線条体におけるカルシウム振動の描出と生理学的意義の解明

• Project Area: Non-linear Neuro-oscillology: Towards Integrative Understanding of Human Nature
• Project/Area Number: 16H01621
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Keio University
• Principal Investigator: 田中 謙二 慶應義塾大学, 医学部(信濃町), 准教授 (30329700)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2017: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2016: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 意欲 / 線条体 / 島皮質 / D2 / カルシウム / アパシー

Outline of Annual Research Achievements

意欲行動中に見られる線条体D2-MSNの活動振動がどのような神経入力によって作られるのか調べるために、腹外側線条体D2-MSNの入力先の一つの候補である島皮質の投射神経の活動を調べた。線条体へ投射する島皮質神経軸索の集合カルシウム観察では、トライアル開始時に終末のカルシウム信号が低下すること、線条体D2-MSNはトライアル開始に集合カルシウムが増加することから、島皮質の活動抑制が線条体D2-MSNの興奮をもたらしていることがわかった。この異なる活動を説明するには、両者の間に抑制性の介在神経が存在することが予想される。PV陽性GABA介在神経の集合カルシウム活動を意欲行動中に計測したところ、トライアル開始時に活動が抑制されなかった。このことからPV陽性介在神経以外の介在神経、例えばneuropeptide Y陽性、tyrosine hydroxylase陽性などのGABA介在神経が島皮質-線条体のfeedforward inhibitionを担当していることが示唆された。
更に、ドパミン神経入力が線条体投射神経の集合カルシウム濃度を支配しているか調べた。線条体D1-MSNだけにカルシウムセンサーを発現するマウスを樹立し、意欲行動中の活動を調べた。その結果、線条体D1-MSNは、D2-MSNと同じく、意欲行動の開始時に集合カルシウム濃度が増加した。意欲行動の開始時にドパミン神経からのドパミン放出が起こることが知られている。ドパミンはD1受容体へは活動亢進を、D2受容体へは活動抑制をもたらすので、ドパミン入力が線条体MSNの集合カルシウム濃度を変化させている可能性が低いことがわかった。
以上の結果から、意欲行動中の線条体MSNの活動振動は主に大脳皮質からの入力によって作られることがわかった。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] University of Texas, Austin/University of Pittsburg/University of Miami(米国)
• [Int'l Joint Research] University of Ottawa(Canada)
• [Int'l Joint Research] Universite Libre de Bruxelles(Belgium)
• [Journal Article] A three-dimensional single-cell-resolution whole-brain atlas using CUBIC-X expansion microscopy and tissue clearing (2018)
  • Author(s): Murakami Tatsuya C.、Mano Tomoyuki、Saikawa Shu、Horiguchi Shuhei A.、Shigeta Daichi、Baba Kousuke、Sekiya Hiroshi、Shimizu Yoshihiro、Tanaka Kenji F.、Kiyonari Hiroshi、Iino Masamitsu、Mochizuki Hideki、Tainaka Kazuki、Ueda Hiroki R.
  • Journal Title: Nat Neurosci Volume: 21 Issue: 4 Pages: 627-637
  • DOI: 10.1038/s41593-018-0109-1
  • Peer Reviewed
• [Journal Article] Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics. (2018)
  • Author(s): Chen S, Weitemier AZ, Zeng X, He L, Wang X, Tao Y, Huang AJY, Hashimotodani Y, Kano M, Iwasaki H, Parajuli LK, Okabe S, Teh DBL, All AH, Tsutsui-Kimura I, Tanaka KF, Liu X, McHugh TJ.
