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Deficient Autophagy in Microglia Aggravates Repeated social defeat stress-induced social avoidance

Research Project

Project/Area Number 20K07962
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52030:Psychiatry-related
Research InstitutionTohoku University

Principal Investigator

Yu Zhiqian  東北大学, 医学系研究科, 講師 (60451639)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsAutophagy / Depression / Microglia / オートファジー / ミクログリア / 反復社会挫折ストレスモデル / うつ病 / 反復社会挫折ストレス
Outline of Research at the Start

申請者は雌のうつ病モデルマウスの確立, およびうつ様行動の抑制に伴う中枢神経系のミクログリアのオートファジー活性を初めて突き止めた.この成果を受け, 本研究ではオートファジー機構がうつ病の罹患に及ぼす影響を検討する. 研究期間中, ① ミクログリア特異的にオートファジー欠損マウスを用いてうつ様行動に及ぼす影響およびメカニズムを解明する. ② 中枢神経系のオートファジーを制御できる物質をスクリーニングすることで,うつ病新規治療薬の開発を目指す.③ うつ病罹患者の末梢血,および死後脳検体を用い, オートファジー関連分子の変動を調べることでうつ病の客観的診断マーカーを検討する.

Outline of Final Research Achievements

Repeated environmental stress is widely accepted to be involved in the pathogenesis of depression. Here, we used repeated social defeat (RSD) stress to analyze the transcripts of the autophagy-related gene (Atg) and protein levels of autophagosome markers in mouse prefrontal cortical (PFC) microglia under RSD stress. We found that RSD stress induced initial autophagic signals in the PFC. Similar results were confirmed in the postmortem PFC of patients with depression, which indicates that enhanced autophagic flux may alleviate stress-induced depression. Furthermore, we identified an early-stage autophagy regulator, FKBP5, significantly increased in resilient mice's PFC. In addition, the resilient mice exhibited enhanced autophagic flux in the prefrontal cortical microglia, and the autophagic deficiency in microglia aggravated RSD-induced social avoidance, indicating that microglial autophagy involves stress-induced behavioral changes.

Academic Significance and Societal Importance of the Research Achievements

従来の抗うつ薬の効果が現れるのに数週間がかかる.さらに,既存抗うつ薬の抵抗性も含めて画期的な治療薬の開発が強く求められている. 本研究はうつ病モデル動物およびうつ病の死後脳検体を用い, 前頭前野の免疫担当細胞である三玖における初期オートファジーの活性および制御因子の変動を見出し, 新たな抗うつ薬開発の切口になると期待できる. さらに, 本研究結果は,オートファジーを介したミクログリアとニューロンとの制御ネットワークを解明するための新しい戦略につながり,うつ病だけではなく,他の精神疾患,神経変性疾患,および免疫疾患などの研究にも大きく寄与し,臨床応用に向けた研究基盤を提供できるものと考えられる.

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (21 results)

All 2023 2022 2021 2020 Other

All Int'l Joint Research (2 results) Journal Article (13 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 10 results,  Open Access: 7 results) Presentation (4 results) Remarks (2 results)

  • [Int'l Joint Research] McGill University(カナダ)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] McGill University(カナダ)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Association between low levels of anti-inflammatory cytokines during pregnancy and postpartum depression2023

    • Author(s)
      Ono C, Yu Z, Obara T, Ishikuro M, Murakami K, Kikuya M, Kikuchi S, Kobayashi N, Kudo H, Ogishima S, Minegishi N, Sugawara J, Kuriyama S, Yamamoto, M, Yaegashi N, Tomita H
    • Journal Title

      Psychiatry and Clinical Neurosciences

      Volume: -

    • Related Report
      2022 Annual Research Report
  • [Journal Article] AI を用いたうつ病の病態解明と個別化精神医療に向けた展望2023

    • Author(s)
      富田 博秋, 兪 志前, 李 雪, 高橋 雄太
    • Journal Title

      臨床精神薬理

      Volume: 26 Pages: 285-292

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Decreased β-hydroxybutyrate and ketogenic amino acid levels in depressed human adults2023

