What is the purpose of sleep? A study based on phagocytic elimination of synapses by microglia.

• Project/Area Number: 20K06856
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Ehime University
• Principal Investigator: Choudhury Emamussalehin 愛媛大学, 医学系研究科, 助教 (90726803)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Microglia / MyD88 / LPS / Delirium / Cognition / Dopamine receptor / Sleep / ミクログリア / ドーパミン / せん妄 / 睡眠 / モノアミン / うつ / 行動実験 / ノックアウトマウス / シナプス / 学習 / 記憶 / 社会行動 / サーカディアンリズム / 貪食 / 学習記憶

Outline of Research at the Start

毎日寝るたびにシナプスが20％近くも減少する、よく知られた現象であるが、そのメカニズムはよくわかっていなかった。我々は、毎日入眠時前後にミクログリアが活性化し、シナプスを貪食除去することを発見した。さらに貪食除去されるシナプスは補体やMFG-E8のようなeat-me signal分子でオプソニン化されていることも明らかにした。本研究では、睡眠中にミクログリアが不要なシナプスを貪食除去することで、新規の学習記憶を促進し、すでに得た重要な記憶の強化を行うとの作業仮説を立て、学習行動実験と分子細胞生物学的手法を組み合わせ研究を展開する。

Outline of Final Research Achievements

Toll-like receptors are one of the pattern recognition receptors of innate immune cells where MyD88 acts as an adapter molecule. Microglia in MyD88 knockout mice exhibit reduced phagocytic capacity, leading to cognitive deficits, depressive behavior, and sleep disturbances. Conversely, excessive microglial activation induced by LPS-induced neuroinflammation causes sleep disturbances. Microglia express several dopamime receptors (DR), and D1R-specific agonists effectively suppressed cytokine expression in delirium model rats and partially restored their decreased activity. Taken together, our findings demonstrate the importance of microglia in maintaining sleep and cognition in both physiological and pathological scenarios.

Academic Significance and Societal Importance of the Research Achievements

多くの最近の研究は、ミクログリアが睡眠を維持するために中枢神経系に遍在していることを示しています。 MyD88ノックアウトマウスを用いて、ミクログリアによるシナプスの食作用とシナプスのアポトーシスの概日リズムの破壊が、健康なマウスに不眠症とうつ病様行動を引き起こすことを示した。
また、ミクログリアにおけるドーパミン 1 受容体 (D1R) の発現と、敗血症関連脳症 (SAE) のラットの脳炎症の制御におけるその重要性も実証しました。 私たちの発見は、生理学的シナリオと病理学的シナリオの両方で睡眠と認知の維持におけるミクログリアの重要性を示しています。

