Investigation of a mechanism of prolonged activation induced by electronic stimulation of hypothalamus

• Project/Area Number: 19K17620
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Hospital Organization Murayama Medical Center
• Principal Investigator: KONO YOSUKE 独立行政法人国立病院機構村山医療センター(臨床研究部), 電気生理学研究室, 共同研究員 (00747454)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 高血圧 / 遷延性興奮 / 視床下部 / 延髄 / グリア細胞 / 循環調節 / ストレス / 遷延性応答 / 膜電位イメージング / 摘出視床下部脳幹脊髄標本 / 高血圧症 / アストロサイト

Outline of Research at the Start

高血圧症は心血管疾患の最大のリスク因子であり、本態性高血圧症の発症メカニズムを明らかにすることは急務である。近年、急性ストレスに対する循環反応の回復が遅い人ほど将来的に高血圧を発症しやすいことが報告されたが、そのメカニズムは明らかでない。本研究では、『ストレス刺激後の遷延性交感神経活動亢進にアストロサイトが重要な役割を担っている』との仮説を立て、その妥当性を実験により検証する。

Outline of Final Research Achievements

Acute psychological stress induces elevation of blood pressure, which persists after the stress is relieved. However, the mechanism of this prolonged responses has not been fully elucidated.
We investigated this issue by functional imaging and tract-tracing in rats. By voltage-sensitive dye imaging, although the activation of the ventral medulla induced by single pulse stimulation of the DMH was brief, tetanic stimulation caused activation of the dorsomedial hypothalamus (DMH) sustained into the post-stimulus phase, resulting in delayed recovery. Tract-tracing revealed DMH neurons projected to the ventral medullary cardiovascular regions with axon terminals in contiguity with tyrosine hydroxylase-immunoreactive neurons. The contribution of glial cells to the circulatory response induced by psychological stress was also examined.

Academic Significance and Societal Importance of the Research Achievements

高血圧症は心血管疾患の最大のリスク因子であるが、本態性高血圧発症のメカニズムは明らかでない。身体的あるいは精神的ストレスは血圧上昇・心拍数増加といった循環応答が惹起されるが、ストレス消失後にもこれらの循環応答が遷延する場合には、将来、高血圧を発症するリスクが高まることが報告されている。
本研究では、精神的ストレスを模した視床下部背内側核へのテタヌス刺激が延髄腹側循環調節領域の遷延性興奮を惹起することを明らかにし、その解剖学的結合およびグリア細胞の関与についての知見を得た。本成果はストレスによる交感神経活動の持続的増強のメカニズムを理解するための解剖学的および病態生理学的基盤となると考える。

