mTOR signaling contributes to motor skill learning in mice
mTOR signaling contributes to motor skill learning in mice
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DOI：
10.3389/fnmol.2014.00026
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发表时间：
2014-04-03
影响因子：
4.8
通讯作者：
Cyr, Michel
中科院分区：
文献类型：
--
作者：
Bergeron, Yan;Chagniel, Laure;Cyr, Michel
哺乳动物靶标雷帕霉素(MTOR)激酶是mRNA翻译的关键调节因子，被怀疑参与了多种持久形式的突触和行为可塑性。然而，它在运动学习和控制中的作用从未被研究过。这项研究在小鼠身上调查了mTOR在与加速旋转棒任务相关的学习过程中的意义。我们首先观察到，学习旋转棒并没有改变训练小鼠的纹状体、海马体、小脑和前皮层的总mTOR水平。然而，在第一次训练中，它只增加了纹状体和海马区磷酸化mTOR的水平；在第二次和第三次训练中没有观察到变化。为了进一步研究mTOR在运动技能学习中的潜在作用，我们使用药物抑制剂雷帕霉素对mTOR进行了全身性和纹状体内抑制，并使用纹状体内注射mTOR siRNA对纹状体mTOR进行了基因敲除。这三个独立的办法都与轮转业绩的大幅下降有关，这使人想起受损的合并进程。值得注意的是，这些治疗并没有影响小鼠进行杆位测试的能力，这表明mTOR活动主要控制运动学习，而不是运动能力。此外，所有处理都降低了mTORC1下游的两个分子靶标--磷酸化4EBP1和p70S6K的水平。我们的研究结果表明，纹状体mTOR激酶通过4EBP1和p70S6K的磷酸化，在参与运动技能学习的细胞和分子过程中发挥重要作用。
The mammalian target of rapamycin (mTOR) kinase is a critical regulator of mRNA translation and is suspected to be involved in various long-lasting forms of synaptic and behavioral plasticity. However, its role in motor learning and control has never been examined. This study investigated, in mice, the implication of mTOR in the learning processes associated with the accelerating rotarod task. We first observed that the rotarod learning did not alter the levels of total mTOR in the striatum, hippocampus, cerebellum, and anterior cortex of trained mice. However, it increased the levels of phosphorylated mTOR in the striatum and hippocampus exclusively during the first session of training; no change was observed at the second and third sessions. In order to further investigate the potential role of mTOR during motor skill learning, we performed systemic and intrastriatal inhibitions of mTOR using the pharmacological inhibitor rapamycin, as well as a genetic knockdown of striatal mTOR using intrastriatal infusion of mTOR siRNA. These three independent approaches were all associated with a significant reduction in rotarod performances that were reminiscent of impaired consolidation processes. Notably, these treatments did not affect the capacity of mice to execute the pole test, suggesting that mTOR activity was mainly controlling motor learning rather than motor abilities. Moreover, all treatments decreased the levels of phosphorylated 4EBP1 and P70S6K, two molecular downstream targets of mTORC1. Our findings demonstrate that striatal mTOR kinase, via the phosphorylation of 4EBP1 and P70S6K, plays an important role in the cellular and molecular processes involved in motor skill learning.