Research Products

• [Journal Article] Anti-inflammatory effects of dopamine on microglia and a D1 receptor agonist ameliorates neuroinflammation of the brain in a rat delirium model (2023)
  • Author(s): Nishikawa Yuki、Choudhury Mohammed E.、Mikami Kanta、Matsuura Taisei、Kubo Madoka、Nagai Masahiro、Yamagishi Satoru、Doi Tomomi、Hisai Manami、Yamamoto Haruto、Yajima Chisato、Nishihara Tasuku、Abe Naoki、Yano Hajime、Yorozuya Toshihiro、Tanaka Junya
  • Journal Title: Neurochemistry International Volume: 163 Pages: 105479-105479
  • DOI: 10.1016/j.neuint.2023.105479
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bromovalerylurea modulates GABAA receptor-mediated inhibitory neurotransmission while inducing sleep. (2023)
  • Author(s): Takeda H, Yoshimura Y, Takagi M, Sato A, Kihara N, Choudhury ME, Yano H, Tanaka J.
  • Journal Title: Biochem Biophys Res Commun. Volume: 638 Pages: 176-183
  • DOI: 10.1016/j.bbrc.2022.11.062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chloride Intracellular Channel Protein 2 Promotes Microglial Invasion: A Link to Microgliosis in the Parkinson's Disease Brain. (2022)
  • Author(s): Choudhury ME, Ozaki S, Miyaue N, Matsuura T, Mikami K, Islam A, Kubo M, Ando R, Yano H, Kunieda T, Nagai M, Tanaka J.
  • Journal Title: Brain Sci. Volume: 13(1) Issue: 1 Pages: 55-55
  • DOI: 10.3390/brainsci13010055
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Zonisamide Ameliorates Microglial Mitochondriopathy in Parkinson’s Disease Models (2022)
  • Author(s): Tada Satoshi、Choudhury Mohammed E.、Kubo Madoka、Ando Rina、Tanaka Junya、Nagai Masahiro
  • Journal Title: Brain Sciences Volume: 12 Issue: 2 Pages: 268-268
  • DOI: 10.3390/brainsci12020268
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microglial re-modeling contributes to recovery from ischemic injury of rat brain: A study using a cytokine mixture containing granulocyte-macrophage colony-stimulating factor and interleukin-3. (2022)
  • Author(s): Matsumoto S, Choudhury ME, Takeda H, Sato A, Kihara N, Mikami K, Inoue A, Yano H, Watanabe H, Kumon Y, Kunieda T, Tanaka J.
  • Journal Title: Front Neurosci. Volume: 16 Pages: 941363-941363
  • DOI: 10.3389/fnins.2022.941363
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Treadmill Exercise as a Preventive Measure Against Age-Related Anxiety and Social Behavioral Disorders in Rats: When Is It Worth Starting? (2022)
  • Author(s): Taguchi S, Choudhury ME, Mikami K, Utsunomiya R, Yano H, Tanaka J.
  • Journal Title: Ann Rehabil Med. Volume: 46(6) Issue: 6 Pages: 320-328
  • DOI: 10.5535/arm.22105
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rearing in an Enriched Environment Ameliorates the ADHD-like Behaviors of Lister Hooded Rats While Suppressing Neuronal Activities in the Medial Prefrontal Cortex. (2022)
  • Author(s): Utsunomiya R, Mikami K, Doi T, Choudhury ME, Jogamoto T, Tokunaga N, Ishii E, Eguchi M, Yano H, Tanaka J.
  • Journal Title: Cells. Volume: 11(22) Issue: 22 Pages: 3649-3649
  • DOI: 10.3390/cells11223649
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Utility of Rectus Abdominis Ultrasound as a Respiratory Function Test for Amyotrophic Lateral Sclerosis (2022)
  • Author(s): Ando Rina、Yamanishi Yuki、Tada Satoshi、Miyaue Noriyuki、Choudhury Mohammed Emamussalehin、Nagai Masahiro
  • Journal Title: Respiratory Care Volume: 67 Issue: 5 Pages: 520-525
  • DOI: 10.4187/respcare.09317
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Surgical stress quickly affects the numbers of circulating B-cells and neutrophils in murine septic and aseptic models through a β2 adrenergic receptor (2022)
  • Author(s): Ryutaro Nishioka, Yusuke Nishi, Mohammed E. Choudhury, Riko Miyaike, Ayataka Shinnishi, Kensuke Umakoshi, Yasutsugu Takada, Norio Sato, Mayuki Aibiki, Hajime Yano, Junya Tanaka
  • Journal Title: Journal of Immunotoxicology Volume: 19 Issue: 1 Pages: 8-16
  • DOI: 10.1080/1547691x.2022.2029630