Research Products

• [Journal Article] Activation of Astrocytes in the Persistence of Post-hypoxic Respiratory Augmentation (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Astrocytes play an active role in persistence of respiratory augmentation in the recovery phase after hypoxic exposure (2020)
  • Author(s): Fukushi Isato、Kono Yosuke、Takeda Kotaro、Yokota Shigefumi、Onimaru Hiroshi、Pokorski Mieczyslaw、Okada Yasumasa
  • Journal Title: The FASEB Journal Volume: 34 Issue: S1 Pages: 1-1
  • DOI: 10.1096/fasebj.2020.34.s1.03235
  • Peer Reviewed
• [Journal Article] Role of Microglia in Ventilatory and Blood Pressure Responses to Acute Hypoxia (2020)
  • Author(s): Okada Yasumasa、Yoshizawa Masashi、Fukushi Isato、Takeda Kotaro、Kono Yosuke、Hasebe Yohei、Koizumi Keiichi、Toda Takako
  • Journal Title: The FASEB Journal Volume: 34 Issue: S1 Pages: 1-1
  • DOI: 10.1096/fasebj.2020.34.s1.02871
  • Peer Reviewed
• [Journal Article] Microglial Involvement in Stress‐induced Prolonged Sympathetic Nervous Excitation in Rats (2020)
  • Author(s): Yoshizawa Masashi、Fukushi Isato、Takeda Kotaro、Kono Yousuke、Hasebe Yohei、Koizumi Keiichi、Toda Takako、Okada Yasumasa
  • Journal Title: The FASEB Journal Volume: 34 Issue: S1 Pages: 1-1
  • DOI: 10.1096/fasebj.2020.34.s1.02865
  • Peer Reviewed
• [Presentation] Astrocytes are involved in the maintenance of respiratory augmentation in the post hypoxic recovery phase (2021)
  • Author(s): Fukushi I, Takeda K, Yoshizawa M, Kono Y, Hasebe Y, Onimaru H, Okada Y
  • Organizer: The 7th Conference of Japanese Society of Respiratory Physical Therapy
• [Presentation] Astrocytes mediate the post-hypoxic persistent respiratory augmentation. (2021)
  • Author(s): Fukushi I, Takeda K, Pokorski M, Kono Y, Yoshizawa M, Hasebe Y, Nakao A, Mori Y, Onimaru H, Okada Y.
  • Organizer: Experimental Biology 2021 Meeting
• [Presentation] トレス刺激による循環応答におけるマイクログリアの関与. (2020)
  • Author(s): 吉沢雅史, 福士勇人, 河野洋介, 長谷部洋平, 小泉敬一, 武田湖太郎, 岡田泰昌, 戸田孝子.
  • Organizer: 第54回小児循環器学会総会・学術集会,
• [Presentation] Role of microglia in sustenance of stress-induced sympathetic excitation in rats. (2020)
  • Author(s): Yoshizawa M, Fukushi I, Takeda K, Kono Y, Hasebe Y, Koizumi K, Toda T, Okada Y.
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Astrocytes play an active role in persistence of respiratory augmentation in the recovery phase after hypoxic exposure. (2020)
  • Author(s): Fukushi I, Kono Y, Takeda K, Yokota S, Onimaru H, Pokorski M, Okada Y.
  • Organizer: Experimental Biology 2020 Meeting
• [Presentation] Role of Microglia in Ventilatory and Blood Pressure Responses to Acute Hypoxia (2020)
  • Author(s): Okada Y, Yoshizawa M, Fukushi I, Takeda K, Kono Y, Hasebe Y, Koizumi K, Toda T
  • Organizer: Experimental Biology 2020 Meeting
• [Presentation] Microglial Involvement in Stress‐induced Prolonged Sympathetic Nervous Excitation in Rats (2020)
  • Author(s): Yoshizawa M, Fukushi I, Takeda K, Kono Y, Hasebe Y, Koizumi K, Toda T, Okada Y
  • Organizer: Experimental Biology 2020 Meeting
• [Presentation] ストレス刺激後に遷延する血圧上昇・脈拍増加応答に対するマイクログリア抑制の効果. (2019)
  • Author(s): 吉沢 雅史、福士 勇人、河野 洋介、長谷部洋平、小泉 敬一、戸田 孝子、岡田 泰昌.
  • Organizer: 第42回日本高血圧学会
• [Presentation] 急性エアジェットストレス負荷によるラット交感神経興奮の持続におけるマイクログリアの役割 (2019)
  • Author(s): 吉沢 雅史、福士 勇人、河野 洋介、長谷部洋平、小泉 敬一、戸田 孝子、岡田 泰昌.
  • Organizer: 第72回日本自律神経学会総会
• [Presentation] ストレス刺激に伴う血圧上昇の遷延メカニズム (2019)
  • Author(s): 岡田泰昌、長谷部洋平、河野洋介、吉沢雅史、横田茂文、福士勇人、小泉敬一、戸田孝子
  • Organizer: 第72回日本自律神経学会総会
• [Presentation] The diencephalon augments respiration in the isolated diencephalon-lower brainstem-spinal cord preparations of newborn rats. (2019)
  • Author(s): Isato FUKUSHI, Yosuke KONO, Shigefumi YOKOTA, Kotaro TAKEDA, Itaru YAZAWA, Hiroshi ONIMARU, Yasumasa OKADA.
  • Organizer: 第6回日本呼吸理学療法学会学術大会