Identification of antidepressive serotonin projection as a possible target of cell transplantation therapy

• Project/Area Number: 18K14919
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• 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): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: セロトニン / 抗うつ薬 / 光遺伝学 / うつ病 / ウイルスベクター / 幹細胞

Outline of Final Research Achievements

Major depression and anxiety disorders are a social and economic burden worldwide. Serotonergic signaling has been implicated in the pathophysiology of these disorders and thus has been a crucial target for pharmacotherapy. However, the precise mechanisms underlying these disorders are still unclear. Here, we used species-optimized lentiviral and adeno-associated viral vectors, capable of efficient and specific transduction of serotonergic neurons in mice and rats for elucidation of serotonergic roles in anxiety-like behaviors and active coping behavior in both species. By using these vectors, we found that activation of dorsal raphe serotonin neurons elicited rapid antidepressant-like effect in mice and rat and that activation of VTA-projecting dorsal raphe serotonin neurons induced strong reward-like effect.

Academic Significance and Societal Importance of the Research Achievements

セロトニン神経自体も、その受容体であるセロトニン受容体も、脳全体に広く投射、分布していることから、セロトニン神経全体の活性化や、脳全体のセロトニン受容体の刺激/阻害のみでは、副作用なく抗うつ作用のみを引き起こすことは困難である。本研究により、各セロトニン神経投射の個別の機能解析が可能となり、報酬効果に関わる投射の同定に至ったことから、今後同様の解析を継続することで、副作用なく抗うつ作用のみを引き起こす医薬品の開発に資する知見を得ることができると考えられる。

