Regulation of cognitive functions by inverse synaptic tagging mechanism of Arc

• Project/Area Number: 19H03328
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Kagoshima University
• Principal Investigator: 3 3 鹿児島大学, 医歯学域医学系, 教授 (80272417)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2021: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2019: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 長期記憶 / シナプス / 学習 / 遺伝子 / 活動依存的遺伝子発現 / 記憶 / 学習・記憶 / 最初期遺伝子 / 実行機能 / シナプス可塑性 / 神経活動依存的遺伝子発現 / 認知機能 / 前初期遺伝子 / 海馬 / Arc

Outline of Research at the Start

大脳長期記憶に関与する遺伝子Arcは神経伝達効率の調節を行う「逆シナプスタグ」として働く。本研究では、Arcの逆シナプスタグ機構に基づくシナプス制御の分子機構を明らかにし、マウスモデルにおいて実行機能を含めた大脳認知機能へのArcの寄与を解明する。さらに、Arcと共発現する新規の活動依存的遺伝子を同定しネットワーク解析等を行うことにより、遺伝子と行動をつなぐ新たな多階層モデルの構築をめざす。

Outline of Final Research Achievements

The activity-regulated gene Arc is one of the genes that show robust and transient gene induction upon strong synaptic activity associated with cognitive processes in the brain. Arc is implicated in maintenance of various types of cognitive function and dysfunction of Arc-related signaling has been proposed to be associated with amnesic and psychiatric disorders. However, how Arc regulates cognitive function is still largely unknown. In this study, we investigated cognitive functions of Arc knockout (KO) mice, and found that the ability to retain memory more than months was severely impaired in Arc KO mice as compared with wild-type controls. We also found abnormality of Arc KO mice in behavioral flexibility. These findings indicate usefulness of Arc KO mice for further understanding of molecular basis of cognitive processes in the brain.

Academic Significance and Societal Importance of the Research Achievements

長長期記憶や行動柔軟性の異常は認知症や精神疾患、発達障害の患者に頻繁に報告されていることから、これらに関わる神経回路や分子機構の解明が望まれている。本研究で明らかになったArc遺伝子による１カ月以上続く長期記憶や行動柔軟性の調節機構は、今後これらの機能を支える神経回路の同定に向けて大きな手掛かりとなる。また、分子機構の解明は新たな創薬標的の創出に発展する可能性があり、将来の認知症や精神疾患、発達障害に対する治療法の開発へとつながることが期待される。

