純系ゲノム背景における脳システム制御の分子解析

2009 Fiscal Year Annual Research Report

• Project/Area Number: 17024011
• Research Institution: The University of Tokyo
• Principal Investigator: 三品 昌美 The University of Tokyo, 大学院・医学系研究科, 教授 (80144351)
• Co-Investigator(Kenkyū-buntansha): 植村 健 東京大学, 大学院・医学系研究科, 助教 (00372368)
• Keywords: 情動記憶 / 線条体 / 音刺激恐怖条件付け学習 / 長期記憶 / 誘導型Cre組換え酵素 / マウス / NMDA受容体 / medium spiny neuron

Research Abstract

音刺激恐怖条件付け学習による情動記憶の形成には扁桃体が中心的役割を担っており、文脈依存学習には海馬も重要であることはよく知られている。線条体medium spiny neuronに選択的に発現するGタンパク質γ7サブユニットをコードする遺伝子のプロモーター下にCre組換え酵素とプロゲステロン受容体のリガンド結合領域を融合させたCrePR遺伝子を挿入したGγ7-mCrePRマウスをCre依存的にジフテリア毒素Aを発現するEno2-STOP-DTAマウスに掛け合わせ、6週齢マウスにアンチプロゲステロンRU-486を投与することにより、線条体特異的にNeuN陽性神経細胞を誘導欠損させた。この線条体特異的神経細胞除去マウスを用いて恐怖条件付けを行った。線条体ニューロンの選択的除去を誘導してもthin rodやrotarod試験でマウスの協調運動に障害は認められなかった。また、音刺激恐怖条件付け学習にも障害は認められず、恐怖記憶に線条体は関与しないとの従来の研究と同様な結果が得られた。しかしながら、通常の電気ショックより弱いショックを用いた条件付けでは、1～3時間後の記憶は正常に形成されるが、24時間後の記憶が減弱した。また、条件付けの24時間後すなわち長期記憶が形成された後に線条体ニューロン除去を誘導すると記憶が減弱した。さらに、野生マウスを恐怖条件付けした後、線条体にNMDA受容体阻害薬APVあるいは蛋白質合成阻害薬アニソマイシンを注入したところ、通常の電気ショックによる記憶形成には影響しないが、弱いショックを用いた条件付けでは恐怖記憶の形成が障害された。これらの結果から、線条体は刺激強度が弱い条件下における情動記憶形成に重要な役割を担っており、音刺激恐怖条件付け学習には線条体依存性と非依存性の二種類があることが明らかとなった。

