Lee Joon-Hyuk, Guo Chong, Wu Shuting, Norton Aliya, Seo Soobin, Yao Zhiyi, Regehr Wade G
Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2025 Jul 2;16(1):6101. doi: 10.1038/s41467-025-61190-6.
Mossy fiber inputs are transformed into cerebellar Purkinje cell (PC) outputs by granule cell (GC)-dependent processing. Cerebellar dysfunction leads to motor, learning, emotional, and social deficits that are usually attributed to altered PC firing arising from impaired processing of mossy fiber inputs, even though PCs also fire independently of GCs. To isolate their contributions to cerebellum-dependent behaviors, we either disrupt GC signaling while leaving PC firing intact, or disrupt PC signaling to eliminate the influence of PCs. Experiments were performed in mice of both sexes. We find that both GC and PC signaling are essential for eyeblink conditioning and vestibulo-ocular reflex (VOR) learning. Remarkably, disrupting PC signaling impairs VOR, anxiety, and social behavior, but abolishing GC signaling does not. This establishes that while GC signaling is critical for motor learning, it does not influence many behaviors including those associated with autism-spectrum disorder. It suggests that GC-independent behaviors can potentially be rescued by restoring altered firing in downstream regions.
苔藓纤维输入通过颗粒细胞（GC）依赖的处理过程转化为小脑浦肯野细胞（PC）输出。小脑功能障碍会导致运动、学习、情绪和社交缺陷，这些通常归因于苔藓纤维输入处理受损引起的PC放电改变，尽管PC也能独立于GC放电。为了分离它们对小脑依赖行为的贡献，我们要么在保持PC放电完整的同时破坏GC信号，要么破坏PC信号以消除PC的影响。实验在两性小鼠中进行。我们发现GC和PC信号对于眨眼条件反射和前庭眼反射（VOR）学习都是必不可少的。值得注意的是，破坏PC信号会损害VOR、焦虑和社交行为，但消除GC信号则不会。这表明虽然GC信号对运动学习至关重要，但它不会影响包括与自闭症谱系障碍相关的许多行为。这表明不依赖GC的行为有可能通过恢复下游区域改变的放电来挽救。
