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Roles of dopamine and serotonin in regulating motivation

Research Project

Project/Area Number 18H04037
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 51:Brain sciences and related fields
Research InstitutionNational Institutes for Quantum Science and Technology

Principal Investigator

南本 敬史  国立研究開発法人量子科学技術研究開発機構, 量子医科学研究所 脳機能イメージング研究部, 上席研究員 (50506813)

Project Period (FY) 2018-04-01 – 2023-03-31
Project Status Granted (Fiscal Year 2022)
Budget Amount *help
¥43,940,000 (Direct Cost: ¥33,800,000、Indirect Cost: ¥10,140,000)
Fiscal Year 2022: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2021: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Fiscal Year 2020: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
Fiscal Year 2019: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
Fiscal Year 2018: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
Keywords脳・神経 / イメージング / 操作技術 / DREADDs / サル / ドーパミン / セロトニン / モチベーション / DREADD
Outline of Annual Research Achievements

本研究では,ヒトに近い脳回路基盤を有するサルを対象とし、最新の化学遺伝学手法(DREADDs)によるドーパミン/セロトニンの操作で生じる意欲低下を独自の行動実験系と数理モデルで捉えるとともに、イメージング・電気生理手法により脳ネットワーク情報処理・動機価値の脳内表現の変容を特定し、正常の意欲制御の神経機構から病態まで統一的に説明するモデルを提唱することを目的とする。
R3年度はDA神経細胞に特異的にDREADDsを発現するサルを作出し、DCZ投与に伴う神経活動変化をイメージングで捉えるとともに、行動変容を生じることを確認し論文で発表した(MimuraらiScience 2021)。また報酬量に基づく行動課題を遂行中のマカクザルにDA受容体阻害剤を全身投与し、動機価値およびコストベネフィットトレードオフの神経機構における影響について調べ、モデルを用いた解析を通じDA受容体サブタイプごとの影響の違いを定量的に明らかにした結果について論文を発表した(Horiら2021)。同様の実験を5-HT受容体についても実施し、解析を進めて論文化を進めている。さらに5-HT神経細胞特異的プロモーターにより抑制性DREADDを発現するウイルしベクターを背側縫線核・正中縫線核にそれぞれ投与した2頭のマカクザル作出、DCZを用いたPETイメージング法により注入部位での発現を可視化するとともに、動機付け行動課題への影響についてテストを行い、背側縫線核5-HT神経細胞の活動抑制が遅延報酬割引率の増加を、正中縫線核5-HT神経細胞の活動抑制が価値に依存しない意欲の低下をそれぞれ引き起こすことを見出した。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

DA、5-HT受容体阻害による意欲制御機構解明が進み、局在や回路機能との繋がりも明らかとなってきた。さらに、DREADDsによるDA/5-HT神経活動の操作性を高める技術開発が確立でき、薬理学操作では不可能であった細胞レベルでの操作など、特異性を高めた機能制御が霊長類でも可能となった。

Strategy for Future Research Activity

R4年度は引き続きDREADDによる5-HT神経操作技術の確立を進めるとともに、5-HT神経連絡を明らかにして、回路特異的な介入操作を開始することで行動や神経回路への影響を特定する。またセロトニンの伝達を阻害することにより生じる意欲低下についてモデルによる解析を進め、論文化を目指す。

Report

(4 results)
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(40 results)

All 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (7 results) Journal Article (11 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 10 results) Presentation (18 results) (of which Int'l Joint Research: 7 results,  Invited: 15 results) Remarks (2 results) Patent(Industrial Property Rights) (2 results)

  • [Int'l Joint Research] ICM/CNRS(フランス)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] NIH(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] ICM(フランス)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] U. North Carolina/Mt Sinai(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] National Institute of Health/Univ. North Carolina(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] CNRS(フランス)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Univ. South Carolina/Mount Sinai(米国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Chronic Behavioral Manipulation via Orally Delivered Chemogenetic Actuator in Macaques2022

    • Author(s)
      Oyama Kei、Hori Yukiko、Nagai Yuji、Miyakawa Naohisa、Mimura Koki、Hirabayashi Toshiyuki、Inoue Ken-ichi、Takada Masahiko、Higuchi Makoto、Minamimoto Takafumi
    • Journal Title

      J Neurosci

      Volume: 42 Pages: 2552-2561

    • DOI

      10.1523/jneurosci.1657-21.2021

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chemogenetic sensory fMRI reveals behaviorally-relevant bidirectional changes in primate somatosensory network.2021

    • Author(s)
      Hirabayashi T, Nagai Y, Hori Y, Inoue KI, Aoki I, Takada M, Suhara T, Higuchi M, Minamimoto T.
    • Journal Title

