Identification of determinants of depression pathogenesis and treatment

• Project/Area Number: 20K07064
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Kyoto University
• Principal Investigator: Nagayasu Kazuki 京都大学, 薬学研究科, 助教 (00717902)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: セロトニン / うつ病 / 光遺伝学 / ウイルスベクター / うつ / 背側縫線核 / 正中縫線核 / TRAP

Outline of Research at the Start

うつ病は、長期にわたる抑うつ症状や、意欲の低下などを主症状とする精神疾患であり、本邦を含む先進国において大きな社会問題となっている。本研究では、セロトニン神経に着目し、その活動計測/活動への介入を用いて、セロトニン神経活動変化がうつ症状表出/消失の決定因子であるという仮説を検証するとともに、その活動変化の「臨界点」およびその分子メカニズムの解明に挑む。

Outline of Final Research Achievements

Using optogenetic techniques, we investigated whether chronic activation of serotonergic neurons in the dorsal raphe nucleus (DRN) causes persistent antidepressant effects. We found that chronic activation of DRN serotonergic neurons induces persistent antidepressant effects and that the mechanism is selective activation of the pleasant experience neural ensemble in the hippocampus. Furthermore, we found that the median raphe nucleus (MRN) serotonergic neurons are responsible for unpleasant emotions, in contrast to the DRN serotonergic neurons. These results suggest that among serotonergic neurons, the DRN serotonergic neurons play a central role in antidepressant effects and that the MRN serotonergic neurons may have an antagonistic role.

Academic Significance and Societal Importance of the Research Achievements

本研究により明らかにされた、背側縫線核セロトニン神経と正中縫線核セロトニン神経の機能的対照性と、背側縫線核セロトニン神経による持続的な抗うつ作用を併せて考えると、セロトニン神経伝達を個別に制御が可能な薬剤を開発することで、既存薬を超える抗うつ薬開発が可能になると考えられることから、本研究によりその基礎的知見が得られたものと考えられる。

