Sleep spindle generation: physiological significance

• Project/Area Number: 17K18395
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Basic / Social brain science; Brain biometrics
• Research Institution: National Center of Neurology and Psychiatry (2018); Tokyo Metropolitan Institute of Medical Science (2017)
• Principal Investigator: MIWA HIDEKI 国立研究開発法人国立精神・神経医療研究センター, 精神保健研究所 精神薬理研究部, 室長 (80468488)
• Research Collaborator: McCarley Robert W. Harvard medical school/VA Boston Healthcare System
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 統合失調症 / GABA / 睡眠 / スピンドル波 / 視床網様核 / パルブアルブミン / GABA作動性ニューロン / 記憶 / スピンドル / NREM

Outline of Final Research Achievements

We selectively deleted GAD67 in the thalamic reticular nucleus (TRN) and tested its effect on sleep spindle generation. For that purpose, we reduced GAD67 levels in TRN neurons by injecting an adeno-associated virus (AAV) constitutively expressing a Cre recombinase-Green fluorescence protein (GFP) fusion protein (AAV-CreGFP) into TRN of heterozygous and homozygous GAD67 floxed mice. EEG activity from frontal cortex and nuchal muscle EMG were recorded and sleep-wake states were analyzed. We found that NREM sleep spindle density at 4 week in virally injected GAD67 flox mice was significantly different from control animals. Those virally injected GAD67 flox mice have also shown abnormal sleep-dependent memory in Y maze test. Our results suggest GAD67 floxed mice are a useful tool to test whether reduced levels of GAD67 levels in TRN results in decreased spindle density, similar to the findings observed in schizophrenia patients.

Academic Significance and Societal Importance of the Research Achievements

統合失調症モデルマウスにおいて、スピンドル波発生の異常および睡眠依存性記憶固定の異常を観察することができ、視床網様核GABA作動性ニューロンのスピンドル波発生における役割を明らかにできたことが学術的意義である。このことは、精神疾患と睡眠障害の病態の関連性を理解でき、これを拡張して、他の精神疾患と睡眠障害との関連性についても明らかにできる可能性を示唆できた。これらを明らかにすることで、睡眠異常の有無を診断することで発症の予防や、発症後に睡眠障害がある場合は睡眠異常を改善することにより、精神疾患の症状の改善など新たな治療法および回復のメカニズムを提唱できる可能性があることが社会的意義である。

Research Products

• [Int'l Joint Research] Harvard medical school/VA Boston Healthcare System(米国)
• [Presentation] 統合失調症の病態に迫る－From bench to bedsideを目指して－ (2018)
  • Author(s): 三輪秀樹
  • Organizer: 医療心理懇話会第3回集会
  • Invited
• [Presentation] 視床網様核におけるGAD67遺伝子欠損のノンレム睡眠スピンドル波発生への影響 (2018)
  • Author(s): 三輪秀樹
  • Organizer: 第28回日本臨床精神神経薬理学会 第48回日本神経精神薬理学会合同年会
  • Invited
• [Presentation] Roles of GAD67 in the thalamic reticular nucleus for regulating sleep spindle generation (2017)
  • Author(s): Hideki Miwa, Radhika Basheer, James T. McKenna, James M. McNally, Robert W. McCarley, Ritchie E Brown
  • Organizer: SLEEP 2017: 31st Annual Meeting of the Associated Professional Sleep Societies
  • Int'l Joint Research
• [Presentation] Effect of GAD67 deletion in the thalamic reticular nucleus on sleep spindle regulating activity. (2017)
  • Author(s): Hideki Miwa, Radhika Basheer, Hanan Bouaouda, David S. Uygun, James T. McKenna, James M. McNally, Robert W. McCarley, Ritchie E. Brown
  • Organizer: The 47th Annual Meeting of the Society for Neuroscience
  • Int'l Joint Research
• [Presentation] 睡眠スピンドル波発生制御における視床網様核のGAD67遺伝子の役割 (2017)
  • Author(s): Hideki Miwa, Radhika Basheer, Hanan Bouaouda, David S. Uygun, James T. McKenna, James M. McNally, Robert W. McCarley, Ritchie E. Brown
  • Organizer: Neuroscience2017（第40回日本神経科学大会）
  • Int'l Joint Research