Development of simultaneous visualization technology for neurotransmitters and its application to psychiatry disease research

• Project/Area Number: 16H06145
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Keio University
• Principal Investigator: SUGIURA Yuki 慶應義塾大学, 医学部(信濃町), 講師 (30590202)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥27,040,000 (Direct Cost: ¥20,800,000、Indirect Cost: ¥6,240,000); Fiscal Year 2019: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2018: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: イメージング質量分析 / 神経伝達物質 / モノアミン / マイクロダイアリシス / イメーシング質量分析 / イメージング質量 / うつ病モデル

Outline of Final Research Achievements

Until now, there is no available molecular imaging technique which is capable of direct visualizations of neurotransmitters and their metabolism. In this research, we developed a highly sensitive mass spectrometry imaging technique that simultaneously and quantitatively visualizes neurotransmitters including monoamines. Furthermore, we have established a method for monitoring the released transmitters in behaving animals by combining microdialysis and mass spectrometry based metabolomics.
By applying these techniques, we generated a three-dimensional monoamine atlas by whole brain monoamine mapping. Moreover, the mechanism of abnormal brain monoamine reduction triggered by immune activation was elucidated. Finally, visualization of the dynamic fluctuation of dopamine in the nucleus accumbens in response to pain stimulation was achieved.

Academic Significance and Societal Importance of the Research Achievements

一連の技術開発により、感情や行動の調節を担うモノアミン量（セロトニン、ドーパミン、ノルエピネフリン）をイメージングする事が可能になった。公開したモノアミンの全脳地図からは、複数のモノアミン集積核が新たに同定された。なかでも恐怖、不安といった情動調節に深く関わる『視床室傍核』と呼ばれる神経核に、セロトニンとノルエピネフリンが極めて多く集積することが明らかになった。さらに視床室傍核のセロトニンは動的に変動し、行動異常を呈す疾患モデルマウスでは大きく減少していた。本研究で発見された視床室傍核を含む新しいセロトニン神経回路は、精神疾患に対する新規治療薬開発のための新しい創薬標的となることが期待される。

