Focal white matter lesions drive inflammation, neuronal dysfunction and synapse loss in the grey matter

Focal white matter lesions occur in most neurodegenerative disorders1-4. They are well characterised in multiple sclerosis (MS) but much less understood in other conditions. Despite occurring early in disease, white matter lesions are considered either independent of or secondary to grey matter neuroinflammation, synaptic loss and altered neuronal activity5-8. Notably their functional impact on neuronal circuits has been overlooked. To address this, we performed a focal white matter lesion in an anatomically well-defined circuit, in which white matter lesions occur in many neurodegenerative disorders. Here we show that focal white matter lesions evoke transient neuronal activity changes and microgliosis, synaptic loss and increased engulfment in the grey matter, which resolves by the time myelin regeneration completes. Synaptic loss and microgliosis are often considered detrimental but we show they are instead an integral part of the myelin regenerative process. When we prevent these transient changes in the grey matter, myelin regeneration is blocked in the white matter. Conversely, inducing myelin regeneration failure leads to chronic neuroinflammation in the grey matter, suggesting that myelin regeneration failure drives sustained microglial activation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration8-11. Hence, we present a novel mechanism that may underlie multiple conditions and highlight the potential of targeting myelin regeneration to prevent chronic neuroinflammation.局灶性白质病变（focal white matter lesions）广泛存在于绝大多数神经退行性疾病中1-4。此类病变在多发性硬化症（multiple sclerosis, MS）中的病理特征已得到充分阐明，但在其他神经退行性疾病中的致病机制仍有待深入解析。尽管白质病变可于疾病早期出现，既往研究多将其视为独立于灰质神经炎症（grey matter neuroinflammation）、突触丢失（synaptic loss）及神经元活动异常（altered neuronal activity）的病理改变，或为上述过程的继发表现5-8。值得注意的是，其对神经元环路的功能性影响长期被学界忽视。为填补这一研究空白，我们在解剖学定位明确的环路中构建了局灶性白质病变模型——该环路亦是多种神经退行性疾病中白质病变的好发部位。本研究结果显示，局灶性白质病变可诱发灰质内一过性神经元活动改变、小胶质细胞增生（microgliosis）、突触丢失及吞噬作用增强，上述病理变化可随髓鞘再生（myelin regeneration）完成而逐步消退。既往观点多认为突触丢失与小胶质细胞增生属于有害病理过程，但本研究证实二者实为髓鞘再生过程的固有组成部分。当我们阻断灰质内的上述一过性病理变化时，白质内的髓鞘再生过程亦被阻断。反之，诱导髓鞘再生失败可导致灰质出现慢性神经炎症，提示髓鞘再生失败可驱动小胶质细胞的持续性激活，这一现象与被认为是神经退行性疾病主要致病机制之一的低度炎症8-11高度吻合。综上，我们提出了一种可能参与多种疾病进程的全新机制，并强调靶向调控髓鞘再生或可成为预防慢性神经炎症的潜在治疗策略。