Research Products

• [Int'l Joint Research] ブリストル大学(英国)
• [Int'l Joint Research] University of Bristol(英国)
• [Int'l Joint Research] The Institute of Cytology and Genetics(ロシア連邦)
• [Journal Article] Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes. (2020)
  • Author(s): Matsumura K, (33名中略）, Hashimoto R, (37名中35番目）,Hashimoto H, Nakazawa T.
  • Journal Title: Nat. Commun Volume: 11(1) Issue: 1 Pages: 859-859
  • DOI: 10.1038/s41467-020-14697-z
  • Peer Reviewed / Open Access
• [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
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide modulates dendritic spine maturation and morphogenesis via microRNA-132 upregulation. (2019)
  • Author(s): Hayata-Takano A, Kamo T, Kijima H, Seiriki K, Ogata K, Ago Y, Nakazawa T, Shintani Y, Higashino K, Nagayasu K, Shintani N, Kasai A, Waschek JA, Hashimoto H.
  • Journal Title: J Neurosci. Volume: 印刷中 Issue: 22 Pages: 4208-4220
  • DOI: 10.1523/jneurosci.2468-18.2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glutamatergic neurons in the medial prefrontal cortex mediate the formation and retrieval of cocaine-associated memories in mice (2019)
  • Author(s): Zhang Tong、Yanagida Junko、Kamii Hironori、Wada Shintaro、Domoto Masaki、Sasase Hitoki、Deyama Satoshi、Takarada Takeshi、Hinoi Eiichi、Sakimura Kenji、Yamanaka Akihiro、Maejima Takashi、Mieda Michihiro、Sakurai Takeshi、Nishitani Naoya、Nagayasu Kazuki、Kaneko Shuji、Minami Masabumi、Kaneda Katsuyuki
  • Journal Title: Addiction Biology Volume: 印刷中 Issue: 1 Pages: 1-11
  • DOI: 10.1111/adb.12723
  • Peer Reviewed / Open Access
• [Journal Article] Depletion of microglia ameliorates white matter injury and cognitive impairment in a mouse chronic cerebral hypoperfusion model (2019)
  • Author(s): Kakae Masashi、Tobori Shota、Morishima Misa、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 514 Issue: 4 Pages: 1040-1044
  • DOI: 10.1016/j.bbrc.2019.05.055
  • NAID: 120006636645
  • Peer Reviewed
• [Journal Article] The biological basis and application of lentiviral vector and adeno-associated viral vector in pharmacological research (2019)
  • Author(s): Nagayasu Kazuki
  • Journal Title: Folia Pharmacologica Japonica Volume: 153 Issue: 5 Pages: 204-209
  • DOI: 10.1254/fpj.153.204
  • NAID: 130007649359
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] Pathophysiological role of TRPM2 in age-related cognitive impairment in mice. (2019)
  • Author(s): Kakae M, Miyanohara J, Morishima M, Nagayasu K, Mori Y, Shirakawa H, Kaneko S.
  • Journal Title: Neuroscience Volume: 408 Pages: 204-213
  • DOI: 10.1016/j.neuroscience.2019.04.012
  • NAID: 120006630990
  • Peer Reviewed
• [Journal Article] CRISPR/Cas9-mediated in vivo gene editing reveals that neuronal 5-HT1A receptors in the dorsal raphe nucleus contribute to body temperature regulation in mice (2019)
  • Author(s): Nishitani Naoya、Ohmura Yu、Nagayasu Kazuki、Shibui Norihiro、Kaneko Shuji、Ohashi Akiko、Yoshida Takayuki、Yamanaka Akihiro、Yoshioka Mitsuhiro
  • Journal Title: Brain Research Volume: 1719 Pages: 243-252
  • DOI: 10.1016/j.brainres.2019.06.009
  • NAID: 120006885155
  • Peer Reviewed
• [Journal Article] Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome. (2019)
  • Author(s): Baba M, Yokoyama K, Seiriki K, Naka Y, Matsumura K, Kondo M, Yamamoto K, Hayashida M, Kasai A, Ago Y, Nagayasu K, Hayata-Takano A, Takahashi A, Yamaguchi S, Mori D, Ozaki N, Yamamoto T, Takuma K, Hashimoto R, Hashimoto H, Nakazawa T.
  • Journal Title: Neuropsychopharmacology Volume: 44(12) Issue: 12 Pages: 2125-2135
  • DOI: 10.1038/s41386-019-0441-5
  • NAID: 130007811380
  • Peer Reviewed / Open Access
• [Journal Article] Identification of neuron-type specific promoters in monkey genome and their functional validation in mice. (2019)
  • Author(s): Nagai Y; Nishitani N; Yasuda M; Ueda Y; Fukui Y; Andoh C; Shirakawa H; Nakagawa T; Inoue K; Nagayasu K; Kasparov S; Nakamura K; Kaneko S
  • Journal Title: Biochem Biophys Res Commun. Volume: 518 Issue: 4 Pages: 619-624
  • DOI: 10.1016/j.bbrc.2019.08.101
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autism-associated protein kinase D2 regulates embryonic cortical neuron development. (2019)
