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Elucidation of the mechanism of sleepiness/arousal level control by the parabrachial nucleus: a basic study for improving rehabilitation efficiency

Research Project

Project/Area Number 19K11367
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 59010:Rehabilitation science-related
Research InstitutionShimane University

Principal Investigator

Shigefumi Yokota  島根大学, 学術研究院医学・看護学系, 准教授 (50294369)

Co-Investigator(Kenkyū-buntansha) 武田 湖太郎  藤田医科大学, 保健学研究科, 准教授 (50618733)
濱 徳行  島根大学, 学術研究院医学・看護学系, 助教 (60422010)
Project Period (FY) 2019-04-01 – 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 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords低酸素 / 孤束核 / 結合腕傍核 / 覚醒中枢 / 呼吸中枢 / 前脳基底部 / 睡眠時無呼吸症 / CGRP / 視床下部脳弓周囲領域 / 延髄腹外側部 / 覚醒 / 脊髄後角 / 後台形体核
Outline of Research at the Start

日中の「眠気」は、リハビリテーションへの意欲を低下させ、また、集中力の欠如から訓練効果を低下させる。この「眠気」の原因は、睡眠時無呼吸による断眠や痛みによる不眠などの睡眠障害であるが、これら疾患の神経学的なメカニズムはいまだ不明な点が多い。そこで本研究では、眠気の原因となる睡眠障害を引き起こす神経機構を形態学的・機能学的に解明する。そして、その神経機構によって生じた睡眠障害が運動機能へ与える影響を明確にすることで、神経路特異的な睡眠障害のモデルマウスとなることを実証し、リハビリテーション医学におけるモデル動物研究の基盤を築く。

Outline of Final Research Achievements

In this study, morphological investigations were conducted to determine the neural pathways that transmit blood chemical information to the arousal center (hypothalamic perifornical region) and the respiratory center (ventrolateral medulla). In the solitary nucleus, where peripheral chemical information is input, many glutamatergic neurons responded to intermittent hypoxic exposure. Analysis of neural pathways using genetically modified animals revealed that glutamatergic neurons in the solitary nucleus projected to the hypothalamic perifornical region or medullary respiratory center via the parabrachial nucleus. Furthermore, neurons constituting these neural pathways were found to be activated by intermittent hypoxic exposure. These neural pathways may be involved in the arousal and respiratory arousal induced by obstructive sleep apnea.

Academic Significance and Societal Importance of the Research Achievements

本研究では血中低酸素情報を覚醒中枢および呼吸中枢へ至る神経路を明らかにした。睡眠時無呼吸のような睡眠障害が引き起こす日中の眠気や認知機能の低下は転倒リスクを増大させるのみならず、リハビリテーション訓練への意欲を低下させ、また、集中力を欠如させるため訓練効果が低下するなど重大な負の影響が報告されている。したがって、血中酸素分圧の低下が覚醒および呼吸の増大を惹起する神経路を明らかにすることは、睡眠時無呼吸症の発症メカニズムを解明し、臨床的な治療へつながる基礎的な知見を与えるものである。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (30 results)

All 2022 2021 2020 2019 2018

All Journal Article (6 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 6 results,  Open Access: 3 results) Presentation (23 results) (of which Int'l Joint Research: 5 results) Book (1 results)

  • [Journal Article] Dual orexin receptor blocker suvorexant attenuates hypercapnic ventilatory augmentation in mice2022

    • Author(s)
      Fukushi Isato、Yokota Shigefumi、Takeda Kotaro、Terada Jiro、Umeda Akira、Yoshizawa Masashi、Kono Yosuke、Hasebe Yohei、Onimaru Hiroshi、Pokorski Mieczyslaw、Okada Yasumasa
    • Journal Title

      Brain Research

      Volume: 1795 Pages: 148061-148061

    • DOI

      10.1016/j.brainres.2022.148061

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Coherence analysis of the calcium activity of putative astrocytic and neuronal cells on the L5 ventral horn and neural output in activated lumbar CPG networks2022

    • Author(s)
      Yazawa Itaru、Okazaki Shuntaro、Yokota Shigefumi、Takeda Kotaro、Fukushi Isato、Yoshizawa Masashi、Onimaru Hiroshi、Okada Yasumasa
    • Journal Title

      Neuroscience Letters

      Volume: 771 Pages: 136421-136421

    • DOI

      10.1016/j.neulet.2021.136421

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] VGLUT2-expressing neurons in the vestibular nuclear complex mediate gravitational stress-induced hypothermia in mice2020

    • Author(s)
      Abe C, Yamaoka Y, Maejima Y, Mikami T, Yokota S, Yamanaka A, Morita H
    • Journal Title

      Communications Biology

      Volume: 227 Issue: 1 Pages: 1-13

    • DOI

      10.1038/s42003-020-0950-0

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural and functional connectivity from the dorsomedial hypothalamus to the ventral medulla as a chronological amplifier of sympathetic outflow.2020

    • Author(s)
      Kono Y, Yokota S, Fukushi I, Arima Y, Onimaru H, Okazaki S, Takeda K, Yazawa I, Yoshizawa M, Hasebe Y, Koizumi K, Pokorski M, Toda T, Sugita K, Okada Y.
    • Journal Title

      Sci Rep.

