Emerging evidence implicates experience-dependent myelination in learning and memory. However, the specific signals underlying this process remain unresolved. We demonstrate that the neuropeptide dynorphin, which is released from neurons upon high levels of activity, promotes experience-dependent myelination. Following forced swim stress, an experience that induces striatal dynorphin release, we observe increased striatal oligodendrocyte precursor cell (OPC) differentiation and myelination, which is abolished by deleting dynorphin or blocking its endogenous receptor, kappa opioid receptor (KOR). We find that dynorphin also promotes developmental OPC differentiation and myelination and demonstrate that this effect requires KOR expression specifically in OPCs. We characterize dynorphin-expressing neurons and use genetic sparse labeling to trace their axonal projections. Surprisingly, we find that they are unmyelinated normally and following forced swim stress. We propose a new model whereby experience-dependent and developmental myelination is mediated by unmyelinated, neuropeptide-expressing neurons that promote OPC differentiation for the myelination of neighboring axons.

新出现的证据表明学习和记忆中依赖于经验的髓鞘形成。然而，这一过程背后的具体信号仍未得到解决。我们证明神经肽强啡肽是在高水平活动时从神经元释放的，可促进经验依赖性髓鞘形成。在强迫游泳应激（一种诱导纹状体强啡肽释放的经历）之后，我们观察到纹状体少突胶质前体细胞 (OPC) 分化和髓鞘形成增加，这可以通过删除强啡肽或阻断其内源性受体 kappa 阿片受体 (KOR) 来消除。我们发现强啡肽还促进发育的 OPC 分化和髓鞘形成，并证明这种作用需要在 OPC 中特异性表达 KOR。我们描述了强啡肽表达神经元的特征，并使用遗传稀疏标记来追踪它们的轴突投射。令人惊讶的是，我们发现它们在正常情况下是无髓鞘的，并且会受到强迫游泳的压力。我们提出了一种新模型，其中依赖于经验和发育的髓鞘形成由无髓鞘、表达神经肽的神经元介导，这些神经元促进 OPC 分化以促进相邻轴突的髓鞘形成。