Research Products

• [Int'l Joint Research] ブリストル大学(英国)
• [Int'l Joint Research] ブリストル大学(英国)
• [Journal Article] Wild-Type DCTN1 Suppresses the Aggregation of DCTN1 Mutants Associated with Perry Disease (2024)
  • Author(s): Fukui Yuto、Shirakawa Hisashi、Kaneko Shuji、Nagayasu Kazuki
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 47 Issue: 1 Pages: 253-258
  • DOI: 10.1248/bpb.b23-00828
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2024-01-24
  • Peer Reviewed / Open Access
• [Journal Article] Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor (2024)
  • Author(s): Hatakama Hikari、Asaoka Nozomi、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Translational Psychiatry Volume: 14 Issue: 1 Pages: 27-27
  • DOI: 10.1038/s41398-024-02731-3
  • Peer Reviewed / Open Access
• [Journal Article] Specific Cellular Effects of Low Bortezomib Concentrations on Purified Cultures of Schwann Cells, Satellite Glial Cells, Macrophages, and Dorsal Root Ganglion Neurons (2023)
  • Author(s): Zhou Zijian、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 46 Issue: 1 Pages: 102-110
  • DOI: 10.1248/bpb.b22-00668
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2023-01-01
  • Peer Reviewed / Open Access
• [Journal Article] The States of Different 5-HT Receptors Located in the Dorsal Raphe Nucleus Are Crucial for Regulating the Awakening During General Anesthesia (2023)
  • Author(s): Ma HaiXiang、Gu LeYuan、Wang YuLing、Xu Qing、Zhang Yuanli、Shao WeiHui、Yu Qian、Lian XiTing、Liu Lu、Gu JiaXuan、Ji Na、Liu XiaoLing、Nagayasu Kazuki、Zhang HongHai
  • Journal Title: Molecular Neurobiology Volume: 60 Issue: 12 Pages: 6931-6948
  • DOI: 10.1007/s12035-023-03519-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The astrocytic TRPA1 channel mediates an intrinsic protective response to vascular cognitive impairment via LIF production (2023)
  • Author(s): Kakae Masashi、Nakajima Hiroki、Tobori Shota、Kawashita Ayaka、Miyanohara Jun、Morishima Misa、Nagayasu Kazuki、Nakagawa Takayuki、Shigetomi Eiji、Koizumi Schuichi、Mori Yasuo、Kaneko Shuji、Shirakawa Hisashi
  • Journal Title: Science Advances Volume: 9 Issue: 29 Pages: 29-29
  • DOI: 10.1126/sciadv.adh0102
  • Peer Reviewed / Open Access
• [Journal Article] Early Detection of Adverse Drug Reaction Signals by Association Rule Mining Using Large-Scale Administrative Claims Data (2023)
  • Author(s): Hiroki Yamamoto, Gen Kayanuma, Takuya Nagashima, Chihiro Toda, Kazuki Nagayasu, Shuji Kaneko
  • Journal Title: Drug Safety Volume: - Issue: 4 Pages: 371-389
  • DOI: 10.1007/s40264-023-01278-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dorsal raphe serotonergic neurons preferentially reactivate dorsal dentate gyrus cell ensembles associated with positive experience (2023)
  • Author(s): Nagai Yuma、Kisaka Yuri、Nomura Kento、Nishitani Naoya、Andoh Chihiro、Koda Masashi、Kawai Hiroyuki、Seiriki Kaoru、Nagayasu Kazuki、Kasai Atsushi、Shirakawa Hisashi、Nakazawa Takanobu、Hashimoto Hitoshi、Kaneko Shuji
  • Journal Title: Cell Reports Volume: 42 Issue: 3 Pages: 112149-112149
  • DOI: 10.1016/j.celrep.2023.112149
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Increased expression of glutathione peroxidase 3 prevents tendinopathy by suppressing oxidative stress (2023)
  • Author(s): Furuta Haruka、Yamada Mari、Nagashima Takuya、Matsuda Shuichi、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Frontiers in Pharmacology Volume: 14 Pages: 1137952-1137952
  • DOI: 10.3389/fphar.2023.1137952
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vitamin D supplementation is effective for olanzapine-induced dyslipidemia (2023)
  • Author(s): Zhou Zijian、Nagashima Takuya、Toda Chihiro、Kobayashi Mone、Suzuki Takahide、Nagayasu Kazuki、Shirakawa Hisashi、Asai Satoshi、Kaneko Shuji
  • Journal Title: Frontiers in Pharmacology Volume: 14 Pages: 1135516-1135516
  • DOI: 10.3389/fphar.2023.1135516
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peripheral Beta-2 Adrenergic Receptors Mediate the Sympathetic Efferent Activation from Central Nervous System to Splenocytes in a Mouse Model of Fibromyalgia (2023)
  • Author(s): Yamashita Shiori、Dozono Naoki、Tobori Shota、Nagayasu Kazuki、Kaneko Shuji、Shirakawa Hisashi、Ueda Hiroshi
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 4 Pages: 3465-3465
  • DOI: 10.3390/ijms24043465
  • Peer Reviewed / Open Access
• [Journal Article] Enhancement of adenosine A2A signaling improves dopamine D2 receptor antagonist-induced dyskinesia via β-arrestin signaling (2023)
  • Author(s): Nagaoka Koki、Asaoka Nozomi、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Frontiers in Neuroscience Volume: 16 Pages: 1082375-1082375
