In the adult brain, activity-dependent myelin plasticity is required for proper learning and memory consolidation. Myelin loss, alteration, or even subtle structural modifications can therefore compromise the network activity, leading to functional impairment. In multiple sclerosis, spontaneous myelin repair process is possible, but it is heterogeneous among patients, sometimes leading to functional recovery, often more visible at the motor level than at the cognitive level. In cuprizone-treated mouse model, massive brain demyelination is followed by spontaneous and robust remyelination. However, reformed myelin, although functional, may not exhibit the same morphological characteristics as developmental myelin, which can have an impact on the activity of neural networks. In this context, we used the cuprizone-treated mouse model to analyze the structural, functional, and cognitive long-term effects of transient demyelination. Our results show that an episode of demyelination induces despite remyelination long-term cognitive impairment, such as deficits in spatial working memory, social memory, cognitive flexibility, and hyperactivity. These deficits were associated with a reduction in myelin content in the medial prefrontal cortex (mPFC) and hippocampus (HPC), as well as structural myelin modifications, suggesting that the remyelination process may be imperfect in these structures. In vivo electrophysiological recordings showed that the demyelination episode altered the synchronization of HPC-mPFC activity, which is crucial for memory processes. Altogether, our data indicate that the myelin repair process following transient demyelination does not allow the complete recovery of the initial myelin properties in cortical structures. These subtle modifications alter network features, leading to prolonged cognitive deficits in mice.

中文翻译：

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短暂性脱髓鞘导致长期认知障碍、髓磷脂改变和网络同步缺陷

在成人大脑中，活动依赖性髓磷脂可塑性是正确学习和记忆巩固所必需的。因此，髓磷脂的丢失、改变，甚至细微的结构修改都会损害网络活动，导致功能障碍。在多发性硬化症中，自发的髓磷脂修复过程是可能的，但患者之间存在异质性，有时会导致功能恢复，通常在运动水平比在认知水平更明显。在铜宗处理的小鼠模型中，大量脑脱髓鞘随后发生自发且强烈的髓鞘再生。然而，重组髓磷脂虽然具有功能，但可能不会表现出与发育髓磷脂相同的形态特征，这可能会对神经网络的活动产生影响。在这种情况下，我们使用铜宗处理的小鼠模型来分析短暂性脱髓鞘对结构、功能和认知的长期影响。我们的研究结果表明，尽管存在髓鞘再生，但脱髓鞘的发作仍会导致长期认知障碍，例如空间工作记忆、社会记忆、认知灵活性和多动症的缺陷。这些缺陷与内侧前额叶皮层 (mPFC) 和海马体 (HPC) 髓磷脂含量的减少以及结构髓磷脂修饰有关，表明这些结构中的髓鞘再生过程可能不完善。体内电生理记录表明，脱髓鞘事件改变了 HPC-mPFC 活动的同步性，这对于记忆过程至关重要。总而言之，我们的数据表明，短暂脱髓鞘后的髓磷脂修复过程不允许完全恢复皮质结构中的初始髓磷脂特性。这些微妙的修改改变了网络特征，导致小鼠长期认知缺陷。