Interrogation of the spatiotemporal integration of dopaminergic signaling in striatal medium spiny neurons

• Project/Area Number: 20H03349
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• Research Institution: Niigata University
• Principal Investigator: Uchigashima Motokazu 新潟大学, 脳研究所, 准教授 (10614662)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2022: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2021: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2020: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: ドーパミン / 線条体 / グルタミン酸 / スパイン / ゲノム編集 / 分子標識 / 中型有棘ニューロン / 遺伝子組み換え / イメージング / シナプス

Outline of Research at the Start

動物やヒトはどのような感覚情報や行動が報酬に結びつくのかを学習する(報酬学習)。 線条体ニューロンは感覚・運動情報をコードした大脳皮質からのグルタミン酸入力と報酬情報をコードした中脳からのドーパミン入力を受けるため、両者のシグナル統合が報酬学習の細胞基盤と想定されている。しかし、この統合が時空間的にどのように行われているのかは十分わかっていない。本研究は、ドーパミン伝達を可視化・操作する技術の開発を通じて、ドーパミンとグルタミン酸の細胞内シグナル統合過程の時空間選択性の理解を目指す。

Outline of Final Research Achievements

Dopaminergic transmission is essential for our normal brain function, and its dysfunction causes many brain disorders such as Parkinson's disease and schizophrenia. However, our current knowledge is not sufficient about where dopamine is released from and what it targets to, and how it functions on its target cells. To address these questions, we newly developed a genome editing-based platform to visualize molecularly-defined dopamine release sites and simultaneously introduce Cre recombinase for neuronal labeling or manipulation in the same neurons in mammalian brains.

Academic Significance and Societal Importance of the Research Achievements

本研究にて確立した新たな技術は、中脳ドーパミンニューロンへの応用を通じて、これまで不十分であった脳組織中におけるドーパミン伝達の多元的かつ高精度な理解が可能となる。この結果、正常な脳の機能する仕組みの理解が深まるだけでなく、多数の罹患者が存在する多様な脳機能疾患におけるドーパミン伝達異常の高精度な理解が可能となることで、そこから生み出される新たな治療アプローチの創出にも結びつくと期待できる。

