2026年3月18日出版的《自然》杂志发表了美国科学家的一项最新研究成果。来自哈佛医学院Wade G. Regehr小组的研究发现攀爬纤维招募解除抑制以增强浦肯野细胞钙信号。

为了确定CF如何在不抑制可塑性和学习所需的PC钙信号的情况下激活MLIs，课题组人员研究了CF输入到MLIs的特异性。序列电镜重建显示，CFs与两种MLI2亚型的接触没有形成传统的突触，但更多的CFs通过更多的位点和更大的接触面积与每个MLI2进行接触。切片实验表明，CFs通过谷氨酸溢出优先激活MLI2s。与这些解剖和切片实验一致，体内神经像素记录显示，自发的CF活动激发MLI2s，抑制MLI1s并去抑制pc。

相比之下，与学习相关的感觉刺激产生更复杂的反应，驱动趋同的CF和颗粒细胞输入，可以激活或抑制MLI1s。当CFs同步活跃时，这种平衡会自动转向MLI1抑制，从而提高长期抑郁所必需的PC树突钙信号。这些数据揭示了一个关键的去抑制回路，该回路允许CF通过MLI1增强可塑性所必需的PC树突钙信号，从而为为什么CF同步在诱导小脑学习方面非常有效提供了机制上的见解。

据了解，攀爬纤维（CF）输入浦肯野细胞（PCs）指导小脑的可塑性和学习。矛盾的是，CFs也会激发分子层中间神经元（MLIs），这是一种抑制PC的细胞类型，可以限制可塑性和学习。然而，最近发现了两种具有相反影响的MLI: MLI1s抑制PC，减少树突钙信号，抑制颗粒细胞对PC突触的可塑性，而MLI2s抑制MLI1s并去抑制PCs8。

附：英文原文

Title: Climbing fibres recruit disinhibition to enhance Purkinje cell calcium signals

Author: Santos-Valencia, Fernando, Lackey, Elizabeth P., Norton, Aliya, Wardak, Asem, Gaynor, Cole S., Ediger, Sean, Hemelt, Marie E., Nguyen, Tri M., Lee, Wei-Chung Allen, Brunel, Nicolas, Hull, Court A., Regehr, Wade G.

Issue&Volume: 2026-03-18

Abstract: Climbing fibre (CF) inputs to Purkinje cells (PCs) instruct plasticity and learning in the cerebellum1,2,3. Paradoxically, CFs also excite molecular layer interneurons (MLIs)4,5, a cell type that inhibits PCs and can restrict plasticity and learning6,7. However, two types of MLI with opposing influences have recently been identified: MLI1s inhibit PCs, reduce dendritic calcium signals and suppress plasticity of granule cell to PC synapses2,6,7,8,9, whereas MLI2s inhibit MLI1s and disinhibit PCs8. To determine how CFs can activate MLIs without also suppressing the PC calcium signals necessary for plasticity and learning, we investigated the specificity of CF inputs onto MLIs. Serial electron microscopy reconstructions indicate that CFs contact both MLI subtypes without making conventional synapses, but more CFs contact each MLI2 through more sites with larger contact areas. Slice experiments indicate that CFs preferentially excite MLI2s through glutamate spillover4,5. In agreement with these anatomical and slice experiments, in vivo Neuropixels recordings show that spontaneous CF activity excites MLI2s, inhibits MLI1s and disinhibits PCs. By contrast, learning-related sensory stimulation produces more complex responses, driving convergent CF and granule cell inputs that could either activate or suppress MLI1s. This balance was robustly shifted towards MLI1 suppression when CFs were synchronously active, in turn elevating the PC dendritic calcium signals necessary for long-term depression. These data provide mechanistic insight into why CF synchrony can be highly effective at inducing cerebellar learning2,3 by revealing a critical disinhibitory circuit that allows CFs to act through MLIs to enhance PC dendritic calcium signals necessary for plasticity.

DOI: 10.1038/s41586-026-10220-4

Source: https://www.nature.com/articles/s41586-026-10220-4