Neuronal circuit for sedative/hypnotic actions of alpha-2 adrenergic agonist

• Project/Area Number: 21K20699
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0704:Neuroscience, brain sciences, and related fields
• Research Institution: Toho University
• Principal Investigator: Yamagata Tomoko 東邦大学, 医学部, 助教 (90584433)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 睡眠 / 鎮静 / α２作動薬 / デクスメデトミジン / マウス / アドレナリンα２受容体

Outline of Research at the Start

デクスメデトミジンは鎮静薬として広く用いられている。しかし、深いノンレム睡眠（ステージ２ないし３）に近い脳波が現れること、睡眠のように脳のクリアランス作用（老廃物除去作用）があることから、睡眠機能を阻害せずにねむりを促すことができる睡眠薬として期待できる。本研究は、α２作動性鎮静薬であるデクスメデトミジンの作用機序を、薬理遺伝学・光遺伝学的に、神経回路レベルから解明することを目指している。

Outline of Final Research Achievements

Dexmedetomidine, an alpha 2 agonist, is widely used in clinical practice as a pre- and post-operative sedative, but it remains unclear how it exerts its sedative effects and why it induces deep non-REM sleep-like EEG and inhibits REM sleep. To this end, this study aimed to elucidate the neuronal mechanism of sedation by dexmedetomidine (DEX), an adrenergic α2-receptor agonist, using pharmacogenetic and photogenetic methods. By using a genetical method to visualize specific neuronal cell populations in an activity-dependent manner (TRAP), we identified cell populations that are activated by DEX. We further manipulated those cell populations pharmacogenetically and optogenetically and examined the causal role of those cells on sedation and sleep/arousal.

Academic Significance and Societal Importance of the Research Achievements

α２作動薬のデクスメデトミジンは、術前・術後の鎮静薬として臨床の場でひろく使われているが、どのように鎮静作用が出現するのか、また、なぜこの薬による鎮静が深いノンレム睡眠様の脳波を誘発し、かつレム睡眠を抑制するかは不明なままである。本研究は、鎮静時に活性化される神経回路についてその睡眠・覚醒への役割を検証した。鎮静と睡眠・覚醒の神経基盤について明らかにしたという点で、学術的に意義がある。

Research Products

• [Journal Article] Intracellular chloride regulation mediates local sleep pressure in the cortex (2022)
  • Author(s): Hannah Alfonsa, Richard J. Burman, Paul J. N. Brodersen, Sarah E. Newey, Kashif Mahfooz, Tomoko Yamagata, Marios C. Panayi, David M. Bannerman, Vladyslav V. Vyazovskiy, Colin J. Akerman
  • Journal Title: Nature Neuroscience Volume: 26 Issue: 1 Pages: 64-78
  • DOI: 10.1038/s41593-022-01214-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The hypothalamic link between arousal and sleep homeostasis in mice (2021)
  • Author(s): Tomoko Yamagata, Martin C. Kahn, Jose Prius-Mengual, Elise Meijer, Merima Sabanovic, Mathilde C. C. Guillaumin, Vincent van der Vinne, Yi-Ge Huang, Laura E. McKillop, Aarti Jagannath, Stuart N Peirson, Edward O. Mann, Russell G. Foster, and Vladyslav V. Vyazovskiy
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 51
  • DOI: 10.1073/pnas.2101580118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A role for the cortex in sleep-wake regulation (2021)
  • Author(s): Lukas B. Krone, Tomoko Yamagata, Cristina Blanco-Duque, Mathilde C. C. Guillaumin, Martin C. Kahn, Vincent van der Vinne, Laura E. McKillop, Shu K. E. Tam, Stuart N. Peirson, Colin J. Akerman, Anna Hoerder-Suabedissen, Zoltan Molner, Vladyslav V. Vyazovskiy
  • Journal Title: Nature Neuroscience Volume: 24 Issue: 9 Pages: 1210-1215
  • DOI: 10.1038/s41593-021-00894-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intraneuronal chloride levels encode tiredness in cortex (2021)
  • Author(s): Hannah Alfonsa, Paul Brodersen, Sarah E. Newey, Tomoko Yamagata, Marios C. Panayi, David M. Bannerman, Vladyslav V. Vyazovskiy, Colin J. Akerman
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/2021.05.14.444189
  • Open Access / Int'l Joint Research
• [Journal Article] Waking experience modulates sleep need in mice (2021)
  • Author(s): Linus Milinski, Simon P. Fisher, Nanyi Cui, Laura E. McKillop, Cristina Blanco-Duque, Gauri Ang, Tomoko Yamagata, David M. Bannerman, Vladyslav V. Vyazovskiy
  • Journal Title: BMC Biology Volume: 19 Issue: 1
  • DOI: 10.1186/s12915-021-00982-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Somnotate: An accurate, robust, and flexible sleep stage classifier for the experimentalist (2021)
  • Author(s): Paul J. N. Brodersen, Hannah Alfonsa, Lukas B. Krone, Cristina Blanco Duque, Angus S. Fisk, Sarah J. Flaherty, Mathilde C. C. Guillaumin, Yi-Ge Huang, Martin C. Kahn, Laura E. McKillop, Linus Milinski, Lewis Taylor, Christopher W. Thomas, Tomoko Yamagata, Russell G. Foster, Vladyslav V. Vyazovskiy, Colin J. Akerman
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/2021.10.06.463356
  • Open Access / Int'l Joint Research
• [Presentation] Rapid state reversibility from deep dexmedetomidine sedation induced by photoactivation of lateral preoptic GAD2 neurons in mice (2021)
  • Author(s): Tomoko Yamagata, Stuart N. Peirson, Edward O. Mann, Russell G. Foster, Vladyslav V. Vyazovskiy
  • Organizer: SfN2021
  • Int'l Joint Research
• [Remarks] Toho University Department of Anatomy
  • URL: https://www.toho-funatolab.jp/
• [Remarks] 理研CBS 思考・実行機能研究チーム
  • URL: https://www.kentaromiyamoto-lab.com/