Research Products

• [Journal Article] Estrogen regulates the expression of N-methyl-D-aspartate(NMDA)receptor subunit epsilon 4(Grin2d), that is essential for the normal sexual behavior in female mice (2010)
  • Author(s): Ikeda, K., Fukushima, T., Ogura, H., Tsukui, T., Mishina, M., Muramatsu, M., Inoue, S.
  • Journal Title: FEBS Lett. 584 Pages: 806-810
  • Peer Reviewed
• [Journal Article] Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability (2010)
  • Author(s): Mozhui, K., Karlsson, R-M., Kash, T., Ihne, J., Norcross, M., Patel, S., Farrell, M., Hill, E., Martin, K., Camp, M., Fitzgerald, P., Ciobanu, D., Sprengel, R., Mishina, M., Wellman, C., Winder, D., Williams, R.W., Holmes, A.
  • Journal Title: J.Neurosci. (印刷中(掲載確定))
  • Peer Reviewed
• [Journal Article] Trans-synaptic interaction of GluRδ2 and neurexin through Cbln1 mediates synapse formation in the cerebellum (2010)
  • Author(s): Uemura, T., Lee, S., Yasumura, M., Takeuchi, T., Yoshida, T., Ra, M., Taguchi, R., Sakimura, K., Mishina, M.
  • Journal Title: Cell (印刷中(掲載確定))
  • Peer Reviewed
• [Journal Article] Ablation of NMDA receptors enhances the excitability of hippocampal CA3 neurons (2009)
  • Author(s): Fukushima, F., Nakao, K., Shinoe, T., Fukaya, M., Muramatsu, S., Sakimura, K., Kataoka, H., Mori, H., Watanabe, M., Manabe, T., Mishina, M.
  • Journal Title: PLoS ONE 4 Pages: e3993
  • Peer Reviewed
• [Journal Article] A novel form of memory for auditory fear conditioning at a low-intensity unconditioned stimulus (2009)
  • Author(s): Kishioka, A., Fukushima, F., Ito, T., Kataoka, H., Mori, H., Ikeda, T., Itohara, S., Sakimura, K., Mishina, M.
  • Journal Title: PLoS ONE 4 Pages: e4157
  • Peer Reviewed
• [Journal Article] NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal plasticity to sleep loss (2009)
  • Author(s): Longordo, F., Kopp, C., Mishina, M., Lujan, R., Luthi, A.
  • Journal Title: J.Neurosci. 29 Pages: 9026-9041
  • Peer Reviewed
• [Journal Article] Influence of parallel fiber-Purkinje cell synapse formation on postnatal development of climbing fiber-Purkinje cell synapses : Lessons from GluRδ2 knockout mice (2009)
  • Author(s): Hashimoto, K., Yoshida, T., Sakimura, K., Mishina, M., Watanabe, M., Kano, M.
  • Journal Title: Neuroscience 162 Pages: 601-611
  • Peer Reviewed
• [Journal Article] Regulation of synaptic vesicle accumulation and axon terminal remodeling during synapse formation by distinct Ca^<2+> signaling (2009)
  • Author(s): Yoshida, T., Uchida, S., Mishina, M.
  • Journal Title: J.Neurochem. 111 Pages: 160-170
  • Peer Reviewed
• [Presentation] A study of the role of the layer 4 of the cerebral cortex in fear memory (2010)
  • Author(s): N.Endo, T.Uemura, K.Sakimura, S.Itohara, M.Mishina
  • Organizer: The 83^<nd> Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: Osaka International Convention Center, Osaka, Japan
  • Year and Date: 2010-03-18
• [Presentation] Control of synaptic connection by Cbln1 in the adult cerebellum (2010)
  • Author(s): M.Yasumura, T.Takeuchi, T.Uemura, K.Sakimura, M.Mishina
  • Organizer: The 83^<nd> Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: Osaka International Convention Center, Osaka, Japan
  • Year and Date: 2010-03-17
• [Presentation] Identification of Cbln1 as a novel ligand for glutamate receptor δ2 (2010)
  • Author(s): T.Uemura, S-J.Lee, M.Yasumura, T.Yoshida, M.Ra, R.Taguchi, M.Mishina
  • Organizer: The 83^<nd> Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: Osaka International Convention Center, Osaka, Japan
  • Year and Date: 2010-03-17
• [Presentation] High-affinity and selective binding of Cbln1 to glutamate receptor δ2 (2010)
  • Author(s): S.J.Lee, T.Uemura, M.Mishina
  • Organizer: The 83^<nd> Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: Osaka International Convention Center, Osaka, Japan
  • Year and Date: 2010-03-17
• [Presentation] Establishment of a mouse line for inducible ablation of neurons in the layer 4 of the cerebral cortex (2009)
  • Author(s): N.Endo, T.Uemura, K.Sakimura, S.Itohara, M.Mishina
  • Organizer: The 32^<nd> Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Nagoya Congress Center, Nagoya, Japan
  • Year and Date: 2009-09-18
• [Presentation] Effects of inducible ablation of cerebellar granule or Purkinje cells on motor control (2009)
  • Author(s): E.Kato, T.Uemura, X.Chen, F.Watanabe, M.Yasumura, S.Itohara, K.Sakimura, M.Mishina
  • Organizer: The 32^<nd> Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Nagoya Congress Center, Nagoya, Japan
  • Year and Date: 2009-09-18
• [Presentation] The role of the N-terminal domain of glutamate receptor δ2 in synapse formation (2009)
  • Author(s): T.Uemura, M.Mishina
  • Organizer: The 32^<nd> Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Nagoya Congress Center, Nagoya, Japan
  • Year and Date: 2009-09-17
• [Presentation] GruRε2(NR2B)is specifically involved in the corticospinal synapse elimination during development (2009)
  • Author(s): T.Ohno, H.Maeda, N.Murabe, T.Kamiyama, N.Yoshioka, M.Mishina, M.Sakurai
  • Organizer: The 32^<nd> Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Nagoya Congress Center, Nagoya, Japan
  • Year and Date: 2009-09-16