Elucidation of the neural network for the sucking rhythm

• Project/Area Number: 20K07266
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Showa University
• Principal Investigator: Iizuka Makito 昭和大学, 医学部, 准教授 (40274980)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
• Keywords: Phox2b / 吸啜 / 新生ラット / 脳幹-脊髄摘出標本 / しゃっくり / Phox2B / 脳幹－脊髄摘出標本

Outline of Research at the Start

脳幹領域の発生・分化に不可欠な転写因子としてPhox2b遺伝子が知られており、我々はPhox2b陽性ニューロンにチャネルロドプシンを発現させた遺伝子改変ラットを作成した。そして新生ラットの頭部背側から光を照射すると吸啜運動が誘発されることを発見した。さらに脳幹-脊髄摘出標本でも吸啜リズムを誘発できることが分かり、吸啜リズム形成に関与する神経回路網・ニューロン・イオンチャネルの研究が初めて可能になった。この新しい誘発方法、脳幹-脊髄摘出標本、電位感受性色素による光学測定、ホールセル記録と免疫組織化学染色法、in situ hybridization法等を用いて吸啜リズム形成回路の全容を解明する。

Outline of Final Research Achievements

Sucking is a rhythmic movement for infants to obtain nourishment from their mothers, but the localization of the neural network and neural mechanisms of this movement are unknown. We have generated transgenic rats expressing channelrhodopsin in Phox2b-positive neurons and found that blue light stimulation from the dorsal surface of the head can induce sucking movements. Light stimulation also elicited rhythmic activity of the phrenic nerve in the isolated brainstem-spinal cord preparations, but the rhythmic activity was synchronized with that of the trigeminal and hypoglossal nerves, indicating that this was not sucking but hiccups. Currently, we are trying to induce sucking motor rhythm by applying various drugs such as glutamate and NMDA to the brainstem-spinal cord preparations, but we have not succeeded yet.

Academic Significance and Societal Importance of the Research Achievements

背側領域にあるPhox2b陽性ニューロンの特異的な刺激により誘発されるリズム活動は吸啜であると考え研究を開始したが、その後の解析によりしゃっくりであることが明らかになった。1ヶ月以上持続する難治性吃逆では患者のQOLを著しく低下させる。しゃっくりの神経機構は未だ不明な点が多く、治療は経験則に基づいて行われている。本研究によりしゃっくり中枢の位置を特定できたことは、今後の難治性しゃっくりの治療法の開発に向けて意義のある研究成果である。

Research Products

• [Presentation] Activity patterns of the digastric, masseter, diaphragm, and abdominal muscles during hiccup-like movements induced by stimulation of Phox2B-positive neurons in the dorsal brainstem (2024)
  • Author(s): Iizuka M, Ikeda K, Igarashi H, Kobayashi K, Onimaru H, Izumizaki M.
  • Organizer: 第101回日本生理学会大会
• [Presentation] Activation of Phox2b neurons in the dorsal brainstem induced sucking-like, swallowing-like and hiccup-like movements (2023)
  • Author(s): Iizuka M, Ikeda K, Igarashi H, Kobayashi K, Onimaru H, Izumizaki M.
  • Organizer: Neuroscience Annual Meeting 2023, Society for Neuroscience
  • Int'l Joint Research
• [Presentation] Activation of Phox2B-positive neurons in the dorsal medulla induced sucking and hiccup (2023)
  • Author(s): Iizuka M, Ikeda K, Igarashi H, Kobayashi K, Onimaru H, Izumizaki M
  • Organizer: The 100th Anniversary Annual Meeting of The Physiological Society of Japan
• [Presentation] Activation of Phox2b neurons in the dorsal medulla induced sucking and hiccup movement. (2022)
  • Author(s): Iizuka M, Ikeda K, Igarashi H, Kobayashi K, Onimaru H, Izumizaki M
  • Organizer: The 15th Oxford Conference on Modelling and Control of Breathing
  • Int'l Joint Research
• [Presentation] Phox2b-positive neurons located in the solitary nucleus is essential to trigger sucking (2021)
  • Author(s): Iizuka M, Ikeda K, Igarashi H, Kobayashi K, Onimaru H, Izumizaki M,
  • Organizer: 第98回日本生理学会大会