Elucidating roles of ventral tegmental area dopaminergic neurons in motivation of appetitive goal-directed behavior

• Project/Area Number: 19K03381
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 10040:Experimental psychology-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Iguchi Yoshio 福島県立医科大学, 医学部, 助教 (20452097)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 目標指向行動 / オペラント学習 / 動機づけ（モチベーション） / 行動経済学 / 中脳辺縁ドーパミン投射系 / ドーパミンD2受容体陽性細胞 / 化学遺伝学（ケモジェ ネティクス）システム / トランスジェニックラット / 化学遺伝学（ケモジェネティクス）システム / 腹側被蓋野ドーパミンニューロン / 欲求性目標指向行動 / 動機づけ / イオンチャネル型化学遺伝学ツール

Outline of Research at the Start

VTAのDAニューロンの活動と目標指向行動の動機づけの間の因果的関係を，異なる事態との間で相互に比較・翻訳可能な程度に明瞭に描出することは，動機づけ過程に異常を来す精神疾患の病態解明やその治療法開発に繋がる重要な課題である。本研究は，ラットのオペラント条件づけに行動経済学的な視点を導入し，動機づけに関わる内在変数の推定を可能にする新たな強化スケジュールを確立する。また，最新の遺伝子改変技術を基盤として，VTA DAニューロンの活動を，一過的かつ両方向性に制御するためのツールを開発し，その最適化を図る。そして，DAニューロンの活動操作が動機づけ関連変数に与える影響を体系的に検討する。

Outline of Final Research Achievements

We investigated the role of D2R-positive ventral tegmental area dopamine neurons in the motivational control of goal-directed behavior. We established a system to specifically and reversibly manipulate the activity of target neurons using chemogenetic technologies and a behavioral experiment to estimate intrinsic variables involved in the motivation of appetitive operant behavior in rats.
By a series of systematic experiments combining histochemical, biochemical, and behavioral methods, we found that D2R-positive ventral tegmental area dopamine neurons play an essential role in the maintenance of motivation associated with increased reward prices through projections to the nucleus accumbens core.

Academic Significance and Societal Importance of the Research Achievements

中脳に起始するドーパミンニューロンが関与する生理機能や，その機能破たんに起因する疾患の病態は多様であり，発現分子に基づいた細胞集団の分離・同定と，それぞれの心理-行動機能の詳細な解析の重要性はますます高まっている。本研究は，D2Rを分子マーカーとする腹側被蓋野ドーパミンニューロンが，側坐核コアへの投射を通じて，報酬価格が増大したときのモチベーションの維持に関与していることを発見した。今後は，D2R以外のマーカーをもつ細胞集団の機能解析を同様の方法論ですすめることで，ドーパミン系に関する包括的理解と，動機づけプロセスが障害される精神-神経疾患の病態理解や治療法開発につながることが期待される。

