Molecular layer disinhibition unlocks climbing-fiber-instructed motor learning in the cerebellum.
Molecular layer disinhibition unlocks climbing-fiber-instructed motor learning in the cerebellum.
复制标题
分子层去抑制开启了小脑中攀爬纤维指导的运动学习。
DOI：
10.1101/2023.08.04.552059
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Christie,JasonM
中科院分区：
文献类型：
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作者：
Zhang,Ke;Yang,Zhen;Gaffield,MichaelA;Gross,GarrettG;Arnold,DonB;Christie,JasonM
爬行纤维通过向浦肯野细胞（PC）提供信号来监督小脑的学习，浦肯野细胞（PC）指示错误执行的动作进行适应性改变。然而，攀爬纤维经常活跃，即使在良好的运动，表明机制动态调节攀爬纤维的能力，以诱导纠正可塑性，以响应运动错误。我们发现，分子层中间神经元（MLI），其抑制PC有力地反对攀登纤维介导的兴奋，担任这一功能。在前庭眼反射（VOR）过程中，光遗传学抑制小鼠絮状MLI的活性诱导了学习性增益增加，尽管没有表现错误。当VOR错误地表现不佳时，抑制MLI揭示了它们的抑制性输出是必要的，通过有条件地允许攀爬纤维在ipsiversive头转向期间指示可塑性诱导来协调增益增加学习。消融MLI回路以实现PC去抑制可以防止VOR表现错误期间的增益增加学习，这是通过MLI活动抑制重新实施PC去抑制来挽救的。我们的研究结果指出，MLI在门控攀爬纤维介导的学习，通过其上下文依赖性抑制PC的决定性作用。
Climbing fibers supervise cerebellar learning by providing signals to Purkinje cells (PCs) that instruct adaptive changes to mistakenly performed movements. Yet, climbing fibers are regularly active, even during well performed movements, suggesting that a mechanism dynamically regulates the ability of climbing fibers to induce corrective plasticity in response to motor errors. We found that molecular layer interneurons (MLIs), whose inhibition of PCs powerfully opposes climbing-fiber-mediated excitation, serve this function. Optogenetically suppressing the activity of floccular MLIs in mice during the vestibulo-ocular reflex (VOR) induces a learned increase in gain despite the absence of performance errors. Suppressing MLIs when the VOR is mistakenly underperformed reveled that their inhibitory output is necessary to orchestrate gain-increase learning by conditionally permitting climbing fibers to instruct plasticity induction during ipsiversive head turns. Ablation of an MLI circuit for PC disinhibition prevents gain-increase learning during VOR performance errors which was rescued by re-imposing PC disinhibition through MLI activity suppression. Our findings point to a decisive role for MLIs in gating climbing-fiber-mediated learning through their context-dependent inhibition of PCs.