      Neuron

      Volume: 109 Pages: 3312-3322

    • DOI

      10.1016/j.neuron.2021.08.032

    • NAID

      120007166034

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chemogenetic activation of nigrostriatal dopamine neurons in freely moving common marmosets.2021

    • Author(s)
      Mimura K, Nagai Y, Inoue K, Matsumoto J, Hori Y, Sato C, Kimura K, Okauchi T, Hirabayashi T, Nishijo H, Yahata N, Takada M, Suhara T, Higuchi M, Minamimoto T
    • Journal Title

      iScience

      Volume: 24(9) Pages: 103066-103066

    • DOI

      10.1016/j.isci.2021.103066

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Single caudate neurons encode temporally discounted value for formulating motivation for action.2021

    • Author(s)
      Hori Y, Mimura K, Nagai Y, Fujimoto A, Oyama K, Kikuchi E, Inoue KI, Takada M, Suhara T, Richmond BJ, Minamimoto T.
    • Journal Title

      eLife

      Volume: 10 Pages: 61248-61248

    • DOI

      10.7554/elife.61248

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] D1- and D2-like receptors differentially mediate the effects of dopaminergic transmission on cost-benefit evaluation and motivation in monkeys2021

    • Author(s)
      Hori Yukiko、Nagai Yuji、Mimura Koki、Suhara Tetsuya、Higuchi Makoto、Bouret Sebastien、Minamimoto Takafumi
    • Journal Title

      PLOS Biology

      Volume: 19 Pages: 3001055-3001055

    • DOI

      10.1371/journal.pbio.3001055

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making2021

    • Author(s)
      Oyama Kei、Hori Yukiko、Nagai Yuji、Miyakawa Naohisa、Mimura Koki、Hirabayashi Toshiyuki、Inoue Ken-ichi、Suhara Tetsuya、Takada Masahiko、Higuchi Makoto、Minamimoto Takafumi
    • Journal Title

      Sci Adv

      Volume: 7 Pages: 1-9

    • DOI

      10.1126/sciadv.abg4246

    • NAID

      120007089253

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys2020

    • Author(s)
      Nagai Yuji, Miyakawa Naohisa et al.
    • Journal Title

      Nature Neuroscience

      Volume: 23 Pages: 1157-1167

    • DOI

      10.1038/s41593-020-0661-3

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Macaques Exhibit Implicit Gaze Bias Anticipating Others’ False-Belief-Driven Actions via Medial Prefrontal Cortex2020

    • Author(s)
      Hayashi Taketsugu、Akikawa Ryota、Kawasaki Keisuke、Egawa Jun、Minamimoto Takafumi、Kobayashi Kazuto、Kato Shigeki、Hori Yukiko、Nagai Yuji、Iijima Atsuhiko、Someya Toshiyuki、Hasegawa Isao
    • Journal Title

      Cell Rep.

      Volume: 30 Pages: 4433-4444

    • DOI

      10.1016/j.celrep.2020.03.013

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Trait and State-Dependent Risk Attitude of Monkeys Measured in a Single-Option Response Task2019

    • Author(s)
      Fujimoto Atsushi、Minamimoto Takafumi
    • Journal Title

      Frontiers in Neuroscience

      Volume: 13 Pages: 816-816

    • DOI

      10.3389/fnins.2019.00816

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Recruitment of calbindin into nigral dopamine neurons protects against drug-induced parkinsonism. Mov Disord [Epub ahead of print] doi: 10.1002/mds.1072019

    • Author(s)
      Inoue K, Miyachi S, Nishi K, Okado H, Nagai Y, Minamimoto T, Nambu A, Takada M
    • Journal Title

      Movement Disorders

      Volume: - Pages: 200-209

    • DOI

      10.1002/mds.107

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Signaling Incentive and Drive in the Primate Ventral Pallidum for Motivational Control of Goal-Directed Action2019

    • Author(s)
      Fujimoto Atsushi、Hori Yukiko、Nagai Yuji、Kikuchi Erika、Oyama Kei、Suhara Tetsuya、Minamimoto Takafumi
    • Journal Title

      The Journal of Neuroscience

      Volume: 39 Pages: 2399-18

    • DOI

      10.1523/jneurosci.2399-18.2018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 化学遺伝学とイメージングの融合によるサル脳回路の可視化と機能理解2022

    • Author(s)
      南本 敬史
    • Organizer
      京都大学霊長類研究所共同利用研究会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Visualizing and manipulating primate brain circuits with DREADDs2022

    • Author(s)
      Minamimoto T.
    • Organizer
      7th CiNet Conference
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ドーパミン伝達による意欲調節機構:サル分子イメージングと行動薬理を用いた解析2021

