Molecularmechanism of motor learning

运动学习的分子机制

• 批准号: 12680745
• 负责人: MORI Hisashi
• 金额: $ 2.56万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12680745/
• 关键词: Glutamate receptor; Gene knockout mice; Learning and memory; NMDA receptor; GluRδ2; GluRδ; 遺伝子組み換え酵素Cre; グルタミン酸受容体チャネル; GluRδ2; 小脳プルキンエ細胞; LTD; 瞬目反射条件付け; GluRε1; 海馬; LTP

To investigate the molecular mechanism of motor learning, we have analyzed the eyeblink conditioning in glutamate receptor (GluR) subunit gene knockout (KO) mice. We have used cerebellar Purkinje cell-specific GluRδ2 KO and NMDA-type GluRε1 KO mice. We have obtained following results.1) We conducted the eyeblink conditioning with GluRδ2 KO mice, using various temporal intervals between the conditioned stimulus (CS) and unconditioned stimulus (US). In the delay paradigm in which the CS overlapped temporally with US, GluRδ2 KO mice exhibited severe learning impairment. In contrast, GluRδ2 KO mice learned well the paradigm in which no temporal overlap between the CS and US. Because the GluRδ2 KO mice have deficient in cerebellar LTD, these results indicates the GluRδ2 and LTD are essential for motor learning when there is CS-US temporal overlap, suggesting that the cerebellar substrates underlying eyeblink conditioning may change, depending on the temporal overlap of the CS and US.2) The NMDA-type GluRε1 KO mice exhibited sever learning impairment in eyeblink conditioning with a long trace interval between the CS and US. In contrast, these mice showed a little slow learning in the delay and short trace paradigms. These results indicate that the NMDA-type GluRε1 is essential for long-trace interval eyeblink conditioning.3) We have also analyzed the acoustic startle response (ASR) of NMDA-type GluRε1 KO, GluRε2 KO, GluRε3 KO and GluRε4 KO mice. The GluRε2 hetero KO mice showed the enhancement of ASR. On the other hand, heterozygous and homozygous mutation of the other NMDA-type GluRε subunits exerted no, or only small effects on ASR. We suggest that the GluRε2 subunit play a distinct role in the regulation of the ASR.

为了研究运动学习的分子机制，我们分析了谷氨酸受体（GLUR）亚基基因基因敲除（KO）小鼠中的骨闪烁调节。我们使用了小脑Purkinje细胞特异性GlurΔ2KO和NMDA型Glurε1KO小鼠。我们已经获得了以下结果。1）我们使用条件刺激（CS）和无条件的刺激（US）之间的各种临时间隔（US）进行了各种临时间隔。在CS暂时与我们重叠的延迟范式中，Glurδ2KO小鼠暴露了严重的学习障碍。相反，GlurΔ2KO小鼠很好地学到了CS和U之间没有暂时重叠的范式。因为GlURΔ2KO小鼠在小脑LTD缺乏，所以这些结果表明，当存在CS-US临时重叠时，Glurδ2和LTD对于运动学习至关重要，这表明逐链链接条件的小脑底物可能会随着CS和US的临时重叠而变化。 CS和我们之间的千篇一律调节中的损伤。相比之下，这些小鼠在延迟和短痕量范例中显示出一些缓慢的学习。这些结果表明，NMDA-typeglurε1对于长期跟踪间隔的眼睛闪烁条件至关重要。3）我们还分析了NMDA-typeGlurε1KO，Glurε2KO，Glurε3KO，Glurε3KO和Glurε4KO小鼠的NMDA-typeGlurε1KO，GLURε2KO。 GLURε2杂波小鼠显示ASR的增强。另一方面，其他NMDA型Glurε亚基对ASR的杂合和纯合突变，或对ASR的影响很小。我们建议Glurε2亚基在ASR的调节中起着独特的作用。

项目成果

Miyamoto,Y et al.,: "Hyperfunction of dopaminergic and serotonergic neural systems in mice lacking NMDA receptor ε1 subunit."J.Neurosci.. 21. 750-757 (2001)

Miyamoto,Y 等人：“缺乏 NMDA 受体 ε1 亚基的小鼠中多巴胺能和血清素能神经系统的功能亢进。”J.Neurosci.. 21. 750-757 (2001)

Kishimoto,Y et al.,: "Long-trace interval eyeblink conditioning is impaired in mutant mice lacking the NMDA receptor subunit ε1"Eur.J.Neurosci. 13. 1221-1227 (2001)

Kishimoto, Y 等人：“缺乏 NMDA 受体亚基 ε1 的突变小鼠的长轨迹眨眼条件反射受损”Eur.J.Neurosci. 13. 1221-1227 (2001)

Nakamura K, Manabe T, Watanabe M, Mamiya T, Ichikawa R, Kiyama Y, Sanbo M, Yagi T, Inoue Y, Nabeshima T, Mori H, Mishina M.: "Enhancement of hippocampal LTP, reference memory and sensorimotor gating in mutant mice lacking a telencephalon-specific cell adh

Nakamura K、Manabe T、Watanabe M、Mamiya T、Ichikawa R、Kiyama Y、Sanbo M、Yagi T、Inoue Y、Nabeshima T、Mori H、Mishina M.：“突变体中海马 LTP、参考记忆和感觉运动门控的增强

Takatsuki K, Kawahara S, Mori H, Mishina M, Kirino Y.: "Scopolamine impairs eyeblink conditioning in cerebellar LTD-deficient mice"NeuroRepoprt. 13. 159-162 (2002)

Takatsuki K、Kawahara S、Mori H、Mishina M、Kirino Y.：“东莨菪碱会损害小脑 LTD 缺陷小鼠的眨眼调节”NeuroRepoprt。

Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M, Nabeshima T.: "Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor ε1 subunit"J. Neurosci. 21. 750-757 (2001)

Miyamoto Y、Yamada K、Noda Y、Mori H、Mishina M、Nabeshima T.：“缺乏 NMDA 受体 ε1 亚基的小鼠的多巴胺能和血清素神经系统功能亢进”J. Neurosci。