Deficient Autophagy in Microglia Aggravates Repeated social defeat stress-induced social avoidance
| Project/Area Number |
20K07962
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52030:Psychiatry-related
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| Research Institution | Tohoku University |
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Principal Investigator |
Yu Zhiqian 東北大学, 医学系研究科, 講師 (60451639)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| 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)
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| Keywords | Autophagy / 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 |
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| 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．
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| 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.
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| 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.
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Report
(4 results)
Research Products
(21 results)
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[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
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Journal Title
Psychiatry and Clinical Neurosciences
Volume: -
Related Report
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[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
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Journal Title
iScience
Volume: 25(12)
Issue: 12
Pages: 105666-105666
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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