Research Products

• [Int'l Joint Research] Uppsala university(スウェーデン)
• [Int'l Joint Research] Uppsala university(スウェーデン)
• [Int'l Joint Research] Uppsala University(スウェーデン)
• [Journal Article] Quantitative MALDI-MS/MS assay for serum cortisol through charged derivatization (2020)
  • Author(s): Nakamura Masahiro、Moritsuna Marina、Yuda Keita、Fujimura Shunsuke、Sugiura Yuki、Shimma Shuichi、Nishimoto Koshiro、Nishikawa Tetsuo、Suematsu Makoto、Ogawa Shoujiro、Higashi Tatsuya
  • Journal Title: Journal of Pharmaceutical and Biomedical Analysis Volume: 178 Pages: 112912-112912
  • DOI: 10.1016/j.jpba.2019.112912
  • Peer Reviewed
• [Journal Article] In situ imaging of monoamine localization and dynamics (2020)
  • Author(s): Sugiyama Eiji、Skelly Ashwin N.、Suematsu Makoto、Sugiura Yuki
  • Journal Title: Pharmacology & Therapeutics Volume: 208 Pages: 107478-107478
  • DOI: 10.1016/j.pharmthera.2020.107478
  • Peer Reviewed / Open Access
• [Journal Article] Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging (2019)
  • Author(s): Sugiyama Eiji、Guerrini Matteo M.、Honda Kurara、Hattori Yuko、Abe Manabu、K?llback Patrik、Andr?n Per E.、Tanaka Kenji F.、Setou Mitsutoshi、Fagarasan Sidonia、Suematsu Makoto、Sugiura Yuki
  • Journal Title: iScience Volume: 20 Pages: 359-372
  • DOI: 10.1016/j.isci.2019.09.036
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mechanical allodynia induced by optogenetic sensory nerve excitation activates dopamine signaling and metabolism in medial nucleus accumbens. (2019)
  • Author(s): Sugiyama E, Kondo T, Kuzumaki N, Honda K, Yamanaka A, Narita M, Suematsu M, Sugiura Y.
  • Journal Title: Neurochem Int Volume: 129 Pages: 104494-104494
  • DOI: 10.1016/j.neuint.2019.104494
  • Peer Reviewed / Open Access
• [Journal Article] Tandem Mass Spectrometry Imaging Reveals Distinct Accumulation Patterns of Steroid Structural Isomers in Human Adrenal Glands (2019)
  • Author(s): Takeo Emi, Sugiura Yuki, Uemura Tatsuki, Nishimoto Koshiro, Yasuda Masanori, Sugiyama Eiji, Ohtsuki Sumio, Higashi Tatsuya, Nishikawa Tetsuo, Suematsu Makoto, Fukusaki Eiichiro, Shimma Shuichi
  • Journal Title: Analytical Chemistry Volume: 91 Issue: 14 Pages: 8918-8925
  • DOI: 10.1021/acs.analchem.9b00619
  • Peer Reviewed / Open Access
• [Journal Article] A thin layer of sucrose octasulfate protects the oesophageal mucosal epithelium in reflux oesophagitis (2019)
  • Author(s): Hayakawa T, Kawasaki S, Hirayama Y, Tsutsui T, Sugiyama E, Adachi K, Kon R, Suematsu M, Sugiura Y.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 3559-3559
  • DOI: 10.1038/s41598-019-39087-4
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemistry for aldosterone synthase CYP11B2 and matrix-assisted laser desorption ionization imaging mass spectrometry for in-situ aldosterone detection (2019)
  • Author(s): Zhang Zhen、Sugiura Yuki、Mune Tomoatsu、Nishiyama Mitsuru、Terada Yoshio、Mukai Kuniaki、Nishimoto Koshiro
  • Journal Title: Current Opinion in Nephrology and Hypertension Volume: 28 Issue: 2 Pages: 105-112
  • DOI: 10.1097/mnh.0000000000000487
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aldosterone and 18-oxocortisol coaccumulation in aldosterone-producing lesions (2018)
  • Author(s): Sugiura Yuki, Takeo Emi, Shimma Shuichi, Yokota Mai, Higashi Tatsuya, Seki Tsugio, Mizuno Yosuke, Oya Mototsugu Kosaka Takeo, Omura Masao, Nishikawa Tetsuo, Suematsu Makoto, Nishimoto Koshiro
  • Journal Title: Hypertension Volume: 72 Issue: 6 Pages: 1345-1354
  • DOI: 10.1161/hypertensionaha.118.11243
  • Peer Reviewed / Open Access