    • Author(s)
      Sato Shiho、Yu Zhiqian、Sakai Mai、Motoike Ikuko N.、Saigusa Daisuke、Hirayama Ryo、Kikuchi Yoshie、Abe Takaaki、Kinoshita Kengo、Koshiba Seizo、Tomita Hiroaki
    • Journal Title

      European Journal of Neuroscience

      Volume: 57 Issue: 6 Pages: 1018

    • DOI

      10.1111/ejn.15931

    • URL

      https://pure.teikyo.jp/en/publications/4ddc0713-2b7d-4b5f-8ab8-2b65dd7dbaea

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-α Signaling2023

    • Author(s)
      Sakai Mai、Yu Zhiqian、Taniguchi Masayuki、Picotin Rosanne、Oyama Nanami、Stellwagen David、Ono Chiaki、Kikuchi Yoshie、Matsui Ko、Nakanishi Miharu、Yoshii Hatsumi、Furuyashiki Tomoyuki、Abe Takaaki、Tomita Hiroaki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 4 Pages: 3798-3798

    • DOI

      10.3390/ijms24043798

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Microarray dataset of gene transcription in mouse microglia and peripheral monocytes in contextual fear conditioning2023

    • Author(s)
      Yu Zhiqian、Sakai Mai、Fukushima Hotaka、Ono Chiaki、Kikuchi Yoshie、Koyama Ryuta、Matsui Ko、Furuyashiki Tomoyuki、Kida Satoshi、Tomita Hiroaki
    • Journal Title

      Data in Brief

      Volume: 46 Pages: 108862-108862

    • DOI

      10.1016/j.dib.2022.108862

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Plasma metabolic disturbances during pregnancy and postpartum in women with depression2022

    • Author(s)
      Z Yu, N Matsukawa, D Saigusa, I. N. Motoike, C Ono, Y Okamura, T Onuma, Y Takahashi, M Sakai, H Kudo, T Obara, K Murakami, M Shirota, S Kikuchi, N Kobayashi, Y Kikuchi, J Sugawara, N Minegishi, S Ogishima, K Kinoshita, M Yamamoto, N Yaegashi, S Kuriyama, S Koshiba, H Tomita
    • Journal Title

      iScience

      Volume: 25(12) Issue: 12 Pages: 105666-105666

    • DOI

      10.1016/j.isci.2022.105666

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of oxytocin expression in human and murine microglia2022

    • Author(s)
      Maejima Yuko、Yokota Shoko、Ono Tomoyuki、Yu Zhiqian、Yamachi Megumi、Hidema Shizu、Nollet Kenneth E.、Nishimori Katsuhiko、Tomita Hiroaki、Yaginuma Hiroyuki、Shimomura Kenju
    • Journal Title

      Progress in Neuro-Psychopharmacology and Biological Psychiatry

      Volume: 119 Pages: 110600-110600

    • DOI

      10.1016/j.pnpbp.2022.110600

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sex-Specific Differences in the Transcriptome of the Human Dorsolateral Prefrontal Cortex in Schizophrenia2022

    • Author(s)
      Yu Zhiqian、Ueno Kazuko、Funayama Ryo、Sakai Mai、Nariai Naoki、Kojima Kaname、Kikuchi Yoshie、Li Xue、Ono Chiaki、Kanatani Junpei、Ono Jiro、Iwamoto Kazuya、Hashimoto Kenji、Kinoshita Kengo、Nakayama Keiko、Nagasaki Masao、Tomita Hiroaki
    • Journal Title

      Molecular Neurobiology

      Volume: 60 Issue: 2 Pages: 1083-1098

    • DOI

      10.1007/s12035-022-03109-6

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Contextual fear conditioning regulates synapse-related gene transcription in mouse microglia2022

    • Author(s)
      Yu Zhiqian、Sakai Mai、Fukushima Hotaka、Ono Chiaki、Kikuchi Yoshie、Koyama Ryuta、Matsui Ko、Furuyashiki Tomoyuki、Kida Satoshi、Tomita Hiroaki
    • Journal Title

