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Cellular mechanisms of responses to hypoxia and hypercapnia in medullary neurons expressing a transcription factor, Phox2b

Research Project

Project/Area Number 19K06946
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 46030:Function of nervous system-related
Research InstitutionShowa University

Principal Investigator

Onimaru Hiroshi  昭和大学, 医学部, 客員教授 (30177258)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords高炭酸ガス応答 / 低酸素応答 / Phox2b / チロシン水酸化酵素 / 吻側腹外側延髄 / 新生児ラット / PAR1 / アストロサイト / TFLLR / 孤束核 / カルシウムイメージング / Phox2b / 延髄 / 低酸素受容 / 高炭酸ガス受容 / チャネルロドプシン
Outline of Research at the Start

転写因子Phox2bは下位脳幹の自律神経ネットワークを構成する神経細胞に広く発現する.腹側延髄Phox2b発現細胞のサブグループ(チロシン水酸化酵素(TH)陰性細胞)は呼吸調節における高炭酸ガス中枢化学受容器細胞そのものであると考えられている.最近申請者はPhox2b陽性細胞の一部(TH陽性細胞)は低酸素に応答することを見出した.Phox2b陽性細胞は,背側延髄孤束核にも高密度で分布している.本研究では,延髄腹側および背側部に分布するPhox2b陽性細胞の機能,特に低酸素あるいは高炭酸ガス刺激に対する応答性,TH遺伝子発現との関連を明らかにし,さらにガス受容のイオン機構を明らかにする.

Outline of Final Research Achievements

We investigated membrane potential responses of cardio-respiratory neurons in the rostral ventrolateral medulla to hypoxic and hypercapnic stimulation in brainstem-spinal cord preparations from newborn rats. Responses were examined in the presence of TTX. Phox2b+/TH+ neurons indicated depolarization of 3.3 mV (n=15) in response to hypoxic stimulation but no significant change to hypercapnic stimulation. Phox2b+/TH- neurons did not respond to hypoxic stimulation but were depolarized by 6.1 mV (n=10) by hypercapnic stimulation. Membrane potential response of Phox2b-/TH- respiratory neurons to hypoxic stimulation varied; depolarization or hyperpolarization and the averaged change was -2.2 mV (n=19). The most noteworthy result in the present study is that Phox2b+/TH+ neurons (so called C1 adrenergic neurons) exhibited membrane depolarization as an intrinsic response to hypoxic stimulation, suggesting that they are central hypoxia-sensitive cells.

Academic Significance and Societal Importance of the Research Achievements

今回の特に注目すべき研究結果は,Phox2b+/TH+ニューロン(いわゆるC1アドレナリンニューロン)が低酸素刺激に直接脱分極応答を示し,中枢性低酸素受容細胞であることが明らかになったことである.低酸素応答の分子機構については今後の課題として残されている.一方,呼吸性ニューロン(Phox2b-/TH-)では低酸素刺激に対しては脱分極を示すものと過分極を示すものがあった.過分極応答にはKATPチャネルが関与すると考えられた.C1アドレナリンニューロンは交感神経活動維持に重要な役割を持つ一方で,中枢低酸素受容器として働くことが示唆されたことは意義深い.

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

    (36 results)

All 2023 2022 2021 2020 2019 Other

All Int'l Joint Research (2 results) Journal Article (19 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 19 results,  Open Access: 13 results) Presentation (14 results) (of which Int'l Joint Research: 6 results,  Invited: 1 results) Book (1 results)

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

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] California State University(米国)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Cannabinoid receptors involved in descending inhibition on spinal seizure-like activity in the phrenic output2023

    • Author(s)
      Lin ST, Iizuka M, Mikami Y, Yoda S, Onimaru H, Izumizaki M
    • Journal Title

      Biomedical Research

      Volume: 44 Issue: 2 Pages: 41-49

    • DOI

      10.2220/biomedres.44.41

    • ISSN
      0388-6107, 1880-313X
    • Year and Date
      2023-04-02
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of cisplatin on respiratory activity in neonatal rats.2023

    • Author(s)
      Ota S, Onimaru H, Izumizaki M.
    • Journal Title

      Pflugers Arch.

