負に立ち向かうウィルパワーをつかさどる神経基盤の解明

• Project Area: Creation and Promotion of the Will-Dynamics
• Project/Area Number: 17H06062
• 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): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2017: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
• Keywords: オペラント行動 / 負の強化子 / 腹側線条体 / ファイバーフォトメトリー / 意欲 / 回避 / 線条体 / ストレス / オペラント条件付け

Outline of Annual Research Achievements

ウィルパワーは、負の事象を回避する/すでに起きてしまった負の事象から脱出するという目的を果たすときにも駆動される。本課題では、これまであまり知られてこなかった「嫌なことから逃げるときに駆動されるウィルパワー」の神経基盤を明らかにすることを目的とした。
まず、負に立ち向かうウィルパワーをマウスで定量する評価系 (active avoidance test)の構築に取り組んだ。嫌なこと（電気ショック）を回避するために、どれだけコストを払うのか、オペラント条件付けを利用した行動評価系である。トライアル開始から60秒間ブザーが鳴る。その間に、要求されたレバー回数（5回）を押しきるとブザーが止み、電気ショックを回避できる。5回押すことができなければ、10秒間の電気ショックを受ける。電気ショックが開始されたとしても5回のレバーを押しを達成できれば電気ショックが止まり、ブザー音も止まる。このようにして、電気ショックを回避するためのオペラント行動、電気ショックから脱出するためのオペラント行動を観察する実験系を確立した。
次に、active avoidance testとファイバーフォトメトリー法を組み合わせて、腹側線条体D2-MSNの神経活動変化を記録した。ショックを回避した直後にD2-MSNの活動が低下することが明らかになった。これは負の強化子の獲得直後にD2-MSNの活動が低下すると解釈できる。一方で、通常の餌とレバーを関連づけたオペラント行動においては、餌の獲得、つまり正の強化子の獲得直後にD2-MSNの活動が増加する。いずれも行動を増やす強化子として位置づけられるものの、強化子獲得時の腹側線条体の活動が全く異なることを明らかにした。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30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 Ottawa/University of British Columbia(カナダ)
• [Int'l Joint Research] University of Texas, Austin/University of Pittsburgh/Columbia University(米国)
• [Int'l Joint Research] Universite Libre de Bruxelles(ベルギー)
• [Int'l Joint Research] University of Ottawa(Canada)
• [Journal Article] Enriched environment alleviates stress-induced dry-eye through the BDNF axis (2019)
  • Author(s): Sano Kokoro、Kawashima Motoko、Imada Toshihiro、Suzuki Toru、Nakamura Shigeru、Mimura Masaru、Tanaka Kenji F.、Tsubota Kazuo
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 3422-3422
  • DOI: 10.1038/s41598-019-39467-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of Adult 5-HT1A Autoreceptors Results in a Paradoxical Anxiogenic Response to Antidepressant Treatment (2018)
  • Author(s): Turcotte-Cardin Valrie、Vahid-Ansari Faranak、Luckhart Christine、Daigle Mireille、Geddes Sean D.、Tanaka Kenji F.、Hen Ren?、James Jonathan、Merali Zul、B??que Jean-Claude、Albert Paul R.
  • Journal Title: The Journal of Neuroscience Volume: 39 Issue: 8 Pages: 1334-1346
  • DOI: 10.1523/jneurosci.0352-18.2018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Calcium Transient Dynamics of Neural Ensembles in the Primary Motor Cortex of Naturally Behaving Monkeys (2018)
  • Author(s): Kondo T, Saito R, Otaka M, Yoshino-Saito K, Yamanaka A, Yamamori T, Watakabe A, Mizukami H, Schnitzer MJ, Tanaka KF, *Ushiba J, *Okano H
  • Journal Title: Cell Rep Volume: 24(8) Issue: 8 Pages: 2191-2195
  • DOI: 10.1016/j.celrep.2018.07.057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships (2018)
  • Author(s): Zhang Peng、Lu Hong、Peixoto Rui T.、Pines Mary K.、Ge Yuan、Oku Shinichiro、Siddiqui Tabrez J.、Xie Yicheng、Wu Wenlan、Archer-Hartmann Stephanie、Yoshida Keitaro、Tanaka Kenji F.、Aricescu A. Radu、Azadi Parastoo、Gordon Michael D.、Sabatini Bernardo L.、Wong Rachel O.L.、Craig Ann Marie
  • Journal Title: Cell Volume: 174 Issue: 6 Pages: 1450-1464.e23
  • DOI: 10.1016/j.cell.2018.07.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 5-HT3 antagonists decrease discounting rate without affecting sensitivity to reward magnitude in the delay discounting task in mice (2018)
  • Author(s): Mori Marina、Tsutsui-Kimura Iku、Mimura Masaru、Tanaka Kenji F.
  • Journal Title: Psychopharmacology Volume: 235 Issue: 9 Pages: 2619-2629
  • DOI: 10.1007/s00213-018-4954-0
  • Peer Reviewed
• [Journal Article] Reward probability and timing uncertainty alter the effect of dorsal raphe serotonin neurons on patience (2018)
  • Author(s): Miyazaki K*, Miyazaki KW*, Yamanaka A, Tokuda T, Tanaka KF, Doya K *These authors contributed equally to this work.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2048-2048
  • DOI: 10.1038/s41467-018-04496-y
  • Peer Reviewed / Open Access
• [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
  • 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)
  • Author(s): Tsutsui-Kimura I, Bouchekioua Y, Mimura M, Tanaka KF.
  • Journal Title: Int J Neuropsychopharmacol. Volume: 20 Issue: 7 Pages: 593-601
  • DOI: 10.1093/ijnp/pyx031
  • Peer Reviewed / Open Access
• [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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 強迫症研究のこれからtranslational researchの可能性について (2017)
  • Author(s): 15.酒井 雄希, 田中 謙二
  • Journal Title: 精神科治療学 Volume: 32 Pages: 399-404
• [Presentation] 光観察と光操作を融合させた神経回路研究 (2018)
  • Author(s): 田中謙二
  • Organizer: 第114回 日本精神神経科学会学術総会
• [Presentation] 意欲行動 (2018)
  • Author(s): 田中謙二
  • Organizer: 第2回三融会
  • Invited
• [Presentation] 意欲の開始と維持の神経基盤 (2018)
  • Author(s): 田中謙二
  • Organizer: 第3回ルミノジェネティクス研究会
  • Invited
• [Presentation] Motivated behavior regulated by the ventral striatum (2018)
  • Author(s): 田中謙二
  • Organizer: The 7th Annual IIIS Symposium.
  • Int'l Joint Research / Invited
• [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
• [Remarks] プレスリリース 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/