  • Journal Title: Science Volume: 359 Issue: 6376 Pages: 679-684
  • DOI: 10.1126/science.aaq1144
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aberrant astrocyte Ca2+ signals “AxCa signals” exacerbate pathological alterations in an Alexander disease model (2018)
  • Author(s): Saito Kozo、Shigetomi Eiji、Yasuda Rei、Sato Ryuichi、Nakano Masakazu、Tashiro Kei、Tanaka Kenji F.、Ikenaka Kazuhiro、Mikoshiba Katsuhiko、Mizuta Ikuko、Yoshida Tomokatsu、Nakagawa Masanori、Mizuno Toshiki、Koizumi Schuichi
  • Journal Title: Glia Volume: 66 Issue: 5 Pages: 1053-1067
  • DOI: 10.1002/glia.23300
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Purinergic Receptor P2Y1 in Spatiotemporal Ca2+ Dynamics in Astrocytes. (2018)
  • Author(s): Shigetomi E, Hirayama YJ, Ikenaka K, Tanaka KF, Koizumi S.
  • Journal Title: The Journal of Neuroscience Volume: 38 Issue: 6 Pages: 1053-1067
  • DOI: 10.1523/jneurosci.2625-17.2017
  • Peer Reviewed / Open Access
• [Journal Article] Maturation of Cerebellar Purkinje Cell Population Activity during Postnatal Refinement of Climbing Fiber Network (2017)
  • Author(s): Good JM, Mahoney M, Miyazaki T, Tanaka KF, Sakimura K, Watanabe M, Kitamura K, Kano M.
  • Journal Title: Cell Rep. Volume: 21 Issue: 8 Pages: 2066
  • DOI: 10.1016/j.celrep.2017.10.101
  • URL: https://pure.teikyo.jp/en/publications/ab9f004b-e71d-4879-a8d4-6f2b187db3f5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior. (2017)
  • Author(s): Vahid-Ansari F, Daigle M, Manzini MC, Tanaka KF, Hen R, Geddes SD, Beique JC, James J, Merali Z, Albert PR.
  • Journal Title: J Neurosci. Volume: 37 Issue: 49 Pages: 11967-11978
  • DOI: 10.1523/jneurosci.1668-17.2017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Time-controllable Nkcc1 knockdown replicates reversible hearing loss in postnatal mice. (2017)
  • Author(s): Watabe T, Xu M, Watanabe M, Nabekura J, Higuchi T, Hori K, Sato MP, Nin F, Hibino H, Ogawa K, Masuda M, Tanaka KF
  • Journal Title: Science Reports Volume: 7 Issue: 1 Pages: 13605-14007
  • DOI: 10.1038/s41598-017-13997-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantitative temporal changes in DTI values coupled with histological properties in cuprizone-induced demyelination and remyelination (2017)
  • Author(s): Ryutaro Yano, Junichi Hata, Yoshifumi Abe, Fumiko Seki, Keitaro Yoshida, Yuji Komaki, Hideyuki Okano, Kenji F. Tanaka
  • Journal Title: Neurochemistry International Volume: 17 Pages: 186-197
  • DOI: 10.1016/j.neuint.2017.10.004
  • Peer Reviewed
• [Journal Article] Hearing Loss Controlled by Optogenetic Stimulation of Nonexcitable Nonglial Cells in the Cochlea of the Inner Ear (2017)
  • Author(s): Sato MP, et al.
  • Journal Title: Frontiers in Molecular Neuroscience Volume: 10 Pages: 300-300
  • DOI: 10.3389/fnmol.2017.00300
  • Peer Reviewed / Open Access
• [Journal Article] Distinct Roles of Ventromedial versus Ventrolateral Striatal Medium Spiny Neurons in Reward-Oriented Behavior. (2017)
  • Author(s): Tsutsui-Kimura I, Natsubori A, Mori M, Kobayashi K, Drew MR, de Kerchove d'Exaerde A, Mimura M, Tanaka KF.
  • Journal Title: Curr Biol Volume: 27 Issue: 19 Pages: 3042-3048
  • DOI: 10.1016/j.cub.2017.08.061
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mitochondrial DNA Double-Strand Breaks in Oligodendrocytes Cause Demyelination, Axonal Injury, and CNS Inflammation. (2017)
  • Author(s): Madsen PM, Pinto M, Patel S, McCarthy S, Gao H, Taherian M, Karmally S, Pereira CV, Dvoriantchikova G, Ivanov D, Tanaka KF, Moraes CT, Brambilla R.