  • Author(s): Matsumura K, Baba M, Nagayasu K, Yamamoto K, Kondo M, Kitagawa K, Takemoto T, Seiriki K, Kasai A, Ago Y, Hayata-Takano A, Shintani N, Kuriu T, Iguchi T, Sato M, Takuma K, Hashimoto R, Hashimoto H.
  • Journal Title: Biochem Biophys Res Commun Volume: 519(3) Issue: 3 Pages: 626-632
  • DOI: 10.1016/j.bbrc.2019.09.048
  • Peer Reviewed / Open Access
• [Journal Article] An Adenosine A2A Receptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis. (2019)
  • Author(s): Asaoka N, Nishitani N, Kinoshita H, Nagai Y, Hatakama H, Nagayasu K, Shirakawa H, Nakagawa T, Kaneko S
  • Journal Title: eNeuro Volume: 6 Issue: 1 Pages: ENEURO.0366-18.2019
  • DOI: 10.1523/eneuro.0366-18.2019
  • Peer Reviewed / Open Access
• [Journal Article] TRPM2 confers susceptibility to social stress but is essential for behavioral flexibility. (2019)
  • Author(s): Andoh C, Nishitani N, Hashimoto E, Nagai Y, Takao K, Miyakawa T, Nakagawa T, Mori Y, Nagayasu K, Shirakawa H, Kaneko S.
  • Journal Title: Brain Res. Volume: 1704 Pages: 68-77
  • DOI: 10.1016/j.brainres.2018.09.031
  • NAID: 120006630995
  • Peer Reviewed
• [Journal Article] Manipulation of dorsal raphe serotonergic neurons modulates active coping to inescapable stress and anxiety-related behaviors in mice and rats. (2018)
  • Author(s): Nishitani N, Nagayasu K, Asaoka N, Yamashiro M, Andoh C, Nagai Y, Kinoshita H, Kawai H, Shibui N, Liu B, Hewinson J, Shirakawa H, Nakagawa T, Hashimoto H, Kasparov S, Kaneko S.
  • Journal Title: Neuropsychopharmacology Volume: 44 Issue: 4 Pages: 721-732
  • DOI: 10.1038/s41386-018-0254-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The impact of mouse strain-specific spatial and temporal immune responses on the progression of neuropathic pain. (2018)
  • Author(s): Isami K, Imai S, Sukeishi A, Nagayasu K, Shirakawa H, Nakagawa T, Kaneko S.
  • Journal Title: Brain Behav Immun. Volume: 74 Pages: 121-132
  • DOI: 10.1016/j.bbi.2018.08.013
  • Peer Reviewed
• [Journal Article] TRPM2 Exacerbates Central Nervous System Inflammation in Experimental Autoimmune Encephalomyelitis by Increasing Production of CXCL2 Chemokines. (2018)
  • Author(s): Tsutsui M, Hirase R, Miyamura S, Nagayasu K, Nakagawa T, Mori Y, Shirakawa H, Kaneko S.
  • Journal Title: J Neurosci. Volume: 38 Issue: 39 Pages: 8484-8495
  • DOI: 10.1523/jneurosci.2203-17.2018
  • NAID: 120006630992
  • Peer Reviewed / Open Access
• [Presentation] Prediction of pharmacological activities from chemical structures with graph convolutional neural network (2019)
  • Author(s): Miyuki Sakai, Kazuki Nagayasu, Shuji Kaneko
  • Organizer: CBI学会
• [Presentation] 情動行動におけるセロトニン神経の役割 (2019)
  • Author(s): 永安 一樹、西谷 直也、金子 周司
  • Organizer: 日本神経精神薬理学会年会
  • Invited
• [Presentation] 抗うつ作用に関わる神経回路/分子機構の解析 (2019)
  • Author(s): 永安 一樹、金子 周司
  • Organizer: 生体機能と創薬シンポジウム2019
• [Presentation] The role of serotonin in emotion and decision making (2019)
  • Author(s): Kazuki Nagayasu, Shuji Kaneko
  • Organizer: The 92nd Annual Meeting of the JPS
  • Invited
• [Presentation] セロトニン神経伝達の亢進が悲観的な意思決定に及ぼす影響 (2018)
  • Author(s): 安藤千紘、西谷直也、澁井紀宏、永安一樹、白川久志、金子周司
  • Organizer: 第68回日本薬学会近畿支部総会大会
• [Presentation] A1 型活性化アストロサイトにおけるサイトカイン産生メカニズムの解析 (2018)
  • Author(s): 藤田沙也香、永安一樹、白川久志、金子周司
  • Organizer: 第68回日本薬学会近畿支部総会大会
• [Presentation] マウス多発性硬化症モデルにおけるTRPC3/6 の役割 (2018)
  • Author(s): 宮村咲映、永安一樹、白川久志、金子周司
  • Organizer: 第68回日本薬学会近畿支部総会大会
• [Presentation] ミクログリアにおけるTRPV4 刺激によるIL-10 産生メカニズムの解析 (2018)
  • Author(s): 桒田沙織、富澤恵里、三宅祟仁、永安一樹、白川久志、金子周司
  • Organizer: 第68回日本薬学会近畿支部総会大会
• [Presentation] オリゴデンドロサイト前駆細胞におけるTRPV4開口は増殖を促進する (2018)
  • Author(s): 大橋佳奈、出屋敷綾音、三宅崇仁、永安一樹、柴崎貢志、白川久志、金子周司
  • Organizer: 第133回日本薬理学会近畿部会
• [Presentation] Neurotropin inhibits neuronal activity through potentiation of sustained Kv currents in primary cultured DRG neurons (2018)
  • Author(s): Hiroyuki Kawai, Nozomi Asaoka, Takahito Miyake, Kazuki Nagayasu, Takayuki Nakagawa, Hisashi Shirakawa, Shuji Kaneko
  • Organizer: 18th World Congress of basic and clinical pharmacology
  • Int'l Joint Research
• [Remarks] 研究室ホームページ
  • URL: http://www.pharm.kyoto-u.ac.jp/channel/