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The role of the amygdala in depression

Research Project

Project/Area Number 19K08079
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52030:Psychiatry-related
Research InstitutionHealth Sciences University of Hokkaido

Principal Investigator

IZUMI Takeshi  北海道医療大学, 薬学部, 教授 (60312360)

Co-Investigator(Kenkyū-buntansha) 鹿内 浩樹  北海道医療大学, 薬学部, 講師 (00632556)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsうつ病 / 動物モデル / ストレス / 扁桃体 / FKBP5 / Akt / mTOR / 拘束ストレス / 海馬 / 抗うつ薬 / 視床下部-下垂体-副腎系 / 副腎皮質ホルモン / HPA axis
Outline of Research at the Start

申請者らは、うつ病の動物モデルを研究する過程で、「うつ病モデルラットの扁桃体で、グルココ ルチコイド受容体(GR)の阻害因子であるFKBP5が増加している。」という所見を得た。本研究で は、この所見を手がかりとして、うつ病における扁桃体の役割を動物実験で解明する。具体的には、(1)扁桃体のFKBP5が視床下部-下垂体-副腎(HPA)系の機能亢進に対して抑制的に作用してい る可能性と、(2)扁桃体のFKBP5が神経新生、DNAメチル化、オートファジーなどHPA系以外の作 用を介してうつ病の病態に関与している可能性を追求する。

Outline of Final Research Achievements

We measured depression-associated molecules such as those involved with the hypothalamic-pituitary-adrenal system, PI3K/Akt/mTOR system and GSK3β/β-catenin/Wnt system in the brains and blood of repeated restraint stress (RS7) rats, an animal model of depression. We found increased blood glucocorticoids (GC), increased FKBP5 (negative feedback regulator of GC) and increased phosphorylation of Akt (Ser-483) in the amygdala, and decreased phosphorylation of mTOR active complex mTORC1 in the hippocampus (Ser-2448). No changes in molecules involved in the GSK3β/β-catenin/Wnt system were detected. In the future, we would like to clarify the pathophysiology of depression by investigating the upstream and downstream events resulting from these molecular changes.

Academic Significance and Societal Importance of the Research Achievements

抗うつ薬によるうつ病の回復率は60%程度であり、更に有効な治療法の開発のために、うつ病の病態解明が必要である。今回、我々はうつ病モデルラットの脳でうつ病関連分子の系統的な評価を行い、視床下部-下垂体-副腎系の調節分子であるFKBP5と、PI3K/Akt/mTOR系の分子であるAktおよびmTORC1が変化している所見を得た。今後、これらの分子変化をさらに追及し、うつ病の病態変化を解明したい。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (10 results)

All 2022 2021 2020 2019

All Journal Article (3 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (7 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] D-serine metabolism in the medial prefrontal cortex, but not the hippocampus, is involved in AD/HD-like behaviors in SHRSP/Ezo2022

    • Author(s)
      Shindo Tsugumi、Shikanai Hiroki、Watarai Akane、Hiraide Sachiko、Iizuka Kenji、Izumi Takeshi
    • Journal Title

      European Journal of Pharmacology

      Volume: 923 Pages: 174930-174930

    • DOI

      10.1016/j.ejphar.2022.174930

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tbx1, a gene encoded in 22q11.2 copy number variant, is a link between alterations in fimbria myelination and cognitive speed in mice2021

    • Author(s)
      Hiramoto Takeshi、Sumiyoshi Akira、Yamauchi Takahira、Tanigaki Kenji、Shi Qian、Kang Gina、Ryoke Rie、Nonaka Hiroi、Enomoto Shingo、Izumi Takeshi、Bhat Manzoor A.、Kawashima Ryuta、Hiroi Noboru
    • Journal Title

      Molecular Psychiatry

      Volume: 未定 Issue: 2 Pages: 929-938

    • DOI

      10.1038/s41380-021-01318-4

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genome-wide association studies identify polygenic effects for completed suicide in the Japanese population.2019

    • Author(s)
      Otsuka I, Akiyama M, Shirakawa O, Okazaki S, Momozawa Y, Kamatani Y, Izumi T, Numata S, Takahashi M, Boku S, Sora I, Yamamoto K, Ueno Y, Toda T, Kubo M, Hishimoto A
    • Journal Title

      Neuropsychopharmacology

      Volume: 44 Issue: 12 Pages: 2119-2124

    • DOI

      10.1038/s41386-019-0506-5

    • NAID

      120007027666

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] うつ病モデル動物における脳内Akt-mTORシグナルの異常2021

    • Author(s)
      進藤つぐみ、鹿内浩樹、高津誠也、泉 剛
    • Organizer
      第51回 日本神経精神薬理学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] うつ病モデル動物における前頭前野および皮質辺縁系Aktシグナルの異常2021

    • Author(s)
      進藤 つぐみ、鹿内 浩樹、高津 誠也、大橋 敦子、泉 剛
    • Organizer
      第68回北海道薬学大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] うつ病モデル動物の脳内Akt-mTORおよびGSK3β系の異常解析2021

    • Author(s)
      進藤 つぐみ、脇田 征太朗、尾崎 和音、高津 誠也、鹿内 浩樹、大橋 敦子、泉 剛
    • Organizer
      第34回北海道薬物作用談話会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Local injection of D-amino acid oxidase inhibitor to the prefrontal cortex improves AD/HD-like behaviors of SHRSP/Ezo.2020

    • Author(s)
      Hiroki Shikanai, Tsugumi Shindo, Sachiko Hiraide, Kenji Iizuka, Takeshi Izumi
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 5-HT1A and 5-HT2A receptors in the amygdala, as target molecules of the anxiolytic action of SSRIs2019

    • Author(s)
      Izumi T, Konno K, Watanabe M, Tanaka K, Yoshida T, Shikanai H, Yoshioka M
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] うつ病モデル動物における扁桃体FKBP5の発現様式2019

    • Author(s)
      鹿内浩樹、Rebel Ghebreab、吉田 隆行、菱本 明豊、吉岡 充弘、泉 剛
    • Organizer
      第49回日本神経精神薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] SSRI exerts anxiolytic effect via 5-HT1A and 5-HT2A receptors in the amygdala2019

    • Author(s)
      Izumi T, Konno K, Watanabe M, Tanaka K, Yoshida T, Shikanai H, Yoshioka M
    • Organizer
      Society for Neuroscience Annual Meeting 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2023-01-30  

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