  • Journal Title: J Neurosci. Volume: 37 Issue: 42 Pages: 10185-10199
  • DOI: 10.1523/jneurosci.1378-17.2017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Serotonin hormonally regulates lacrimal gland secretory function via the serotonin type 3a receptor. (2017)
  • Author(s): Imada T, Nakamura S, Hisamura R, Izuta Y, Jin K, Ito M, Kitamura N, Tanaka KF, Mimura M, Shibuya I, Tsubota K.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 6965-6965
  • DOI: 10.1038/s41598-017-06022-4
  • Peer Reviewed / Open Access
• [Journal Article] High-speed and scalable whole-brain imaging in rodents and primates (2017)
  • Author(s): Seiriki K, Kasai A, Hashimoto T, Schulze W, Niu M, Yamaguchi S, Nakazawa T, Inoue K, Uezono S, Takada M, Naka Y, Igarashi H, Tanuma M, Waschek JA, Ago Y, Tanaka KF, Hayata-Takano A, Nagayasu K, Shintani N, Hashimoto R, Kunii Y, Hino M, Matsumoto J, Yabe H, Nagai T, Fujita K, Matsuda T, Takuma K, Baba A, Hashimoto H
  • Journal Title: Neuron Volume: 94 Issue: 6 Pages: 1085-1100
  • DOI: 10.1016/j.neuron.2017.05.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of impaired neuronal migration with cognitive deficits in extremely preterm infants. (2017)
  • Author(s): Kubo, K.I., Deguchi, K., Nagai, T,, Ito, Y., Yoshida, K., Endo, T., Benner, S., Shan, W., Kitazawa, A., Aramaki, M., Ishii, K., Shin, M., Matsunaga, Y., Hayashi, K., Kakeyama, M., Tohyama, C., Tanaka, K.F., Tanaka, K., Takashima, S., Nakayama, M.
  • Journal Title: JCI Insight. Volume: 2 Issue: 10 Pages: 88609-88609
  • DOI: 10.1172/jci.insight.88609
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior. (2017)
  • Author(s): Zike ID, Chohan MO, Kopelman JM, Krasnow EN, Flicker D, Nautiyal KM, Bubser M, Kellendonk C, Jones CK, Stanwood G, Tanaka KF, Moore H, Ahmari SE, Veenstra-VanderWeele J.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114 Issue: 22 Pages: 5719-5724
  • DOI: 10.1073/pnas.1701736114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y1 Receptor Downregulation. (2017)
  • Author(s): Shinozaki Y, Shibata K, Yoshida K, Shigetomi E, Gachet C, Ikenaka K, Tanaka KF, Koizumi S.
  • Journal Title: Cell Rep Volume: 19 Issue: 6 Pages: 1151-1164
  • DOI: 10.1016/j.celrep.2017.04.047
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A New Paradigm for Evaluating Avoidance/Escape Motivation. (2017)
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  • Journal Title: Int J Neuropsychopharmacol. Volume: 20 Issue: 7 Pages: 593-601
  • DOI: 10.1093/ijnp/pyx031
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• [Journal Article] The balance between Cathepsin C and Cystatin F controls remyelination in the brain of Plp1-overexpressing mouse, a chronic demyelinating disease model. (2017)
  • Author(s): Shimizu T, Wisessmith W, Li J, Abe M, Sakimura K, Chetsawang B, Sahara Y, Tohyama K, Tanaka KF, Ikenaka K
  • Journal Title: Glia Volume: in press Issue: 6 Pages: 917-930
  • DOI: 10.1002/glia.23134
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ventrolateral striatal medium spiny neurons positively regulate food-incentive, goal-directed behavior independently of D1 and D2 selectivity. (2017)
  • Author(s): Akiyo Natsubori, Iku Tsustui-Kimura, Hiroshi Nishida, Youcef Bouchekioua, Hiroshi Sekiya, Motokazu Uchigashima, Masahiko Watanabe, Alban de Kerchove d'Exaerde, Masaru Mimura, Norio Takata, and Kenji Tanaka
  • Journal Title: Journal of Neuroscience Volume: 37 Issue: 10 Pages: 2723-2733
  • DOI: 10.1523/jneurosci.3377-16.2017
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• [Journal Article] 強迫症研究のこれからtranslational researchの可能性について (2017)
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• [Journal Article] Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation. (2017)
  • Author(s): Tsutsui-Kimura I, Takiue H, Yoshida K, Xu M, Yano R, Ohta H, Nishida H, Bouchekioua Y, Okano H, Uchigashima M, Watanabe M, Takata N, Drew MR, Sano H, Mimura M, Tanaka KF.
