Elucidation of the serotonergic pathways underlying emotional functions using optogenetics and genome editing

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07545
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Hokkaido University
• Principal Investigator: Ohmura Yu 北海道大学, 医学研究院, 講師 (80597659)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: セロトニン / 光遺伝学 / オプトジェネティクス / ゲノム編集

Outline of Final Research Achievements

We used optogenetic tools and CRISPR/Cas9-mediated in vivo gene editing to manipulate serotonergic activity and a specific 5-HT receptor in mice. We found that different serotonergic terminals, ventral hippocampus, ventral tegmental area/substantia nigra, and subthalamic/parasubthalamic nucleus, are involved in regulating anxiety-like behavior, antidepressant-like, and anti-impulsive effects, respectively. Furthermore, we found that the stimulation of the 5-HT2C receptor is required to evoke anxiety-like behavior, but not to exert anti-impulsive effects. We also demonstrated that the antidepressant-like effect of a selective serotonin reuptake inhibitor (SSRI) was enhanced by CRISPR/Cas9-mediated 5-HT1A receptor gene knockout in the dorsal raphe nucleus.

Free Research Field

精神薬理学

Academic Significance and Societal Importance of the Research Achievements

精神疾患の治療にはセロトニン神経に作用する薬が広く用いられているが、その治療効果は十分ではない上、しばしば重篤な副作用を引き起こす。これらの問題を解決するためには、それぞれの精神機能を支える明確なセロトニン伝達経路を特定する必要がある。今回の研究成果は、セロトニン神経経路や受容体サブタイプに特異的な治療法の必要性を示唆しており、より効果的で安全な治療法の開発に役立つ重要な知見を提供するものである。