New behavioral animal model to study genetic and environmental factors in the cause of depression

• Project/Area Number: 16K07100
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Hyogo University of Health Sciences
• Principal Investigator: DOE Nobutake 兵庫医療大学, 共通教育センター, 講師 (00434879)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: うつ病 / 動物モデル / 水迷路学習 / マウス / 行動的絶望 / 発症脆弱性 / 個体差 / エピジェネティクス / うつ動物モデル / 脆弱性 / 疾患モデル / 実験系心理学 / 行動学

Outline of Final Research Achievements

We have developed a new animal model of depression by modifying the water maze learning task in mice. When the difficulty of the task is increased by downsizing of the platform and removing external cues, some of the mice gradually abandon adaptive learning and become immobile; this response indicates a depression-like states. In this research, DNA microarray analysis of hippocampus was performed to investigate the genes contributing to depression-like phenotypes of the helpless mice. The analysis followed by validation using real-time PCR revealed significant alteration in the expression of several genes, including downregulation of Ttr (transthyretin). Thus, it is possible that the decrease in Ttr expression in the hippocampus may be involved in the induction of depressant-like states in mice.

Academic Significance and Societal Importance of the Research Achievements

本研究で扱ったうつ動物モデルは、遺伝的相同性が極めて高い近交系マウスを被験体としながら、うつ的状態に陥る個体と健常性を維持する個体を並行して得ることができる実験系である。今回、うつ的状態に陥った個体の海馬において発現低下が認められたTtr(トランスサイレチン)は、エピジェネティックなメカニズムの制御を受けて抗うつ効果の発現に関わっていると推測される遺伝子である。つまり、マウスのうつ的状態の誘発には、Ttr等の遺伝子のエピジェネティックなメカニズムを介した変化が関わっている可能性が示唆された。

