Neonatal hypoxia (Hx) causes white matter (WM) injury, particularly in the cerebellum. We previously demonstrated Hx-induced reduction of cerebellar Purkinje cell (PC) activity results in locomotor deficits. Yet, the mechanism of Hx-induced cerebellar WM injury and associated locomotor abnormalities remains undetermined. Here, we show that the cerebellar WM injury and linked locomotor deficits are driven by PC activity and are reversed when PC activity is restored. Using optogenetics and multielectrode array recordings, we manipulated PC activity and captured the resulting cellular responses in WM oligodendrocyte precursor cells and GABAergic interneurons. To emulate the effects of Hx, we used light activated Halorhodopsin targeted specifically to the PC layer of normal mice. Suppression of PC firing activity at P13 and P21 phenocopied the locomotor deficits observed in Hx. Moreover, histopathologic analysis of the developing cerebellar WM following PC inhibition (P21) revealed a corresponding reduction in oligodendrocyte maturation and myelination, akin to our findings in Hx mice. Conversely, PC stimulation restored PC activity, promoted oligodendrocyte maturation and enhanced myelination, resulting in reversed Hx-induced locomotor deficits. Our findings highlight the crucial role of PC activity in cerebellar WM development and locomotor performance following neonatal injury.Significance statement Adult survivors of prematurity often experience locomotor incoordination secondary to cerebellar dysfunction. The cerebellum develops in the last trimester of pregnancy, a period that preterm neonates miss. Here, we show how neonatal hypoxia alters the crosstalk between neurons and oligodendrocytes in the developing cerebellum. Through loss-of-function and gain-of-function experiments, we unveiled that neuronal activity drives cerebellum-associated white matter injury and locomotor dysfunction after hypoxia. Importantly, restoring neuronal activity using direct neurophysiological stimulation reversed the hypoxia-induced white matter injury and locomotor deficits. Early cerebellar neuronal stimulation could serve as a potential therapeutic intervention for locomotor dysfunction in neonates.

中文翻译：

---

小脑浦肯野细胞活性调节新生儿缺氧后的白质反应和运动功能。


新生儿缺氧 （Hx） 会导致白质 （WM） 损伤，尤其是在小脑中。我们之前证明 Hx 诱导的小脑浦肯野细胞 （PC） 活性降低导致运动缺陷。然而，Hx 诱导的小脑 WM 损伤和相关运动异常的机制仍未确定。在这里，我们表明小脑 WM 损伤和相关的运动缺陷是由 PC 活动驱动的，当 PC 活动恢复时，这些缺陷会逆转。使用光遗传学和多电极阵列记录，我们操纵了 PC 活性并捕获了 WM 少突胶质细胞前体细胞和 GABA 能中间神经元中产生的细胞反应。为了模拟 Hx 的效果，我们使用了专门针对正常小鼠 PC 层的光激活盐视紫红质。P13 和 P21 处 PC 放电活性的抑制表型复制了在 Hx 中观察到的运动缺陷。此外，PC 抑制后发育中的小脑 WM 的组织病理学分析 （P21） 显示少突胶质细胞成熟和髓鞘形成的相应减少，类似于我们在 Hx 小鼠中的发现。相反，PC 刺激恢复 PC 活性，促进少突胶质细胞成熟并增强髓鞘形成，导致逆转 Hx 诱导的运动缺陷。我们的研究结果强调了 PC 活动在新生儿损伤后小脑 WM 发展和运动性能中的关键作用。意义陈述 早产儿的成年幸存者经常经历继发于小脑功能障碍的运动不协调。小脑在怀孕的最后三个月发育，这是早产新生儿错过的时期。在这里，我们展示了新生儿缺氧如何改变发育中的小脑中神经元和少突胶质细胞之间的串扰。 通过功能丧失和功能获得实验，我们揭示了神经元活动会驱动缺氧后小脑相关白质损伤和运动功能障碍。重要的是，使用直接神经生理学刺激恢复神经元活动可逆转缺氧诱导的白质损伤和运动缺陷。早期小脑神经元刺激可作为新生儿运动功能障碍的潜在治疗干预措施。