意欲行動の持続にかかわる神経基盤の解明

• Project Area: Creation and Promotion of the Will-Dynamics
• Project/Area Number: 19H05027
• 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): 2019-04-01 – 2021-03-31
• Project Status: Discontinued (Fiscal Year 2020)
• Budget Amount: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 意欲 / 腹側海馬 / セロトニン / 根気 / 副側海馬 / フォトメトリー

Outline of Research at the Start

意欲行動は、行動の開始、行動の持続、目的の達成という段階に分けることができる。意欲行動の持続にかかわる神経基盤は全く分かっていない。予備実験により、腹側線条体へ投射する腹側海馬が、意欲行動の持続に関与するという仮説をたてるに十分な根拠を得た。本研究では、腹側海馬が意欲行動の持続を制御するという仮説を証明するとともに、その神経回路基盤、分子基盤をも明らかにする。

Outline of Annual Research Achievements

本研究では、腹側海馬が意欲行動の持続を制御するという仮説の証明とその神経回路基盤、分子基盤の解明を行った。
1)意欲行動の持続中に活動変化が見られるのは腹側海馬に限った現象であった。レバー押し行動中に見られる海馬CA1神経細胞活動抑制が、腹側領域特有かどうか、腹側海馬CA1錐体細胞と背側海馬CA1錐体細胞の集合活動記録によって調べた。その結果、腹側海馬特異的な現象であることがわかった。
2) 腹側海馬の光操作によって、腹側海馬の活動低下と意欲行動の持続に因果関係があった。光活性化の実験では、海馬CA1細胞選択的にChR2を発現させたマウス（Htr5b-tTA::tetO-ChR2(C128S)）を、光抑制にはHtr5b-tTA::tetO-ArchTマウスを用いた。腹側海馬CA1錐体細胞の活動抑制が意欲行動持続に必須であることが分かった。
３）意欲行動の持続中に見られる海馬の活動抑制が、セロトニン神経活動増加と相関することが分かった。セロトニン神経特異的にカルシウムインジケーターを発現するマウス（Htr5b-tTA::tetO-yellow cameleon nano50）を発現するマウスを作出した。エサ報酬とレバー押しを条件付けさせ、根気よくレバーを押す行動中に、正中縫線核セロトニン神経の活動が増加することが分かった。
４）セロトニンを介した海馬の活動制御にかかわる分子メカニズムが明らかになった。海馬に発現する受容体アイソフォームのうち、海馬CA1錐体細胞の活動抑制に関わるアイソフォームはHtr1aとHtr3aの2つであった。それぞれの受容体の薬理学的阻害実験を行ったところ、Htr3aを介して海馬CA1錐体細胞の活動抑制がもたらされていることが分かった。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2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 Washington(米国)
• [Int'l Joint Research] University of Texas, Austin(米国)
• [Int'l Joint Research] Uppsala University,(スウェーデン)
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• [Journal Article] Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging (2019)
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• [Presentation] 意欲行動の神経基盤解明 (2019)
  • Author(s): 田中謙二
  • Organizer: 第115回日本精神神経学会学術総会
• [Presentation] Regional blood flow regulation by optogenetics (2019)
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  • Organizer: Neuro2019
• [Presentation] Serotonin-mediated inhibition of ventral hippocampus is required for sustained goal-directed behavior (2019)
  • Author(s): Kenji Tanaka
  • Organizer: 11th Optogenetics meeting
  • Int'l Joint Research / Invited
• [Presentation] 意欲行動の神経基盤 (2019)
  • Author(s): 田中謙二
  • Organizer: 大阪大学蛋白質研究所セミナー
  • Invited
• [Remarks] プレスリリース（新しい脳内情報伝達様式を発見－病態の発症・治療への手掛かりに－）
  • URL: https://www.keio.ac.jp/ja/press-releases/files/2020/7/1/200701-2v3.pdf
• [Patent(Industrial Property Rights)] 衝動抑制薬のスクリーニング方法、及び衝動抑制薬 (2019)
  • Inventor(s): 田中謙二
  • Industrial Property Rights Holder: 田中謙二
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Overseas