      Volume: 475 Issue: 2 Pages: 233-248

    • DOI

      10.1007/s00424-022-02762-z

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of ANP and BNP on the generation of respiratory rhythms in brainstem–spinal cord preparation isolated from newborn rats2022

    • Author(s)
      Katsuki S, Ota S, Yoda S, Onimaru H, Dohi K, Izumizaki M.
    • Journal Title

      Biomedical Research

      Volume: 43 Issue: 4 Pages: 127-135

    • DOI

      10.2220/biomedres.43.127

    • ISSN
      0388-6107, 1880-313X
    • Year and Date
      2022-08-18
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glycine and GABAA receptors suppressively regulate the inspiratory-related calcium rise in the thoracic inspiratory cells of the neonatal rat.2022

    • Author(s)
      Mikami Y, Iizuka M, Onimaru H, Izumizaki M.
    • Journal Title

      J Physiol Sci.

      Volume: 72 Issue: 1 Pages: 24-24

    • DOI

      10.1186/s12576-022-00850-4

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [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] Novel oxygen sensing mechanism in the spinal cord involved in cardiorespiratory responses to hypoxia.2022

    • Author(s)
      Barioni NO, Derakhshan F, Tenorio Lopes L, Onimaru H, Roy A, McDonald F, Scheibli E, Baghdadwala MI, Heidari N, Bharadia M, Ikeda K, Yazawa I, Okada Y, Harris MB, Dutschmann M, Wilson RJA.
    • Journal Title

      Sci Adv.

      Volume: 8 Issue: 12 Pages: 1-21

    • DOI

      10.1126/sciadv.abm1444

    • Related Report
      2021 Research-status 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] Intrinsic properties and synaptic connectivity of Phox2b-expressing neurons in rat rostral parvocellular reticular formation2021

    • Author(s)
      Kajiwara Risa、Nakamura Shiro、Ikeda Keiko、Onimaru Hiroshi、Yoshida Atsushi、Tsutsumi Yumi、Nakayama Kiyomi、Mochizuki Ayako、Dantsuji Masanori、Nishimura Akiko、Tachikawa Satoshi、Iijima Takehiko、Inoue Tomio
    • Journal Title

      Neuroscience Research

      Volume: - Pages: 41-51

    • DOI

      10.1016/j.neures.2021.12.009

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Optogenetic activation of DRN 5-HT neurons induced active wakefulness, not quiet wakefulness.2021

    • Author(s)
      Moriya R, Kanamaru M, Okuma N, Yoshikawa A, Tanaka KF, Hokari S, Ohshima Y, Yamanaka A, Honma M, Onimaru H, Kikuchi T, Izumizaki M.
    • Journal Title

      Brain Res Bull.

      Volume: 177 Pages: 129-142

    • DOI

      10.1016/j.brainresbull.2021.09.019

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of acetylcholine on hypoglossal and C4 nerve activity in brainstem-spinal cord preparations from newborn rat.2021

    • Author(s)
      Katsuki S, Ikeda K, Onimaru H, Dohi K, Izumizaki M.
    • Journal Title

      Respir Physiol Neurobiol.

      Volume: 293 Pages: 103737-103737

    • DOI

      10.1016/j.resp.2021.103737

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Activation of Astrocytes in the Persistence of Post-hypoxic Respiratory Augmentation2021

    • Author(s)
      Fukushi Isato、Takeda Kotaro、Pokorski Mieczyslaw、Kono Yosuke、Yoshizawa Masashi、Hasebe Yohei、Nakao Akito、Mori Yasuo、Onimaru Hiroshi、Okada Yasumasa
    • Journal Title

      Frontiers in Physiology

      Volume: 12 Pages: 757731-757731

    • DOI

      10.3389/fphys.2021.757731

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Calcium Imaging Analysis of Cellular Responses to Hypercapnia and Hypoxia in the NTS of Newborn Rat Brainstem Preparation2021

    • Author(s)
      Hiroshi Onimaru, Itaru Yazawa, Kotaro Takeda, Isato Fukushi and Yasumasa Okada
    • Journal Title

      Front. Physiol.