  • DOI: 10.3389/fnins.2022.1082375
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lisinopril prevents bullous pemphigoid induced by dipeptidyl peptidase 4 inhibitors via the Mas receptor pathway (2023)
  • Author(s): Nozawa Keisuke、Suzuki Takahide、Kayanuma Gen、Yamamoto Hiroki、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Frontiers in Immunology Volume: 13 Pages: 1084960-1084960
  • DOI: 10.3389/fimmu.2022.1084960
  • Peer Reviewed / Open Access
• [Journal Article] Acetaminophen improves tardive akathisia induced by dopamine D2 receptor antagonists (2023)
  • Author(s): Nagaoka Koki、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Journal of Pharmacological Sciences Volume: 151 Issue: 1 Pages: 9-16
  • DOI: 10.1016/j.jphs.2022.10.006
  • Peer Reviewed / Open Access
• [Journal Article] Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion (2022)
  • Author(s): Kawai Hiroyuki、Bouchekioua Youcef、Nishitani Naoya、Niitani Kazuhei、Izumi Shoma、Morishita Hinako、Andoh Chihiro、Nagai Yuma、Koda Masashi、Hagiwara Masako、Toda Koji、Shirakawa Hisashi、Nagayasu Kazuki、Ohmura Yu、Kondo Makoto、Kaneda Katsuyuki、Yoshioka Mitsuhiro、Kaneko Shuji
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 7708-7708
  • DOI: 10.1038/s41467-022-35346-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dorsal raphe nucleus to pre-B?tzinger complex serotonergic neural circuit is involved in seizure-induced respiratory arrest (2022)
  • Author(s): Ma HaiXiang、Yu Qian、Shen Yue、Lian XiTing、Gu LeYuan、Wang YuLing、Xu Qing、Lu Han、Zhao HaiTing、Zeng Chang、Nagayasu Kazuki、Zhang HongHai
  • Journal Title: iScience Volume: 25 Issue: 10 Pages: 105228-105228
  • DOI: 10.1016/j.isci.2022.105228
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Orai2 channel regulates prostaglandin E2 production in TNFα/IL1α‐stimulated astrocytes (2022)
  • Author(s): Nakajima Hiroki、Fujita Sayaka、Kakae Masashi、Nagayasu Kazuki、Oh‐hora Masatsugu、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Glia Volume: 70 Issue: 9 Pages: 1666-1680
  • DOI: 10.1002/glia.24188
  • Peer Reviewed
• [Journal Article] Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses. (2022)
  • Author(s): Niu M, Kasai A, Tanuma M, Seiriki K, Igarashi H, Kuwaki T, Nagayasu K, Miyaji K, Ueno H, Tanabe W, Seo K, Yokoyama R, Ohkubo J, Ago Y, Hayashida M, Inoue KI, Takada M, Yamaguchi S, Nakazawa T, Kaneko S, Okuno H, Yamanaka A, Hashimoto H.
  • Journal Title: Science Advances Volume: 8 Issue: 11
  • DOI: 10.1126/sciadv.abi6375
  • Peer Reviewed / Open Access
• [Journal Article] Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses. (2022)
  • Author(s): Niu M, Kasai A, Tanuma M, Seiriki K, Igarashi H, Kuwaki T, Nagayasu K, Miyaji K, Ueno H, Tanabe W, Seo K, Yokoyama R, Ohkubo J, Ago Y, Hayashida M, Inoue KI, Takada M, Yamaguchi S, Nakazawa T, Kaneko S, Okuno H, Yamanaka A, Hashimoto H.
  • Journal Title: Sci Adv. Volume: 8
  • Peer Reviewed / Open Access
• [Journal Article] A selective serotonin reuptake inhibitor ameliorates obsessive compulsive disorder-like perseverative behavior by attenuating 5-HT2C receptor signaling in the orbitofrontal cortex (2022)
  • Author(s): Hatakama Hikari、Asaoka Nozomi、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Neuropharmacology Volume: 206 Pages: 108926-108926
  • DOI: 10.1016/j.neuropharm.2021.108926
  • Peer Reviewed
• [Journal Article] Serotonin transporter: Recent progress of in silico ligand prediction methods and structural biology towards structure-guided in silico design of therapeutic agents (2022)
  • Author(s): Nagayasu Kazuki
  • Journal Title: Journal of Pharmacological Sciences Volume: 148 Issue: 3 Pages: 295-299
  • DOI: 10.1016/j.jphs.2022.01.004
  • Peer Reviewed
• [Journal Article] Transient Receptor Potential Melastatin 3 Is Functionally Expressed in Oligodendrocyte Precursor Cells and Is Upregulated in Ischemic Demyelinated Lesions (2021)
  • Author(s): Ohashi Kana、Shibasaki Koji、Nakazawa Hayaki、Kunimasa Ryotaro、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 44 Issue: 2 Pages: 181-187
  • DOI: 10.1248/bpb.b20-00510
  • NAID: 130007979613
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2021-02-01
  • Peer Reviewed / Open Access
• [Journal Article] Multiple alterations in glutamatergic transmission and dopamine D2 receptor splicing in induced pluripotent stem cell-derived neurons from patients with familial schizophrenia (2021)
  • Author(s): Yamamoto Kana、Kuriu Toshihiko、Takuma Kazuhiro、Ono Fumihito、Matsumoto Naomichi、Hashimoto Ryota、Hashimoto Hitoshi、Nakazawa Takanobu
  • Journal Title: Translational Psychiatry Volume: 11 Issue: 1 Pages: 548-548
  • DOI: 10.1038/s41398-021-01676-1