Research Products

• [Int'l Joint Research] マサチューセッツ州立大学医学部(米国)
• [Int'l Joint Research] マサチューセッツ州立大学医学部(米国)
• [Int'l Joint Research] マサチューセッツ大学医学部(米国)
• [Journal Article] General Design Strategy to Precisely Control the Emission of Fluorophores via a Twisted Intramolecular Charge Transfer (TICT) Process (2022)
  • Author(s): Hanaoka Kenjiro、Iwaki Shimpei、Yagi Kiyoshi、Myochin Takuya、Ikeno Takayuki、Ohno Hisashi、Sasaki Eita、Komatsu Toru、Ueno Tasuku、Uchigashima Motokazu、Mikuni Takayasu、Tainaka Kazuki、Tahara Shinya、Takeuchi Satoshi、Tahara Tahei、Uchiyama Masanobu、Nagano Tetsuo、Urano Yasuteru
  • Journal Title: Journal of the American Chemical Society Volume: 144 Issue: 43 Pages: 19778-19790
  • DOI: 10.1021/jacs.2c06397
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neuroligin-3: A Circuit-Specific Synapse Organizer That Shapes Normal Function and Autism Spectrum Disorder-Associated Dysfunction (2021)
  • Author(s): Uchigashima Motokazu、Cheung Amy、Futai Kensuke
  • Journal Title: Frontiers in Molecular Neuroscience Volume: 14 Pages: 749164-749164
  • DOI: 10.3389/fnmol.2021.749164
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Specific Neuroligin3?αNeurexin1 signaling regulates GABAergic synaptic function in mouse hippocampus (2020)
  • Author(s): Uchigashima Motokazu、Konno Kohtarou、Demchak Emily、Cheung Amy、Watanabe Takuya、Keener David G、Abe Manabu、Le Timmy、Sakimura Kenji、Sasaoka Toshikuni、Uemura Takeshi、Imamura Kawasawa Yuka、Watanabe Masahiko、Futai Kensuke
  • Journal Title: eLife Volume: 9
  • DOI: 10.7554/elife.59545
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced Retrieval of Taste Associative Memory by Chemogenetic Activation of Locus Coeruleus Norepinephrine Neurons (2020)
  • Author(s): Fukabori R, Iguchi Y, Kato S, Takahashi K, Eifuku S, Tsuji S, Hazama A, Uchigashima M, Watanabe M, Mizuma H, Cui Y, Onoe H, Hikishima K, Yasoshima Y, Osanai M, Inagaki R, Fukunaga K, Nishijo T, Momiyama T, Benton R, & Kobayashi K
  • Journal Title: The Journal of Neuroscience Volume: 40 Issue: 43 Pages: 8367-8385
  • DOI: 10.1523/jneurosci.1720-20.2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroligin3 splice isoforms shape inhibitory synaptic function in the mouse hippocampus (2020)
  • Author(s): Uchigashima Motokazu、Leung Ming、Watanabe Takuya、Cheung Amy、Le Timmy、Pallat Sabine、Dinis Alexandre Luis Marques、Watanabe Masahiko、Kawasawa Yuka Imamura、Futai Kensuke
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 25 Pages: 8589-8595
  • DOI: 10.1074/jbc.ac120.012571
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methodological approaches to understand the molecular mechanism of structural plasticity of dendritic spines (2020)
  • Author(s): Mikuni Takayasu、Uchigashima Motokazu
  • Journal Title: European Journal of Neuroscience Volume: in press Issue: 8 Pages: 6902-6911
  • DOI: 10.1111/ejn.14734
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Development of Single-Cell, Spatiotemporal, Quantitative Imaging Method for Endogenous Proteins in Mammalian Brains (2023)
  • Author(s): Motokazu Uchigashima, Risa Iguchi, Kazuma Fujii, Pratik Kumar, Manabu Abe, Motohiro Nozumi, Michihiro Igarashi, Kenji Sakimura, Ryoma Bise, Luke D Lavis, and Takayasu Mikuni
  • Organizer: 第128回日本解剖学会総会・全国学術集会
• [Presentation] Quantitative, Spatiotemporal Profiling of Endogenous Proteins in Mammalian Brain Tissues via CRISPR/Cas9-Based Knock-in of Chemical Tags (2022)
  • Author(s): Motokazu Uchigashima, Risa Iguchi, Xinyi Liu, Kazuma Fujii, Manabu Abe, Kenji Sakimura, Ryoma Bise, Takayasu Mikuni
  • Organizer: NEURO2022
• [Presentation] SeeThrough - live neuronal imaging through cleared skull in mammalian brain (2022)
  • Author(s): Xinyi Liu, Motokazu Uchigashima, Manabu Abe, Kenji Sakimura, Kazuki Tainaka, Takayasu Mikuni
  • Organizer: 第11回 生理研‐霊長研‐脳研 合同シンポジウム
• [Presentation] シナプス構成タンパク質をハイスループットに可視化するための技術開発 (2021)
  • Author(s): 内ヶ島基政
  • Organizer: 第759回新潟医学会例会
  • Invited
• [Presentation] Specific Neuroligin3-αNeurexin1 Trans-synaptic Interaction Regulates GABAergic Synaptic Function in an Input Cell Type-Dependent Manner (2021)
  • Author(s): Uchigashima Motokazu、Konno Kohtarou、Demchak Emily、Cheung Amy、Watanabe Takuya、Keener David G、Abe Manabu、Le Timmy、Sakimura Kenji、Sasaoka Toshikuni、Uemura Takeshi、Imamura Kawasawa Yuka、Watanabe Masahiko、Futai Kensuke
  • Organizer: 第126回 日本解剖学会総会・全国学術集会