      Brain Research Bulletin

      Volume: 189 Pages: 57-68

    • DOI

      10.1016/j.brainresbull.2022.08.017

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Depression and anxiety among nursing students during the COVID‐19 pandemic in Tohoku region, Japan: A cross‐sectional survey2022

    • Author(s)
      Sakai Mai、Nakanishi Miharu、Yu Zhiqian、Takagi Gen、Toshi Keita、Wakashima Koubun、Yoshii Hatsumi
    • Journal Title

      Japan Journal of Nursing Science

      Volume: 19 Issue: 3

    • DOI

      10.1111/jjns.12483

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Surface translocation of Kir2.1 channel induces IL-1β secretion in microglia2022

    • Author(s)
      Maejima Yuko、Horita Shoichiro、Yokota Shoko、Yamachi Megumi、Shimizu Masaru、Ono Tomoyuki、Yu Zhiquian、Tomita Hiroaki、Shimomura Kenju
    • Journal Title

      Molecular and Cellular Neuroscience

      Volume: 120 Pages: 103734-103734

    • DOI

      10.1016/j.mcn.2022.103734

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A psychiatric disorder risk polymorphism of ITIH3 is associated with multiple neuroimaging phenotypes in young healthy adults2022

    • Author(s)
      Takeuchi H, Tomita H, Taki Y, Kikuchi Y, Ono Tanaka C, Yu Z, Matsudaira I, Nouchi R, Imanishi T, and Kawashima R
    • Journal Title

      Psychiatry and Clinical Neurosciences

      Volume: in press Issue: 6 Pages: 271-273

    • DOI

      10.1111/pcn.13347

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance2022

    • Author(s)
      Sakai Mai、Yu Zhiqian、Hirayama Ryo、Nakasato Masa、Kikuchi Yoshie、Ono Chiaki、Komatsu Hiroshi、Nakanishi Miharu、Yoshii Hatsumi、Stellwagen David、Furuyashiki Tomoyuki、Komatsu Masaaki、Tomita Hiroaki
    • Journal Title

      Neural Plasticity

      Volume: 2022 Pages: 1-13

    • DOI

      10.1155/2022/7503553

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Contextual fear conditioning regulates microglial synapse-related gene transcription in mouse2022

    • Author(s)
      Z Yu, M Sakai, H Fukushima, C Ono, Y Kikuchi, R Koyama, K Matsui, T Furuyashiki, S Kida, H Tomita
    • Organizer
      第45回日本神経科学大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] オートファジー機構がうつ病発症メカニズムに及ぼす影響2021

    • Author(s)
      兪志前、平山凌、坂井舞、佐藤志保、富田博秋
    • Organizer
      第43回日本生物学的精神医学会
    • Related Report
      2021 Research-status Report
  • [Presentation] オートファジーを介したうつ病発症メカニズムの解明.2020

    • Author(s)
      平山 凌, 兪 志前, 坂井 舞, 佐藤 志保, 富田 博秋.
    • Organizer
      NPBPPP2020合同年会.
    • Related Report
      2020 Research-status Report
  • [Presentation] オートファジー制御に着目したうつ病発症機構の性差の解明.2020

    • Author(s)
      Zhou Yuan, 兪 志前, 坂井 舞, 富田博秋.
    • Organizer
      NPBPPP2020合同年会.
    • Related Report
      2020 Research-status Report
  • [Remarks] 妊娠中血中代謝物による産後うつ症状の予測 -健やかな母子家庭環境を維持するために-

    • URL

      https://www.tohoku.ac.jp/japanese/2022/12/press20221212-01-postpartum.html

    • Related Report
      2022 Annual Research Report
  • [Remarks] 統合失調症の病態に男女差はあるか? 脳内トランスクリプトーム解析に基づく疾患病態の性差の解明

    • URL

      https://www.tohoku.ac.jp/japanese/2022/12/press20221208-04-schizophrenia.html

    • Related Report
      2022 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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