      Volume: 10 Issue: 1 Pages: 13325-13325

    • DOI

      10.1038/s41598-020-70234-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Blockade of astrocytic activation delays the occurrence of severe hypoxia‐induced seizure and respiratory arrest in mice2020

    • Author(s)
      Fukushi Isato、Takeda Kotaro、Uchiyama Makoto、Kurita Yuki、Pokorski Mieczyslaw、Yokota Shigefumi、Okazaki Shuntaro、Horiuchi Jouji、Mori Yasuo、Okada Yasumasa
    • Journal Title

      Journal of Comparative Neurology

      Volume: 528 Issue: 8 Pages: 1257-1264

    • DOI

      10.1002/cne.24828

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The role of the hypothalamus in modulation of respiration2018

    • Author(s)
      Fukushi Isato、Yokota Shigefumi、Okada Yasumasa
    • Journal Title

      Respiratory Physiology & Neurobiology

      Volume: in press Pages: 172-179

    • DOI

      10.1016/j.resp.2018.07.003

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] Chemical organization of solitary nucleus neurons activated by vagal afferents from the respiratory tracts2022

    • Author(s)
      Shigefumi Yokota, Kotaro Takeda, Noriyuki Hama, Yasumasa Okada
    • Organizer
      The 15th Oxford Conference on Modelling and Control of Breathing
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The neuronal mechanism controlling respiratory rate by excitatory neurons within the solitary nucleus Noriyuki Hama2022

    • Author(s)
      Noriyuki Hama, Yasumasa Okada, Shigefumi Yokota
    • Organizer
      The 15th Oxford Conference on Modelling and Control of Breathing
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hypothalamic respiration-synchronized rhythmic activity in the diencephalon-lower brainstem-spinal cord preparation2022

    • Author(s)
      Isato Fukushi, Yosuke Kono, Shigefumi Yokota, Kotaro Takeda, Masashi Yoshizawa, Yohei Hasebe, Mieczyslaw Pokorski, Yasumasa Okada
    • Organizer
      The 15th Oxford Conference on Modelling and Control of Breathing
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] LINC complex regulates the plasticity of axon initial segment2022

    • Author(s)
      Koichi Hasegawa, Takeshi K Matsui, Junpei Kondo, Shizuka Shoji, Noriyuki Hama and Ken-ichiro Kuwako
    • Organizer
      第99回日本生理学会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] Analysis of the synaptic connections in the developing preBotzinger complex2021

    • Author(s)
      Noriyuki Hama, Tasuku Kato, Shigefumi Yokota, Koichi Hasegawa, Ken-ichiro Kuwako
    • Organizer
      第44回日本神経科学大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 孤束核抑制性ニューロンによる呼吸調節に関わる神経機構の生理学的・解剖学的解析2021

    • Author(s)
      濱徳行, 武田湖太郎, 岡田泰昌, 越谷直弘, 小泉英彦, 横田茂文
    • Organizer
      第126回日本解剖学会総会・全国学術集会 第98回日本生理学会大会 合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 低酸素が引き起こす呼吸喚起と覚醒の神経路2021

    • Author(s)
      横田茂文, 濱徳行, 武田湖太郎, 岡田泰昌
    • Organizer
      第126回日本解剖学会総会・全国学術集会 第98回日本生理学会大会 合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] アストロサイトは低酸素負荷後の呼吸増強を持続させる2021

    • Author(s)
      福士 勇人, 武田 湖太郎, Pokorski Mieczyslaw, 横田茂文, 岡田泰昌
    • Organizer
      第126回日本解剖学会総会・全国学術集会 第98回日本生理学会大会 合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 遺伝子改変動物を用いた孤束核グルタミン酸作動性ニューロンによる呼吸循環調節機構の解析2020

    • Author(s)
      横田茂文, 武田湖太郎, 濱 徳行, 有馬陽介, 藤谷昌司, 岡田泰昌
    • Organizer
      第72回日本生理学会中国・四国地方回
    • Related Report
      2020 Research-status Report
  • [Presentation] マウス孤束核興奮性ニューロンによる呼吸調節機構の解析2020