Research Products

• [Journal Article] Intravenous administration of human adipose-derived stem cells ameliorates motor and cognitive function for intracerebral hemorrhage mouse model (2019)
  • Author(s): Kuramoto Yoji, Takagi Toshinori, Tatebayashi Kotaro, Beppu Mikiya, Doe Nobutaka, Fujita Mitsugu, & Yoshimura Shinichi
  • Journal Title: Brain Research Volume: 1711 Pages: 58-67
  • DOI: 10.1016/j.brainres.2018.12.042
  • Peer Reviewed
• [Journal Article] Adipose-derived stem cell therapy inhibits the deterioration of cerebral infarction by altering macrophage kinetics (2019)
  • Author(s): Tatebayashi Kotaro, Takagi Toshinori, Fujita Mitsugu, Doe Nobutaka, Nakagomi Takayuki, Matsuyama Tomohiro, & Yoshimura Shinichi
  • Journal Title: Brain Research Volume: 1712 Pages: 139-150
  • DOI: 10.1016/j.brainres.2019.01.037
  • Peer Reviewed
• [Journal Article] Interleukin-18-deficient mice develop hippocampal abnormalities related to possible depressive-like behaviors (2019)
  • Author(s): Yamanishi Kyosuke, Doe Nobutaka, Mukai Keiichiro, Ikubo Kaoru, Hashimoto Takuya, Uwa Noriko, Sumida Miho, El-Darawish Yosif, Gamachi Naomi, Li Wen, Kuwahara-Otani Sachi, Maeda Seishi, Watanabe Yuko, Hayakawa Tetsu, Yamanishi Hiromichi, Matsuyama Tomohiro, Yagi Hideshi, Okamura Haruki, & Matsunaga Hisato
  • Journal Title: Neuroscience Volume: 408 Pages: 147-160
  • DOI: 10.1016/j.neuroscience.2019.04.003
  • Peer Reviewed
• [Journal Article] Molecular analysis of the mouse brain exposed to chronic mild stress: The influence of hepatocyte nuclear factor 4α on physiological homeostasis (2017)
  • Author(s): Ikubo Kaoru、Yamanishi Kyosuke、Doe Nobutaka、Hashimoto Takuya、Sumida Miho、Watanabe Yuko、El-Darawish Yosif、Li Wen、Okamura Haruki、Yamanishi Hiromichi、Matsunaga Hisato
  • Journal Title: Molecular Medicine Reports Volume: 16 Issue: 1 Pages: 301-309
  • DOI: 10.3892/mmr.2017.6577
  • Peer Reviewed / Open Access
• [Journal Article] マウスのモリス型水迷路学習課題における実験装置の条件設定の重要性 (2017)
  • Author(s): 土江伸誉
  • Journal Title: 行動科学 Volume: 55 Pages: 1-11
  • NAID: 40021180529
  • Peer Reviewed
• [Journal Article] CAPS1 RNA Editing Promotes Dense Core Vesicle Exocytosis. (2016)
  • Author(s): Miyake K, Ohta T, Nakayama H, Doe N, Terao Y, Oiki E, Nagatomo I, Yamashita Y, Abe T, Nishikura K, Kumanogoh A, Hashimoto K, Kawahara Y.
  • Journal Title: Cell Reports Volume: 17 Issue: 8 Pages: 2004-2014
  • DOI: 10.1016/j.celrep.2016.10.073
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] インターロイキン18の欠損状態がうつ病など精神症状発現に及ぼす影響について～精神と免疫のクロストーク～ (2018)
  • Author(s): 山西恭輔、土江伸誉、橋本卓也、井窪薫、向井馨一郎、澄田美保、大谷（桑原）佐知、前田誠司、李 文、渡邊優子、宇和典子、早川 徹、山西博道、岡村春樹、松永寿人
  • Organizer: 第114回日本精神神経学会学術総会
• [Presentation] 複数の行動実験課題を併用したマウスのうつ的傾向の評価 (2018)
  • Author(s): 土江伸誉・高橋佑奈・長永夕奈
  • Organizer: 日本実験動物技術者協会関西支部平成29年度春季大会
• [Presentation] IL-18 の欠損状態がうつ病など精神症状発現に及ぼす影響について -IL-18欠損マウスを用いた多角的検討- (2017)
  • Author(s): 山西恭輔・松永寿人・土江伸誉・橋本卓也・井窪薫・澄田美保・大谷(桑原)佐知・前田誠司・李文・渡辺優子・宇和典子・早川徹・山西博道・岡村春樹
  • Organizer: 第113回日本精神神経学会学術総会
• [Presentation] Interleukin-18-deficient mice develop dysfunction of hippocampus resulting in depression-like behavior (2017)
  • Author(s): Yamanishi, K., Doe, N., Mukai, K., Ikubo, K., Hashimoto, T., Uwa, N., Sumida, M., Kuwahara-Otani, S., Maeda, S., Watanabe, Y., Li, W., Hayakawa, T., Okamura, H., Yamanishi, H., & Matsunaga, H.
  • Organizer: WPA XVII World Congress of Psychiatry
  • Int'l Joint Research
• [Presentation] 水迷路学習場面で出現する行動的絶望マウスの血中サイトカイン濃度パターンの分析 (2016)
  • Author(s): 村山真人・笠原恵美子・澤野俊憲・山本英幸・桐山美香・土江伸誉・関山敦生
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県, 横浜市)
  • Year and Date: 2016-12-01
• [Presentation] Interleukin-18-deficient mice develop dysfunction of hippocampus resulting in depression-like behavior (2016)
  • Author(s): Yamanishi, K., Doe, N., Ikubo, K., Sumida, M., Kuwahara-Otani, S., Maeda, S., Watanabe, Y., Yoshida, M., Li, W., Hayakawa, T., Okamura, H., Yamanishi, H., & Matsunaga, H.
  • Organizer: 30th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: COEX(Seoul, KOREA)
  • Year and Date: 2016-07-03
  • Int'l Joint Research