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of Intestinal Bacteria on Levodopa Pharmacokinetics in <scp>LCIG</scp> Therapy (2022)
  • Author(s): Yamanishi Yuki、Choudhury Mohammed Emamussalehin、Yoshida Akira、Hosokawa Yuko、Miyaue Noriyuki、Tada Satoshi、Ando Rina、Murakami Shinobu、Miyamoto Hitoshi、Nagai Masahiro
  • Journal Title: Movement Disorders Clinical Practice Volume: 9 Issue: 3 Pages: 362-368
  • DOI: 10.1002/mdc3.13417
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Insomnia and depressive behavior of MyD88-deficient mice: Relationships with altered microglial functions (2022)
  • Author(s): Mohammed E. Choudhury, Kanta Mikami, Yuiko Nakanishi, Taisei Matsuura, Ryo Utsunomiya, Hajime Yano, Madoka Kubo, Rina Ando, Jun Iwanami, Masakatsu Yamashita, Masahiro Nagai, JunyaTanaka
  • Journal Title: Journal of Neuroimmunology Volume: 363 Pages: 577794-577794
  • DOI: 10.1016/j.jneuroim.2021.577794
  • Peer Reviewed
• [Journal Article] Microglia and the aging brain: Are geriatric microglia linked to poor sleep quality? (2021)
  • Author(s): Choudhury, M.E., Miyanishi, K., Takeda, H., Tanaka, J.
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 15 Pages: 7824-7824
  • DOI: 10.3390/ijms22157824
  • Peer Reviewed / Open Access
• [Journal Article] Chloride intracellular channel protein 2 is secreted and inhibits MMP14 activity, while preventing tumor cell invasion and metastasis (2021)
  • Author(s): Saya Ozaki, Akihiro Umakoshi, Hajime Yano, ............ Junya Tanaka
  • Journal Title: Neoplasia Volume: 23 Issue: 8 Pages: 754-765
  • DOI: 10.1016/j.neo.2021.06.001
  • Peer Reviewed / Open Access
• [Journal Article] Dual Roles of Microglia in the Basal Ganglia in Parkinson’s Disease (2021)
  • Author(s): Mohammed E. Choudhury, Yuka Kigami, Junya Tanaka
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 8 Pages: 3907-3907
  • DOI: 10.3390/ijms22083907
  • Peer Reviewed / Open Access
• [Journal Article] Lister hooded rats as a novel animal model of attention-deficit/hyperactivity disorder (2020)
  • Author(s): Jogamoto Toshihiro、Utsunomiya Ryo、Sato Arisa、Kihara Nanako、Choudhury Mohammed E.、Miyanishi Kazuya、Kubo Madoka、Nagai Masahiro、Nomoto Masahiro、Yano Hajime、Shimizu Yusuke I.、Fukuda Mitsumasa、Ishii Eiichi、Eguchi Mariko、Tanaka Junya
  • Journal Title: Neurochemistry International Volume: 141 Pages: 104857-104857
  • DOI: 10.1016/j.neuint.2020.104857
  • Peer Reviewed
• [Journal Article] Chronic constriction injury of the sciatic nerve in rats causes different activation modes of microglia between the anterior and posterior horns of the spinal cord (2020)
  • Author(s): Nishihara T, Tanaka J, Sekiya K, Nishikawa Y, Abe N, Hamada T, Kitamura S, Ikemune K, Ochi S, Choudhury ME, Yano H, Yorozuya T
  • Journal Title: Neurochemistry International Volume: 134 Pages: 104672-104672
  • DOI: 10.1016/j.neuint.2020.104672
  • Peer Reviewed / Open Access
• [Journal Article] B lymphocytopenia and Bregs in a not-to-die murine sepsis model. (2020)
  • Author(s): Umakoshi K, Choudhury ME, Nishioka R, Matsumoto H, Abe N, Nishikawa Y, Kikuchi S, Takeba J, Yano H, Yorozuya T, Sato N, Aibiki M, Tanaka J.
  • Journal Title: Biochem Biophys Res Commun. Volume: 523 Issue: 1 Pages: 202-207
  • DOI: 10.1016/j.bbrc.2019.12.041
  • Peer Reviewed / Open Access
• [Presentation] Systemic infection triggers a dopamine surge that suppresses microglial inflammation via dopamine D1 receptor (2022)
  • Author(s): Choudhury Mohammed E
  • Organizer: Novel Insights into Glia Function & Dysfunction meeting
  • Int'l Joint Research
• [Presentation] Acute neuroinflammation triggers a dopaminergic surge: a D1 dopamine receptors mediated compensatory role against inhibited spontaneous activity and sleep disturbances (2022)
  • Author(s): Choudhury Mohammed E
  • Organizer: The 100th Anniversary Annual Meeting of The Physiological Society of Japan