  • Journal Title: Nat Commun. Volume: 8 Issue: 1 Pages: 14304-14304
  • DOI: 10.1038/ncomms14304
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• [Journal Article] YAP functions as a mechanotransducer in oligodendrocyte morphogenesis and maturation. (2017)
  • Author(s): Shimizu T, Osanai Y, Tanaka KF, Abe M, Natsume R, Sakimura K, Ikenaka K.
  • Journal Title: Glia Volume: 65 Issue: 2 Pages: 360-374
  • DOI: 10.1002/glia.23096
  • Peer Reviewed
• [Journal Article] Astrocyte-mediated infantile-onset leukoencephalopathy mouse model (2017)
  • Author(s): Sugio S, Tohyama K, Oku S, Fujiyoshi K, Yoshimura T, Hikishima K, Yano R, Fukuda T, Nakamura M, Okano H, Watanabe M1, Fukata M, Ikenaka K, F Tanaka K
  • Journal Title: Glia Volume: 65 Issue: 1 Pages: 150-168
  • DOI: 10.1002/glia.23084
  • Peer Reviewed / Open Access
• [Journal Article] Physiological effects of a habituation procedure for functional MRI in awake mice using a cryogenic radiofrequency probe (2016)
  • Author(s): Keitaro Yoshida, Yu Mimura, Ryosuke Ishihara, Hiroshi Nishida, Yuji Komaki, Tomohito Minakuchi, Tomokazu Tsurugizawa, Masaru Mimura, Hideyuki Okano, Kenji F. Tanaka, Norio Takata
  • Journal Title: J Neurosci Methods. Volume: 274 Pages: 38-48
  • DOI: 10.1016/j.jneumeth.2016.09.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microglial phospholipase D4 deficiency influences myelination during brain development (2016)
  • Author(s): Chiba T, Otani Y, Yamaguchi Y, Ishibashi T, Hayashi A, Tanaka KF, Yamazaki M, Sakimura K, Baba H.
  • Journal Title: Proceedings of the Japan Academy, Series B Volume: 92 Issue: 7 Pages: 237-254
  • DOI: 10.2183/pjab.92.237
  • NAID: 130005253188
  • ISSN: 0386-2208, 1349-2896
  • Peer Reviewed / Open Access
• [Journal Article] Subcellular calcium dynamics during juvenile development in mouse hippocampal astrocytes. (2016)
  • Author(s): R. Nakayama, T. Sasaki*, KF. Tanaka, Y. Ikegaya*
  • Journal Title: European Journal of Neuroscience Volume: 43 Issue: 7 Pages: 923-32
  • DOI: 10.1111/ejn.13188
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Photoactivated adenylyl cyclase (PAC) reveals novel mechanisms underlying cAMP-dependent axonal morphogenesis (2016)
  • Author(s): Zhou Z, Tanaka KF, Matsunaga S, Iseki M, Watanabe M, Matsuki N, Ikegaya Y, Koyama R
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 19679-19679
  • DOI: 10.1038/srep19679
  • Peer Reviewed / Open Access
• [Journal Article] Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies. (2016)
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  • Journal Title: Mol Neurobiol Volume: 53 Pages: 6869-6881
  • Peer Reviewed / Open Access / Int'l Joint Research
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  • Journal Title: Am J Respir Cell Mol Biol. Volume: 54 Issue: 4 Pages: 584-593
  • DOI: 10.1165/rcmb.2014-0425oc
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 光観察と光操作を組み合わせた意欲行動研究 (2017)