    • Author(s)
      濱 徳行, 横田茂文, 藤谷昌司, 岡田泰昌, 越谷直弘, 小泉英彦
    • Organizer
      第72回日本生理学会中国・四国地方回
    • Related Report
      2020 Research-status Report
  • [Presentation] 低酸素負荷後の呼吸増強にはアストロサイト活性化が必要である2020

    • Author(s)
      福士 勇人, 武田 湖太郎, Pokorski Mieczyslaw, 矢澤 格, 岡崎俊太郎, 河野洋介, 吉沢雅史, 横田茂文, 池田啓子, 鬼丸 洋, 岡田泰昌
    • Organizer
      第43回日本神経科学大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 血中低酸素情報を伝達する孤束核から結合腕傍核を介して視床下部へ至る神経路2020

    • Author(s)
      横田茂文、濱 徳行、武田湖太郎、藤谷昌司
    • Organizer
      第125回日本解剖学会総会・全国学術集会(誌上開催)
    • Related Report
      2019 Research-status Report
  • [Presentation] The pathway transmitting hypoxia information from the solitary nucleus to the hypothalamus.2020

    • Author(s)
      Yokota S, Hama N, Takeda K, Fujitani M
    • Organizer
      第97回日本生理学会大会, 大分, 2020年 3/17-19(誌上開催)
    • Related Report
      2019 Research-status Report
  • [Presentation] A dual orexin receptor blocker suvorexant inhibits hypercapnic ventilatory augmentation.2020

    • Author(s)
      Fukushi F,Yokota S,Takeda K,Terada J,Okada Y.
    • Organizer
      第97回日本生理学会大会, 大分, 2020年 3/17-19(誌上開催)
    • Related Report
      2019 Research-status Report
  • [Presentation] Decrease in the expiratory duration induced by the photostimulation of inhibitory neurons within the lateral solitary nucleus during inspiration.2020

    • Author(s)
      Hama H Yokota S,Fujitani M,Okada Y, Koshiya N,Koizumi H.
    • Organizer
      第97回日本生理学会大会, 大分, 2020年 3/17-19(誌上開催)
    • Related Report
      2019 Research-status Report
  • [Presentation] Dual blockade of orexin receptors does not affect ventilation in mice.2019

    • Author(s)
      Fukushi I, Yokota S, Takeda K, Terada J, Okada Y.
    • Organizer
      The 24th Congress of the Asian Pacific Society of Respirology (APSR 2019)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Dual orexin receptor antagonism and ventilatory function in mice.2019

    • Author(s)
      Fukushi I, Yokota S, Takeda K, Terada J, Okada Y.
    • Organizer
      The 48th Annual Meeting Society for Neuroscience, Chicago
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effects of suvorexant (Belsomra(R)) on ventilation in mice.2019

    • Author(s)
      Fukushi I, Yokota S, Takeda K, Okazaki S, Terada J, Okada Y.
    • Organizer
      第59回日本呼吸器学会学術講演会
    • Related Report
      2019 Research-status Report
  • [Presentation] Effects of a dual orexin receptor blocker suvorexant on breathing.2019

    • Author(s)
      Fukushi I, Yokota S, Takeda K, Terada J, Okada Y.
    • Organizer
      第42回神経科学大会
    • Related Report
      2019 Research-status Report
  • [Presentation] The diencephalon augments respiration in the isolated diencephalon-lower brainstem-spinal cord preparations of newborn rats.2019

    • Author(s)
      Fukushi I, Kono Y, Yokota S, Takeda K, Yazawa I, Onimaru H, Okada Y.
    • Organizer
      The 6th Conference of Japanese Society of Respiratory Physical Therapy
    • Related Report
      2019 Research-status Report
  • [Presentation] ラット外側結合腕傍核は脳幹覚醒調節領域へ投射する視床下部オレキシン産生ニューロンを支配する2019

    • Author(s)
      有馬陽介、横田茂文、藤谷昌司
    • Organizer
      日本解剖学会第74回中国・四国支部学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 孤束核グルタミン酸作動性ニューロンによる呼吸循環調節機構の機能的・形態学的解析2019

    • Author(s)
      横田茂文、武田湖太郎、濱 徳行、有馬陽介、藤谷昌司、岡田泰昌
    • Organizer
      日本解剖学会第74回中国・四国支部学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 孤束核抑制性投射ニューロンによる呼息相の短縮2019

    • Author(s)
      濱 徳行、横田茂文、藤谷昌司、岡田泰昌、越谷直弘、小泉英彦
    • Organizer
      日本生理学会 第71回中国四国地方会
    • Related Report
      2019 Research-status Report
  • [Book] Anatomy and physiology of respiratory control system: How are respiratory controlling cells communicating in the brain?; In Structure-Function Relationships in Various Respiratory Systems2020

    • Author(s)
      Okada Y, Yokota S, Fukushi I
    • Total Pages
      20
    • Publisher
      Springer
    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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