  • Peer Reviewed / Open Access
• [Journal Article] Drug Repurposing Prediction and Validation From Clinical Big Data for the Effective Treatment of Interstitial Lung Disease (2021)
  • Author(s): Siswanto Soni、Yamamoto Hiroki、Furuta Haruka、Kobayashi Mone、Nagashima Takuya、Kayanuma Gen、Nagayasu Kazuki、Imai Yumiko、Kaneko Shuji
  • Journal Title: Frontiers in Pharmacology Volume: 12 Pages: 635293-635293
  • DOI: 10.3389/fphar.2021.635293
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Secreted PLA2-III is a possible therapeutic target to treat neuropathic pain (2021)
  • Author(s): Tanaka Keigo、Dozono Naoki、Neyama Hiroyuki、Nagai Jun、Tsukahara Ryoko、Nagayasu Kazuki、Kaneko Shuji、Ueda Hiroshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 568 Pages: 167-173
  • DOI: 10.1016/j.bbrc.2021.06.058
  • Peer Reviewed
• [Journal Article] TRPM7 is an essential regulator for volume-sensitive outwardly rectifying anion channel. (2021)
  • Author(s): Numata T, Sato-Numata K, Hermosura MC, Mori Y, Okada Y
  • Journal Title: Commun. Biol. Volume: 4 Issue: 4 Pages: 599-599
  • DOI: 10.1016/j.jphs.2021.04.006
  • Peer Reviewed / Open Access
• [Journal Article] Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonists-induced orofacial dyskinesia (2021)
  • Author(s): Nagaoka Koki、Nagashima Takuya、Asaoka Nozomi、Yamamoto Hiroki、Toda Chihiro、Kayanuma Gen、Siswanto Soni、Funahashi Yasuhiro、Kuroda Keisuke、Kaibuchi Kozo、Mori Yasuo、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: JCI Insight Volume: in press Issue: 10 Pages: 1-16
  • DOI: 10.1172/jci.insight.145632
  • NAID: 120007038817
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pronociceptive Roles of Schwann Cell?Derived Galectin-3 in Taxane-Induced Peripheral Neuropathy (2021)
  • Author(s): Koyanagi Madoka、Imai Satoshi、Matsumoto Mayuna、Iguma Yoko、Kawaguchi-Sakita Nobuko、Kotake Takeshi、Iwamitsu Yuki、Ntogwa Mpumelelo、Hiraiwa Ren、Nagayasu Kazuki、Saigo Mamiko、Ogihara Takashi、Yonezawa Atsushi、Omura Tomohiro、Nakagawa Shunsaku、Nakagawa Takayuki、Matsubara Kazuo
  • Journal Title: Cancer Research Volume: 81 Issue: 8 Pages: 2207-2219
  • DOI: 10.1158/0008-5472.can-20-2799
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of pharmacological activities from chemical structures with graph convolutional neural networks (2021)
  • Author(s): Sakai Miyuki、Nagayasu Kazuki、Shibui Norihiro、Andoh Chihiro、Takayama Kaito、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 525-525
  • DOI: 10.1038/s41598-020-80113-7
  • NAID: 120006951708
  • Peer Reviewed / Open Access
• [Journal Article] Transient receptor potential vanilloid 4 agonist GSK1016790A improves neurological outcomes after intracerebral hemorrhage in mice (2020)
  • Author(s): Asao Yasunori、Tobori Shota、Kakae Masashi、Nagayasu Kazuki、Shibasaki Koji、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 529 Issue: 3 Pages: 590-595
  • DOI: 10.1016/j.bbrc.2020.06.103
  • Peer Reviewed
• [Journal Article] Acute restraint stress augments the rewarding memory of cocaine through activation of α1 adrenoceptors in the medial prefrontal cortex of mice. (2020)
  • Author(s): Wada, S., Yanagida, J., Sasase, H., Zhang, T., Li, X., Kamii, H., Domoto, M., Deyama, S., Hinoi, E., Yamanaka, A., Nishitani, N., Nagayasu, K., Kaneko, S., Minami, M., Kaneda, K.
  • Journal Title: Neuropharmacology Volume: 166 Pages: 107968-107968
  • DOI: 10.1016/j.neuropharm.2020.107968
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Dorsal Raphe Serotonin Neurons in the Balance between Reward and Aversion (2020)
  • Author(s): Nagai Yuma、Takayama Kaito、Nishitani Naoya、Andoh Chihiro、Koda Masashi、Shirakawa Hisashi、Nakagawa Takayuki、Nagayasu Kazuki、Yamanaka Akihiro、Kaneko Shuji
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 6 Pages: 2160-2160
  • DOI: 10.3390/ijms21062160
  • NAID: 120006826701
  • Peer Reviewed / Open Access
• [Presentation] セロトニン神経による情動制御およびストレス適応とその神経機序 (2023)
  • Author(s): 永安 一樹
  • Organizer: 第64回日本神経病理学会総会学術研究会 /第66回日本神経化学会大会 合同大会
  • Invited
• [Presentation] 縫線核セロトニン神経による抗うつ効果・情動制御の神経機構 (2023)
  • Author(s): 永安 一樹
  • Organizer: 第53回神経精神薬理学会年会
  • Invited
• [Presentation] 光遺伝学と幹細胞技術を用いたうつ・Perry病の神経・分子機序解明 (2023)
  • Author(s): 永安 一樹
  • Organizer: 第53回神経精神薬理学会年会
  • Invited
• [Remarks] 研究室HP
  • URL: https://molpharm.pharm.kyoto-u.ac.jp/
• [Remarks] 研究室ホームページ
  • URL: https://molpharm.pharm.kyoto-u.ac.jp/molpharm/
• [Remarks] 不快感を誘発するセロトニン神経を発見
  • URL: https://www.kyoto-u.ac.jp/ja/research-news/2022-12-23-0
• [Remarks] セロトニン神経による海馬神経アンサンブル制御
  • URL: https://www.kyoto-u.ac.jp/ja/research-news/2023-02-28-1
• [Remarks] 研究室HP
  • URL: https://www.pharm.kyoto-u.ac.jp/channel/