• [Journal Article] Optogenetic astrocyte activation evokes BOLD fMRI response with oxygen consumption without neuronal activity modulation (2018)
  • Author(s): Norio Takata, Yuki Sugiura, Keitaro Yoshida, Miwako Koizumi, Hiroshi Nishida, Kurara Honda, Ryutaro Yano, Yuji Komaki, Ko Matsui, Makoto Suematsu , Masaru Mimura, Hideyuki Okano, Kenji F. Tanaka
  • Journal Title: Glia Volume: 印刷中 Issue: 9 Pages: 2013-2023
  • DOI: 10.1002/glia.23454
  • Peer Reviewed
• [Journal Article] Extracellular N-acetylaspartylglutamate released in the nucleus accumbens modulates the pain sensation: Analysis using a microdialysis/mass spectrometry integrated system (2018)
  • Author(s): Watanabe M, Sugiura Y, Sugiyama E, Narita M, Navratilova E, Kondo T, Uchiyama N, Yamanaka A, Kuzumaki N, Porreca F, Narita M
  • Journal Title: Molecular Pain Volume: 14 Pages: 1-10
  • DOI: 10.1177/1744806918754934
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior (2017)
  • Author(s): Miyajima M、Zhang B、Sugiura Y、Sonomura K、Guerrini MM、Tsutsui Y、Maruya M、Vogelzang A、Chamoto K、Honda K、Hikida T、Ito S、Qin H、Sanuki R、Suzuki K、Furukawa T、Ishihama Y、Matsuda F、Suematsu M、Honjo T、Fagarasan S
  • Journal Title: Nature Immunology Volume: 18 Issue: 12 Pages: 1342-1352
  • DOI: 10.1038/ni.3867
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Arl8b is required for lysosomal degradation of maternal proteins in the visceral yolk sac endoderm of mouse embryos (2017)
  • Author(s): Oka M, Hashimoto K, Yamaguchi Y, Saitoh SI, Sugiura Y, Motoi Y, Honda K, Kikko Y, Ohata S, Suematsu M, Miura M, Miyake K, Katada T and Kontani K
  • Journal Title: J Cell Sci Volume: 130 Issue: 20 Pages: 3568-3577
  • DOI: 10.1242/jcs.200519
  • Peer Reviewed / Open Access
• [Journal Article] Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling (2017)
  • Author(s): Tai-Nagara Ikue、Yoshikawa Yusuke、Numata Naoko、Ando Tomofumi、Okabe Keisuke、Sugiura Yuki、Ieda Masaki、Takakura Nobuyuki、Nakagawa Osamu、Zhou Bin、Okabayashi Koji、Suematsu Makoto、Kitagawa Yuko、Bastmeyer Martin、Sato Kohji、Klein R?diger、Navankasattusas Sutip、Li Dean Y.、Yamagishi Satoru、Kubota Yoshiaki
  • Journal Title: Development Volume: 144 Pages: 2392-2401
  • DOI: 10.1242/dev.149757
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Decreased 16:0/20:4-phosphatidylinositol level in the post-mortem prefrontal cortex of elderly patients with schizophrenia. (2017)
  • Author(s): Matsumoto J, Nakanishi H, Kunii Y, Sugiura Y, Yuki D, Wada A, Hino M, Niwa SI, Kondo T, Waki M, Hayasaka T, Masaki N, Akatsu H, Hashizume Y, Yamamoto S, Sato S, Sasaki T, Setou M, Yabe H.
  • Journal Title: Sci Rep. Volume: 7 Issue: 7 Pages: 45050-45050
  • DOI: 10.1038/srep45050
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching (2017)
  • Author(s): Miyazawa, H., Yamaguchi, Y., Sugiura, Y., Honda, K., Kondo, K., Matsuda, F., Yamamoto, T., Suematsu, M., and Miura, M
  • Journal Title: Development Volume: 144 Issue: 1 Pages: 63-73
  • DOI: 10.1242/dev.138545
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Visualization of in vivo metabolic flows reveals accelerated utilization of glucose and lactate in penumbra of ischemic heart (2017)
  • Author(s): Yuki Sugiura, Yoshinori Katsumata, Motoaki Sano, Kurara Honda, Mayumi Kajimura, Keiichi Fukuda, Makoto Suematsu
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 32361-32361
  • DOI: 10.1038/srep32361
  • Peer Reviewed / Open Access
• [Journal Article] HIF-1alpha-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity (2016)
