Multiscale analysis of stress susceptobility and resilience in mice

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K23775
• 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: Kyoto University
• Principal Investigator: Sakai Yusuke 京都大学, 医学研究科, 特定研究員 (40843066)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Keywords: ストレス / うつ病 / エピゲノム

Outline of Final Research Achievements

The aim of this study is to clarify the molecular mechanisms of stress susceptibility and depression. We used gene x environment animal model and measured mRNA levels of plasticity-related genes in the ventral hippocampus and found that Camk2b mRNA was down regulated in stress-susceptible mice, but not in stress-resilient mice. Camk2 overexpression drives stress resilience, whereas camk2 knockdown increased stress susceptibility in mice. Thus, camk2 function is essential for behavioral response to chronic stress. We also found altered DNA methylation at Camk2b gene promoter. When DNA methylation was ameliorated by epigenome editing technique, aberrant behaviors were rescued, suggesting a critical role of DNA methylation at Camk2b gene for stress susceptibility and resilience. We provide first evidence indicating that epigenome editing rescues aberrant behavior in mice.

Free Research Field

神経化学

Academic Significance and Societal Importance of the Research Achievements

うつ病発症リスクとして遺伝・環境相互作用が知られているが、そのメカニズムは不明である。本研究では、遺伝・環境相互作用に起因するうつ病モデルマウスを用いて、うつ様行動発現に関わる脳部位・原因分子の同定に成功した。さらに、エピゲノム編集技術の介入によって、ストレスレジリエンスの獲得や抗うつ作用を発揮することのできる制御法を開発することができた。これらの成果は、将来的にはストレス性精神疾患の構成的理解ならびに新たな治療法の確立につながることが期待できる。