Research Products

• [Int'l Joint Research] The University of Lausanne(スイス)
• [Journal Article] Multimodal Functional Analysis Platform: 1. Ultrathin Fluorescence Endoscope Imaging System Enables Flexible Functional Brain Imaging (2021)
  • Author(s): Osanai M, Miwa H, Tamura A, Kikuta S, Iguchi Y, Yanagawa Y, Kobayashi K, Katayama N, Tanaka T, & Mushiake H
  • Journal Title: Optogenetics. Advances in Experimental Medicine and Biology Volume: 1293 Pages: 471-479
  • DOI: 10.1007/978-981-15-8763-4_31
  • ISBN: 9789811587627, 9789811587634
  • Peer Reviewed / Open Access
• [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] Maternal dietary imbalance between omega-6 and omega-3 fatty acids triggers the offspring’s overeating in mice (2020)
  • Author(s): Sakayori N, Katakura M, Hamazaki K, Higuchi O, Fujii K, Fukabori R, Iguchi Y, Setogawa S, Takao K, Miyazawa T, Arita M, & Kobayashi K
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s42003-020-01209-4
  • NAID: 120007169782
  • Peer Reviewed / Open Access
• [Journal Article] Sustaining temporal attention prevents habit expression during operant learning in rats (2020)
  • Author(s): Lin Ziqiao、Nishikawa Hiromi、Iguchi Yoshio、Iwanami Akira、Kikuchi Mitsuru、Toda Shigenobu
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 10303-10303
  • DOI: 10.1038/s41598-020-67304-y
  • Peer Reviewed / Open Access
• [Journal Article] Store-Operated Calcium Channels Are Involved in Spontaneous Slow Calcium Oscillations in Striatal Neurons (2019)
  • Author(s): Kikuta Satomi、Iguchi Yoshio、Kakizaki Toshikazu、Kobayashi Kazuto、Yanagawa Yuchio、Takada Masahiko、Osanai Makoto
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 13 Pages: 1-9
  • DOI: 10.3389/fncel.2019.00547
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced aversive memory retrieval by chemogenetic activation of locus coeruleus norepinephrine neurons (2019)
  • Author(s): Fukabori Ryoji、Iguchi Yoshio、Kato Shigeki、Takahashi Kazumi、Eifuku Satoshi...Momiyama Toshihiko、Benton Richard、Kobayashi Kazuto
  • Journal Title: bioRxiv Volume: --
  • DOI: 10.1101/831313
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 味覚連合記憶の想起における青斑核ノルアドレナリン細胞の役割―ハエ嗅覚器由来のイオンチャネルを利用した新規神経活動活性化ツールによる検討― (2020)
  • Author(s): 井口善生
  • Organizer: 生理研研究会2020・行動の多様性を支える神経基盤とその動作様式の解明
  • Invited
• [Presentation] Novel knock-in rat lines created by the Combi-CRISPR method that express Cre recombinase specifically in the central catecholaminergic neurons. (2020)
  • Author(s): Matsushita N, Nishizawa K, Fukabori R, Hashimoto H, Iguchi Y, Kato S, Miyasaka Y, Mashimo T, Takeuchi K, & Kobayashi K
  • Organizer: MBSJ2020 Online
• [Presentation] 青斑核ノルアドレナリン神経細胞の活動亢進による情動記憶の想起の促進：新規神経活動活性化ツールによる検討 (2020)
  • Author(s): 井口善生・深堀良二・加藤成樹・高橋和巳・永福智志・辻真伍・挾間章博・内ケ島基政・渡辺雅彦・水間広・崔翼龍・尾上浩隆・疋島啓吾・八十島安伸・小山内実・稲垣良・福永浩司・西條琢真・籾山俊彦・リチャード＝ベントン・小林和人
  • Organizer: 第52回東北生理談話会
• [Presentation] The individual history of reward learning and stress responsibility: resilience induced by contingency learning between action and reward. (2020)
  • Author(s): Iguchi Y, Hikishima K, & Kobayashi K
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Development and application of the multimodal ultra-thin endoscope for analyzing neuronal circuits in the deep brain region. (2019)
  • Author(s): Osanai, M., Ohkawa, N., Iguchi, Y., Yokose, J., Nakayama, S., Inokuchi, K., Kobayashi, K., Haga, Y., & Mushiake, H.
  • Organizer: Neural Oscillation Conference 2019
  • Int'l Joint Research
• [Presentation] Attempts to visualize neuronal activity by striatal cell type during various learning phases of stimulus discrimination. (2019)
  • Author(s): Iguchi, Y., & Kobayashi, K.
  • Organizer: 新学術領域研究「人工知能と脳科学」第7回領域会議
• [Presentation] Innately induced palatable feeding by dietary imbalance of essential fatty acids. (2019)
  • Author(s): Sakayori, N., Higuchi, O., Fukabori, R. Iguchi, Y., Setogawa, S., Eitsuka, T., Miyazawa, T., & Kobayashi, K.
  • Organizer: The 42th Annual Meeting of the Japan Neuroscience Society (Neuro2019)
• [Presentation] Chemogenetic inhibition of ventral tegmental area dopamine neurons reveals multidimensional roles in motivated behavior reinforced by natural reward. (2019)
  • Author(s): Iguchi, Y., Kato, S., Nishizawa, K., & Kobayashi, K.
  • Organizer: The 42th Annual Meeting of the Japan Neuroscience Society (Neuro2019)
• [Presentation] Enhanced retrieval of learned emotional memory by chemogenetic activation of locus coeruleus noradrenergic neurons. (2019)
  • Author(s): Iguchi, Y., & Kobayashi, K.
  • Organizer: The 19th Annual Meeting of JSNP
  • Invited
• [Remarks] 昆虫のにおい受容体を用いたほ乳類脳神経細胞の新たな活動操作技術の開発とその応用
  • URL: https://www.fmu.ac.jp/univ/kenkyuseika/research/202011091.html