  • Author(s): 田中謙二
  • Organizer: 第2回 ルミノジェネティクス研究会
  • Invited
• [Presentation] Oligodendrocyte is a dynamic modulator of conduction velocity (2017)
  • Author(s): 田中謙二、山崎良彦
  • Organizer: 第60回 日本神経化学会
• [Presentation] 島皮質-線条体回路と意欲行動 (2017)
  • Author(s): 田中謙二
  • Organizer: 第5回 心身医学のニューロサイエンス研究会
  • Invited
• [Presentation] 光操作・光計測 (2017)
  • Author(s): 田中謙二
  • Organizer: 第49回藤田学園医学会・研究最前線セミナー
  • Invited
• [Presentation] Fiberphotometry (2017)
  • Author(s): 田中謙二
  • Organizer: 第28回 マイクロダイアリシス研究会
  • Invited
• [Presentation] 意欲行動の開始を支配する島皮質-線条体回路 (2017)
  • Author(s): 田中謙二
  • Organizer: 次世代脳 新学術領域合同シンポジウム
  • Invited
• [Presentation] Optogenetics (2016)
  • Author(s): 田中謙二
  • Organizer: 第10回ドライアイ研究会
  • Place of Presentation: ヒルトン小田原、小田原、神奈川
  • Year and Date: 2016-05-20
  • Invited
• [Presentation] Optogenetics for neurotrauma research (2016)
  • Author(s): Tanaka KF
  • Organizer: Japan-US Forum on Blast Injury 2016
  • Place of Presentation: 山王ホテル、港区、東京
  • Int'l Joint Research / Invited
• [Presentation] Recent advances in emotional and motivational circuits. (2016)
  • Author(s): Tanaka KF
  • Organizer: The 14th Pacific Rim International Conference on Artificial Intelligence (PRICAI 2016)
  • Place of Presentation: Phuket, Thailand
  • Int'l Joint Research / Invited
• [Presentation] Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation: possible relevance to apathy pathogenesis. (2016)
  • Author(s): Tanaka KF
  • Organizer: 2nd UK-Japan Frontier of Science
  • Place of Presentation: Milton Keynes, UK
  • Int'l Joint Research / Invited
• [Presentation] 階層をつなぎ種を越える脳科学研究 (2016)
  • Author(s): 田中謙二
  • Organizer: 第46回日本神経精神薬理学会年会
  • Place of Presentation: ソウル、韓国
  • Invited
• [Presentation] Ventral striatopallidal neurons govern motivated behaviors (2016)
  • Author(s): 田中謙二
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜、横浜市、神奈川
  • Invited
• [Presentation] ミクロスコピックからメゾスコピックのカルシウムイメージング・計測 (2016)
  • Author(s): 田中謙二
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会合同年会
  • Place of Presentation: 福岡国際会議場、福岡市、福岡
  • Invited
• [Presentation] 遺伝子改変を駆使したGliopsychiatry研究 (2016)
  • Author(s): 田中謙二
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会合同年会
  • Place of Presentation: 福岡国際会議場、福岡市、福岡
  • Invited
• [Presentation] 神経科学・神経化学におけるレジリエンス研究 (2016)
  • Author(s): 田中謙二
  • Organizer: 第32回日本ストレス学会学術総会
  • Place of Presentation: 杏林大学、三鷹市、東京
  • Invited
• [Presentation] 無神経なオプトジェネティクス (2016)
  • Author(s): 田中謙二
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜、横浜市、神奈川
  • Invited
• [Remarks] 柔軟な行動選択を行う脳内メカニズムの発見
  • URL: https://www.keio.ac.jp/ja/press-releases/2017/9/29/28-24433/
• [Remarks] 脳内にある、やる気のスイッチを発見－意欲障害の治療法探索が可能に－
  • URL: https://www.keio.ac.jp/ja/press-releases/2017/2/2/28-19536/
• [Remarks] 動物の意欲を司る2種類の線条体神経の活動と役割分担について解明
  • URL: http://www.igakuken.or.jp/topics/2017/0206.html