      Volume: 12 Pages: 1-11

    • DOI

      10.3389/fphys.2021.645904

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Optogenetic Approach to Local Neuron Network Analysis of the Medullary Respiratory Center2021

    • Author(s)
      Hiroshi Onimaru, Keiko Ikeda
    • Journal Title

      Adv Exp Med Biol .

      Volume: 1293 Pages: 449-458

    • DOI

      10.1007/978-981-15-8763-4_29

    • ISBN
      9789811587627, 9789811587634
    • Related Report
      2021 Research-status 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] Rostral ventrolateral medulla neuron activity is suppressed by Klotho and stimulated by FGF23 in newborn Wistar rats2020

    • Author(s)
      Oshima N, Onimaru H, Yamagata A, Ito S, Imakiire T, Kumagai H.
    • Journal Title

      Auton Neurosci

      Volume: 224 Pages: 102640-102640

    • DOI

      10.1016/j.autneu.2020.102640

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] An aromatic substance, eugenol induces distinct depressant effects on respiratory activity in different postnatal developmental stages of the rat.2019

    • Author(s)
      Kotani S, Yazawa I, Onimaru H, Izumizaki M.
    • Journal Title

      Neurosci Res

      Volume: S0168-0102(19)30170-1 Pages: 20-26

    • DOI

      10.1016/j.neures.2019.06.001

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Optogenetic analysis of respiratory neuronal networks in the ventral medulla of neonatal rats producing channelrhodopsin in Phox2b-positive cells.2019

    • Author(s)
      Ikeda K, Igarashi H, Yawo H, Kobayashi K, Arata S, Kawakami K, Izumizaki M, Onimaru H.
    • Journal Title

      Pflugers Arch

      Volume: 471 Issue: 11-12 Pages: 1419-1439

    • DOI

      10.1007/s00424-019-02317-9

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Structural and functional defects of the respiratory neural system in the medulla and spinal cord of Pax6 mutant rats.2019

    • Author(s)
      Ikeda Keiko, Onimaru Hiroshi, Inada Hitoshi, Tien Lin Shih, Arata Satoru, Osumi Noriko
    • Journal Title

      Brain Research Bulletin

      Volume: 152 Pages: 107-116

    • DOI

      10.1016/j.brainresbull.2019.07.007

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Different impacts on brain function depending on the mode of delivery.2019

    • Author(s)
      Ikeda Keiko、Onimaru Hiroshi、Matsuura Tohru、Kawakami Kiyoshi
    • Journal Title

      Brain Research

      Volume: 1720 Pages: 146289-146289

    • DOI

      10.1016/j.brainres.2019.06.008

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] Activation of astrocytes in the ventrolateral medulla via PAR1 and modulation of respiratory rhythm in newborn rat brainstem-spinal cord preparations2023

    • Author(s)
      Hiroshi Onimaru, Isato Fukushi, Keiko Ikeda, Itaru Yazawa, Kotaro Takeda, Yasumasa Okada, Masahiko Izumizaki
    • Organizer
      第100回日本生理学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Cell responses of the ventrolateral medulla induced by PAR1 activation and changes in respiratory rhythm in newborn rat en bloc preparations2022

    • Author(s)
      Hiroshi Onimaru, Isato Fukushi, Keiko Ikeda, Itaru Yazawa, Kotaro Takeda, Yasumasa Okada, Masahiko Izumizaki
    • Organizer
      The 15th Oxford conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Involvement of cannabinoid receptors in descending inhibition on spinal seizure-like activity in the phrenic output2022

    • Author(s)
      Shih Tien Lin, Makito Iizuka, Shunya Yoda, Hiroshi Onimaru, Masahiko Izumizaki
    • Organizer
      The 15th Oxford conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Effects of Cisplatin on Respiratory Activity in Neonatal Rats2022

