慢性的な社会的敗北ストレスによるうつ様行動は、ミクログリアの活性化を介した脳梁の髄鞘異常を伴う

抄録

White matter abnormalities have been implicated in psychiatric diseases such as major depressive disorder (MDD) ; however, the underlying mechanisms remain poorly understood. The structure and function of the corpus callosum are particularly vulnerable to stress, which may lead to MDD. In the present study, we investigated whether chronic social defeat stress (CSDS) induces myelin abnormalities of the corpus callosum through inflammation that contributes to the pathogenesis of MDD. To produce CSDS, the adult C57BL/6J mouse was exposed to an aggressor ICR mouse for 10 consecutive days. CSDS decreased mature oligodendrocytes in the corpus callosum, and persistently developed depression-like behaviors such as increased immobility in the forced swimming test and impaired social interaction. On transmission electron microscopy, myelin abnormalities and axonal degeneration were observed with necrosis-like cell death of oligodendrocytes in the corpus callosum. Interestingly, CSDS significantly increased the Gasdermin D (Gsdmd), a marker of pyroptosis, concomitantly with enhanced IL-1β production in the corpus callosum. Administration of IL-1β inhibitor prevented the decrease of oligodendrocytes and CSDS-induced depression-like behaviors. These findings suggest that IL-1β acts as a crucial mediator of oligodendroglial pyroptosis induced by the CSDS, which may be responsible for the development of MDD.