  • Author(s): Semba, H., Takeda, N., Isagawa, T., Sugiura, Y., Honda, K., Wake, M., Miyazawa, H., Yamaguchi, Y., Miura, M., Jenkins, DM., Choi, H., Kim, JW., Asagiri, M., Cowburn, AS., Abe, H., Soma, K., Koyama, K., Katoh, M., Sayama, K., Goda, N., Johnson, RS., Manabe, I., Nagai, R., Komuro, I.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 11635-11635
  • DOI: 10.1038/ncomms11635
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance. (2016)
  • Author(s): Kabe Y, Nakane T, Koike I, Yamamoto T, Sugiura Y, Harada E, Sugase K, Shimamura T, Ohmura M, Muraoka K, Yamamoto A, Uchida T, Iwata S, Yamaguchi Y, Krayukhina E, Noda M, Handa H, Ishimori K, Uchiyama S, Kobayashi T, Suematsu M.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 11030-11030
  • DOI: 10.1038/ncomms11030
  • NAID: 130007529314
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 原発性アルドステロン症患者副腎におけるステロイド産生動態イメージング (2019)
  • Author(s): 杉浦 悠毅
  • Organizer: 第84回 日本泌尿器科学会東部総会
  • Invited
• [Presentation] 酸素添加により生成される生理活性分子の局在イメージング (2019)
  • Author(s): 杉浦 悠毅
  • Organizer: 第32回 バイオメディカル分析科学シンポジウム
• [Presentation] Visualization of oxygenase producing bioactive molecules by mass spectrometry imaging (2019)
  • Author(s): Yuki Sugiura
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] 酸素添加により生成される生理活性分子の、質量分析による可視化 (2019)
  • Author(s): 杉浦 悠毅
  • Organizer: 第40回日本炎症・再生医学会
  • Invited
• [Presentation] 酸素添加により生成される生理活性分子の、質量分析による可視化 (2019)
  • Author(s): 杉浦 悠毅
  • Organizer: 第14回日本分子イメージング学会
• [Presentation] Visualization of immune-brain metabolic competition between brain and lymph-nodes by mass spectrometry imaging (2018)
  • Author(s): Yuki Sugiura
  • Organizer: the 47th Annual Meeting of the Japanese Society for Immunology
  • Int'l Joint Research / Invited
• [Presentation] Application of imaging mass spectrometry for visualizing immune metabolism in tissues (2018)
  • Author(s): Yuki Sugiura
  • Organizer: RIKEN IMS-JSI International Symposium on Immunology
  • Int'l Joint Research / Invited
• [Presentation] Monoamine mapping by mass spectrometry identified novel serotonin-rich brain nucleus associating with behavioral changes (2018)
  • Author(s): Yuki Sugiura
  • Organizer: 66th ASMS Conference on Mass Spectrometry and Allied Topics
  • Int'l Joint Research
• [Presentation] Development of an Imaging Mass Spectrometry Technique for Visualizing Localized Cellular Signaling Mediators in Tissues (2017)
  • Author(s): Yuki Sugiura
  • Organizer: SISS-19
  • Int'l Joint Research
• [Presentation] イオンクロマトグラフィーを用いた、質量分析とマイクロダイアリシスの統合 (2017)
  • Author(s): 杉浦 悠毅
  • Organizer: 第42回医用マススペクトル学会年会
• [Presentation] 神経伝達物質代謝のリアルタイム解析 (2017)
  • Author(s): 杉浦 悠毅
  • Organizer: 第30回バイオメディ カル分析科学シンポジウム（BMAS2017）
• [Presentation] 質量分析による行動する動物からの代謝計測 (2017)
  • Author(s): 杉浦 悠毅
  • Organizer: 第一回慶應ライフサイエンスシンポジウム
• [Presentation] Time resolved analysis of brain energy metabolism by micro-dialysis linked ion chromatography-mass spectrometry (2016)
  • Author(s): Yuki Sugiura
  • Organizer: the 16th Annual Conference for American Society for Mass Spectrometry
  • Place of Presentation: San Antonio, USA
  • Year and Date: 2016-06-06
  • Int'l Joint Research
• [Presentation] Highly sensitive Imaging Mass Spectrometry (2016)
  • Author(s): Yuki Sugiura
  • Organizer: the 9th international conference on the Biology, Chemistry, and Therapeutic Appications of Nitric Oxide
  • Place of Presentation: Sendai, Japan
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Book] Chronic Inflammation (2016)
  • Author(s): Yuki Sugiura, Kurara Honda, Makoto Suematsu
  • Publisher: Springer Japan