(s): Yura Y, Amano M, Takefuji M, Bando T, Suzuki K, Kato K, Hamaguchi T, Hasanuzzaman Shohag M, Takano T, Funahashi Y, Nakamuta S, Kuroda K, Nishioka T, Murohara T, Kaibuchi K
  • Journal Title: Cell Structure and Function Volume: 41 Issue: 2 Pages: 105-120
  • DOI: 10.1247/csf.16011
  • NAID: 130005405432
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Phosphorylation of Npas4 by MAPK regulates reward-related gene expression and behaviors (2019)
  • Author(s): Yasuhiro Funahashi, Anthony Ariza, Rhosuke Emi, Shan Wei, Ko Suzuki, Sachi Kozawa, Tetsuya Takano, Yoshimitsu Yura, Keisuke Kuroda, Mutsuki Amano, Taku Nagai, Kiyofumi Yamada, Kozo Kaibuchi
  • Organizer: 第92回日本薬理学会年会
• [Presentation] The transcription factor Npas4 regulates reward-related learning and memory (2019)
  • Author(s): Ryosuke Emi, Yasuhiro Funahashi, Anthony Ariza, Shan Wei, Ko Suzuki, Sachi Kozawa, Keisuke Kuroda, Taku Nagai, Kiyofumi Yamada, Kozo Kaibuchi
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Dopamine-induced phosphorylation of NPAS4 through MAPK regulates reward-related learning and memory (2018)
  • Author(s): Yasuhiro Funahashi, Anthony Ariza, Shan Wei, Sachi Kozawa, Ryosuke Emi, Ko Suzuki, Keiichiro Okuda, Keisuke Kuroda, Taku Nagai, Kozo Kaibuchi
  • Organizer: the 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] MAPK-mediated phosphorylation of MKL2 regulates nuclear localization and transcriptional activity in striatal neurons (2018)
  • Author(s): Anthony Ariza, Yasuhiro Funahashi, Keiichiro Okuda, Sachi Kozawa, Kozo Kaibuchi
  • Organizer: the 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] Phosphorylation of Npas4 by MAPK regulates reward-related gene expression and behaviors (2018)
  • Author(s): Yasuhiro Funahashi, Rhosuke Emi, Anthony Ariza, Shan Wei, Ko Suzuki, Sachi Kozawa, Tetsuya Takano, Yoshimitsu Yura, Keisuke Kuroda, Taku Nagai, Kiyofumi Yamada, Kozo Kaibuchi
  • Organizer: 第41回日本神経科学大会
• [Presentation] Dopamine-induced phosphorylation of NPAS4 through MAPK regulates reward-related learning and memory. (2017)
  • Author(s): Yasuhiro Funahashi, Anthony Ariza, Shan Wei, Sachi Kozawa, Keiichiro Okuda, Ko Suzuki, Tetsuya Takano, Yoshimitsu Yura, Keisuke Kuroda, Taku Nagai, Kozo Kaibuchi
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎パブリックホール (長崎県長崎市)
  • Year and Date: 2017-03-15
• [Presentation] The activity-dependent transcription factor NPAS4 regulates reward-related learning and memory. (2017)
  • Author(s): Ko Suzuki, Yasuhiro Funahashi, Anthony Ariza, Shan Wei, Keisuke Kuroda, Taku Nagai, Kozo Kaibuchi
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎パブリックホール (長崎県長崎市)
  • Year and Date: 2017-03-15
• [Presentation] Dopamine-induced phosphorylation of NPAS4 through MAPK regulates reward-related learning and memory. (2017)
  • Author(s): Yasuhiro Funahashi, Anthony Ariza, Ko Suzuki, Shan Wei, Sachi Kozawa, Tetsuya Takano, Keisuke Kuroda, Taku Nagai, Kozo Kaibuchi
  • Organizer: joint meeting of the International Society of Neurochemistry (ISN) and the European Society for Neurochemistry (ESN)
  • Int'l Joint Research
• [Presentation] Yasuhiro Funahashi, Junichiro Yoshimoto, Takayuki Kannon, Taku Nagai, Keisuke Kuroda, Shinichi Nakamuta, Tomoki Nishioka, Mutsuki Amano, Shiro Usui, Kozo Kaibuchi (2017)
  • Author(s): KANPHOS (Kinase-Associated Neural Phospho-Signaling), a comprehensive database for specific substrates of kinases.
  • Organizer: 第40回日本神経科学大会
• [Presentation] Dopamine-induced phosphorylation of NPAS4 through MAPK regulates reward-related behavior. (2016)
  • Author(s): Yasuhiro Funahashi, Anthony Ariza, Shan Wei, Keisuke Kuroda, Tetsuya Takano, Yoshimitsu Yura, Taku Nagai, Kozo Kaibuchi
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市)
  • Year and Date: 2016-07-20
• [Presentation] Identification of CBP interacting proteins in mouse striatum by proteomic analysis. (2016)
  • Author(s): Keiichiro Okuda, Yasuhiro Funahashi, Anthony Ariza, Kozo Kaibuchi
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市)
  • Year and Date: 2016-07-20
• [Remarks] 名古屋大学大学院医学系研究科 神経情報薬理学講座HP
  • URL: http://www.med.nagoya-u.ac.jp/Yakuri/index.htm
• [Remarks] 名古屋大学大学院医学系研究科 神経情報薬理学
  • URL: https://www.med.nagoya-u.ac.jp/Yakuri/index.htm