    • Author(s)
      Shinichiro Ota, Hiroshi Onimaru, Masahiko Izumizaki
    • Organizer
      The 15th Oxford conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Depression of respiratory activity by aconitine and its recovery by tetrodotoxin or lidocaine in brainstem-spinal cord preparations from newborn rats2022

    • Author(s)
      Shunya Yoda, Hiroshi Onimaru, Masahiko Izumizaki
    • Organizer
      The 15th Oxford conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cell responses of the ventrolateral medulla induced by PAR1 activation and changes in respiratory rhythm in newborn rat en bloc preparations2022

    • Author(s)
      Hiroshi Onimaru, Isato Fukushi, Keiko Ikeda, Itaru Yazawa, Kotaro Takeda, Yasumasa Okada, Masahiko Izumizaki
    • Organizer
      第45回日本神経科学大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Cellular mechanisms of hypoxia/hypercapnia reception in the medullary cardio-respiratory center2021

    • Author(s)
      Hiroshi Onimaru, Itaru Yazawa, Keiko Ikeda, Yasumasa Okada
    • Organizer
      第98回日本生理学会大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] The role of monocarboxylate transporters in maintaining respiratory neuron activity2020

    • Author(s)
      Sayumi Kotani, Shih Tien Lin, Hiroshi Onimaru, Masahiko Izumizaki
    • Organizer
      第97回日本生理学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Involvement of the Phox2b-positive neurons located in the dorsal medulla in the sucking rhythm generation2020

    • Author(s)
      Makito Iizuka, Keiko Ikeda,Hiroyuki Igarashi,Kazuto Kobayashi,Hiroshi Onimaru, Masahiko Izumizaki
    • Organizer
      第97回日本生理学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Calcium imaging analysis of cellular responses to hypercapnia and hypoxia in the NTS of newborn rat brainstem preparation2020

    • Author(s)
      Hiroshi Onimaru, Itaru Yazawa, Kotaro Takeda, Isato Fukushi, Yasumasa Okada
    • Organizer
      第43回日本神経科学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Effects of Cisplatin on Central Respiratory Activity of Neonatal Rat2020

    • Author(s)
      Shinichiro Ota, Hiroshi Onimaru, Kamon Iigaya, Masahiko Izumizaki
    • Organizer
      第43回日本神経科学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Responses to hypercapnia and hypoxia of neurons in the cardio-respiratory center of the ventral medulla of newborn rats2019

    • Author(s)
      Hiroshi Onimaru, Keiko Ikeda, Hiroyuki Igarashi, Hiromu Yawo, Kazuto Kobayashi, Satoru Arata, Kiyoshi Kawakami, Masahiko Izumizaki
    • Organizer
      10th IBRO
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Responses to hypercapnia and hypoxia of Phox2b-positive cells in the ventral medulla of newborn rats2019

    • Author(s)
      Hiroshi Onimaru, Keiko Ikeda, Hiroyuki Igarashi, Hiromu Yawo, Kazuto Kobayashi, Satoru Arata, Kiyoshi Kawakami, Masahiko Izumizaki
    • Organizer
      FAOPS
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Optogenetic analysis of the respiratory center neuron networks of transgenic neonatal rats that produce channelrhodopsin in Phox2b-positive cells2019

    • Author(s)
      Hiroshi Onimaru, Keiko Ikeda, Hiroyuki Igarashi, Hiromu Yawo, Kazuto Kobayashi, Satoru Arata, Kiyoshi Kawakami, Masahiko Izumizaki
    • Organizer
      第42回日本神経科学会
    • Related Report
      2019 Research-status Report
  • [Book] 動物の事典 第6章 動物の生理2021

    • Author(s)
      鬼丸 洋
    • Total Pages
      3
    • Publisher
      朝倉書店
    • ISBN
      9784254171662
    • Related Report
      2020 Research-status Report

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

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