Research Products

• [Int'l Joint Research] Nencki institute of experimental biology(ポーランド)
• [Int'l Joint Research] University of Utah/University of Arizona(米国)
• [Int'l Joint Research] Nenki Institute of Experimental Biology(ポーランド)
• [Int'l Joint Research] Nenki Institute of Experimental Biology(ポーランド)
• [Journal Article] Gastrin-releasing peptide regulates fear learning under stressed conditions via activation of the amygdalostriatal transition area (2022)
  • Author(s): Goto Fumiko、Kiyama Yuji、Ogawa Itone、Okuno Hiroyuki、Ichise Taeko、Ichise Hirotake、Anai Motonobu、Kodama Tatsuhiko、Yoshida Nobuaki、Bito Haruhiko、Manabe Toshiya
  • Journal Title: Molecular Psychiatry Volume: - Issue: 3 Pages: 1694-1703
  • DOI: 10.1038/s41380-021-01408-3
  • Peer Reviewed / Open Access
• [Journal Article] Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses. (2022)
  • Author(s): Niu M, Kasai A, Tanuma M, Seiriki K, Igarashi H, Kuwaki T, Nagayasu K, Miyaji K, Ueno H, Tanabe W, Seo K, Yokoyama R, Ohkubo J, Ago Y, Hayashida M, Inoue KI, Takada M, Yamaguchi S, Nakazawa T, Kaneko S, Okuno H, Yamanaka A, Hashimoto H.
  • Journal Title: Science Advances Volume: 8 Issue: 11
  • DOI: 10.1126/sciadv.abi6375
  • Peer Reviewed / Open Access
• [Journal Article] Rpd3/CoRest-mediated activity-dependent transcription regulates the flexibility in memory updating in Drosophila. (2021)
  • Author(s): Takakura M, Nakagawa R, Ota T, Kimura Y, Okuno H, Hirano Y
  • Journal Title: Nat Commun Volume: 12 Issue: 1 Pages: 628-628
  • DOI: 10.1038/s41467-021-20898-x
  • Peer Reviewed / Open Access
• [Journal Article] Cooperation of LIM domain-binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia. (2021)
  • Author(s): Ohnishi T, Kiyama Y, Arima-Yoshida F, Kadota M, Ichikawa T, Yamada K, Watanabe A, Ohba H, Tanaka K, Nakaya A, Horiuchi Y, Iwayama Y, Toyoshima M, Ogawa I, Shimamoto-Mitsuyama C, Maekawa M, Balan S, Arai M, Miyashita M, Toriumi K, et al.
  • Journal Title: EMBO Mol Med Volume: 13 Issue: 4
  • DOI: 10.15252/emmm.202012574
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Involvement of SRF coactivator MKL2 in BDNF-mediated activation of the synaptic activity-responsive element in the Arc gene. (2019)
  • Author(s): Kikuchi K, Ihara D, Fukuchi M, Tanabe H, Ishibashi Y, Tsujii J, Tsuda M, Kaneda M, Sakagami H, Okuno H, Bito H, Yamazaki Y, Ishikawa M, Tabuchi A.
  • Journal Title: Journal of Neurochemistry Volume: 148 Issue: 2 Pages: 204-218
  • DOI: 10.1111/jnc.14596
  • Peer Reviewed / Open Access
• [Journal Article] Perturbed expression pattern of the immediate early gene Arc in the dentate gyrus of GluA1 C‐terminal palmitoylation‐deficient mice (2018)
  • Author(s): Itoh Masayuki、Okuno Hiroyuki、Yamada Daisuke、Yamashita Mariko、Abe Manabu、Natsume Rie、Kaizuka Toshie、Sakimura Kenji、Hoshino Mikio、Mishina Masayoshi、Wada Keiji、Sekiguchi Masayuki、Hayashi Takashi
  • Journal Title: Neuropsychopharmacology Reports Volume: 39 Issue: 1 Pages: 61-66
  • DOI: 10.1002/npr2.12044
  • Peer Reviewed / Open Access
• [Presentation] Role of Arc in regulation of surface AMPA receptors and cognition (2021)
  • Author(s): Hiroyuki Okuno
  • Organizer: 第44回日本神経科学大会
  • Invited
• [Presentation] 古い記憶想起における海馬歯状回記憶痕跡細胞の関与 (2020)
  • Author(s): 奥野浩行
  • Organizer: 日本神経化学会大会
  • Invited
• [Presentation] Arc deficiency causes impairment in memory precision and cognitive switching (2019)
  • Author(s): Okuno H
  • Organizer: 第４２回日本神経科学学会大会
  • Invited
• [Presentation] Arc/Arg3.1-driven regulation of activity-dependent AMPA receptor dynamics at active and inactive synapses (2019)
  • Author(s): Bito H, Ishii Y, Fujii H, Hayashi T, Okamura M, Kondo Y, Abe M, Sakimura K, Okuno H
  • Organizer: 第４２回日本神経科学学会大会
  • Invited
• [Presentation] Characterization of stress responsive neurons by single-cell RNA-seq (2019)
  • Author(s): Tanuma M, Kasai A, Okuno H, Yamaura K, Niu M, Seiriki K, Nakazawa T, Yamaguchi S, Hashimoto H
  • Organizer: 第４２回日本神経科学学会大会
• [Presentation] Immediate-early gene mapping of neuronal activity related to intraoperative stresses under inhalation anesthesia (2019)
  • Author(s): Oe Y, Hasegawa-Moriyama M, Mukaihara K, Nakahara M, Kanmura Y, Okuno H
  • Organizer: 第４２回日本神経科学学会大会
• [Presentation] Inverse synaptic tagging of Arc and cognitive refinement processes (2019)
  • Author(s): Okuno H
  • Organizer: 14th International Congress of the Polish Neuroscience Society
  • Int'l Joint Research / Invited