    • Author(s)
      南本 敬史
    • Organizer
      大阪大学蛋白質研究所セミナー「多様なドーパミン神経伝達から 脳を探る」大阪大学 蛋白質研究所
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Neural mechanism for valuation and motivation in health and disease2021

    • Author(s)
      Minamimoto T, Hori Y, Oyama K
    • Organizer
      第44回日本神経科学大会, 神戸
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Interrogation of monkey brain circuits with imaging-guided chemogenetics2021

    • Author(s)
      Minamimoto T
    • Organizer
      ASPET 2021, American Society for Pharmacology and Experimental Therapeutics
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 1.Neural mechanisms of motivational control based on cost-benefit comparison in monkey2020

    • Author(s)
      Minamimoto T
    • Organizer
      第98回生理学学会大会シンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Dopamine, Serotonin, and Motivation2020

    • Author(s)
      南本敬史
    • Organizer
      京都大学霊長類研究所 共同利用研究会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] モチベーションの脳内調節機構とその破綻2020

    • Author(s)
      南本敬史
    • Organizer
      日本心理学会第84回大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 化学遺伝学とイメージングの融合による霊長類脳回路の可視化と操作2020

    • Author(s)
      南本敬史
    • Organizer
      第9回マーモセット研究会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] DREADD inactivation reveals critical role of orbitofrontal cortex in reward-based adaptive decision-making in monkeys.2019

    • Author(s)
      Oyama K, Hori Y, Nagai Y, Hirabayashi T, Miyakawa N, Fujimoto A, Mimura K, Inoue K, Eldridge MAG, Saunders RC, Suhara T, Takada M, Higuchi M, Richmond BJ, Minamimoto T.
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] New DREADD compound enables to visualize and manipulate neural circuits in monkeys2019

    • Author(s)
      Minamimoto T
    • Organizer
      NIH BRAIN Initiative Chemogenetic Innovations in the Manipulation and Monitoring of Labeled Neurons Workshop
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 意欲調節の神経メカニズムとその障害―サル分子イメージングによる探索2019

    • Author(s)
      南本敬史、堀由紀子、永井裕司
    • Organizer
      「情動の生起と変容の多面的理解に向けて」情動研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Using PET imaging to monitor chemogenetic manipulation of nigrostriatal dopamine system in common marmoset.2018

    • Author(s)
      三村喬生, 永井裕司, 井上謙一, 須原哲也, 高田昌彦, 南本敬史,
    • Organizer
      第41回日本神経科学大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] PET imaging of selective control of neural activity with a novel DREADD agonist,2018

    • Author(s)
      Nagai Y, ほか26名、Minamimoto T.
    • Organizer
      第41回日本神経科学大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] PET imaging-guided chemogenetic modification of reward-related circuits in monkeys2018

    • Author(s)
      Minamimoto T.
    • Organizer
      第41回日本神経科学大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Chemogenetic imaging: monitoring and manipulating neural circuits in monkeys.2018

    • Author(s)
      Minamimoto T.
    • Organizer
      Viral Manipulation in Monkey, Paris
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] A novel ligand C22b enables selective and rapid chemogenetic neuronal modification in monkeys.2018

    • Author(s)
      Minamimoto T.
    • Organizer
      Genetic Technologies for Systems Neuroscience in NHP, NIH, USA
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] A chemogenetic toolbox for non-human primates2018

    • Author(s)
      Minamimoto T.
    • Organizer
      New Directions in Systems Neuroscience, Germany
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] 量子科学技術研究開発機構 システム神経回路研究グループ

    • URL

      https://www.nirs.qst.go.jp/seika/brain/team/system_09.html

    • Related Report
      2021 Annual Research Report
  • [Remarks] システム神経回路研究グループ

    • URL

      https://www.nirs.qst.go.jp/seika/brain/team/system_09.html

    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 人工受容体に結合する新規化合物、人工受容体のイメージング方法、ア ゴニストまたはアンタゴニスト、治療薬、コンパニオン診断薬、神経細胞のイメージ ング方法2018

    • Inventor(s)
      南本敬史、永井裕司、季斌、宮川尚久、樋口真人、須原哲也
    • Industrial Property Rights Holder
      量子科学技術研究開発機構
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Acquisition Date
      2021
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 人工受容体に結合する新規化合物、人工受容体のイメージング方法、アゴニストまたはアンタゴニスト、治療薬、コンパニオン診断薬、神経細胞のイメージング方法2018

    • Inventor(s)
      南本敬史・永井裕司・季斌・宮川尚久・樋口真人・須原哲也
    • Industrial Property Rights Holder
      量子科学技術研究開発機構
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-118210
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-12-28  

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