Elucidation of molecular mechanisms underlying cognitive decline at adult stage induced by neonatal exposure to midazolam and development of a therapeutic strategy

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K20956
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0905:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Kyushu University
• Principal Investigator: DOI HIROYOSHI 九州大学, 大学病院, 助教 (60906337)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: ニューロン新生 / 神経幹細胞 / 記憶・学習障害 / ミダゾラム / 麻酔薬曝露 / GABA / クロマチン / 自発的運動

Outline of Final Research Achievements

There is abundant evidence that environmental insults, such as exposure to anesthetics, at early-life stages impair brain functions in later life, but the underlying mechanisms are poorly understood. Neural stem cells (NSCs) express inhibitory neurotransmitter γ-aminobutyric acid type A receptors that are the main target of most anesthetics, including midazolam (MDZ). We found that early-life exposure to MDZ persistently alters chromatin accessibility and global transcription to reinforce long-lasting NSC dormancy in the mouse hippocampus until adulthood, resulting in reduced neurogenesis and cognitive decline. Furthermore, a simple physical activity, running, could overcome these adverse outcomes by normalizing MDZ-induced transcriptomic alterations. Our study provides insights for further understanding and developing therapeutic strategies for neurological disorders induced by early-life exposure to anesthetics.

Free Research Field

麻酔学

Academic Significance and Societal Importance of the Research Achievements

これまで不明とされてきた麻酔薬誘導性の遅発性の学習・記憶障害のメカニズム解明に成功した数少ない研究成果であり、本研究によりさらに麻酔学領域での研究が発展するものと思われる。また本研究では、自発的運動がマウスにおける麻酔薬誘導性の認知機能低下を改善することを見出しており、これはヒトにおいても有効な治療法となりうる可能性があり、将来的な臨床への応用が期待できる。