Reducing complement activation during sleep deprivation yields cognitive improvement by dexmedetomidine
Reducing complement activation during sleep deprivation yields cognitive improvement by dexmedetomidine
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DOI：
10.1016/j.bja.2023.04.044
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发表时间：
2023-08-21
影响因子：
9.8
通讯作者：
Wang，Qiang
中科院分区：
文献类型：
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作者：
Zhai，Qian;Zhang，Ying;Wang，Qiang
背景睡眠不足及其相关疾病(如认知缺陷)是一种巨大的社会负担，但这些认知缺陷的潜在机制尚不清楚。本研究旨在探讨右旋美托咪定(DEX)对睡眠不足所致认知功能减退的影响。方法C57BL/6小鼠每天接受20h(下午5点~次日1点)的慢性睡眠限制(CSR)，连续7d后进行认知测试。结果CSR小鼠Y迷宫学习记忆能力下降12%(P<0.0 5)，新物体识别能力下降18%(P<0.0 1)，这些变化与小胶质细胞活化、CD6 8+小胶质细胞吞噬小体计数、星形胶质细胞来源的补体C3分泌和小胶质细胞C3a受体表达增加有关(P<0.0 5)。突触消除，突触素表达下降66%(P=0.0004)和突触后密度蛋白-95表达下降45%(P=0.0003)，与认知障碍的发生有关。地塞米松可激活星形胶质细胞α-2AAR受体，抑制星形胶质细胞补体C3的释放，从而抑制小胶质细胞吞噬突触。地塞米松可恢复突触连接，逆转CSR诱导的认知功能障碍。结论与突触消除相关的补体通路激活参与了睡眠缺失相关的认知功能障碍，右美托咪啶对睡眠剥夺诱导的补体激活有保护作用。右美托咪定具有预防与睡眠缺失相关的认知缺陷的潜力，值得进一步研究。
BackgroundSleep loss and its associated conditions (e.g. cognitive deficits) represent a large societal burden, but the underlying mechanisms of these cognitive deficits remain unknown. This study assessed the effect of dexmedetomidine (DEX) on cognitive decline induced by sleep loss.MethodsC57BL/6 mice were subjected to chronic sleep restriction (CSR) for 20 h (5 pm–1 pm the next day) daily for 7 days, and cognitive tests were subsequently carried out. The neuromolecular and cellular changes that occurred in the presence and absence of DEX (100 μg kg−1, i.v., at 1 pm and 3 pm every day) were also investigated.ResultsCSR mice displayed a decline in learning and memory by 12% (P<0.05) in the Y-maze and by 18% (P<0.01) in the novel object recognition test; these changes were associated with increases in microglial activation, CD68+ microglial phagosome counts, astrocyte-derived complement C3 secretion, and microglial C3a receptor expression (allP<0.05). Synapse elimination, as indicated by a 66% decrease in synaptophysin expression (P=0.0004) and a 45% decrease in postsynaptic density protein-95 expression (P=0.0003), was associated with the occurrence of cognitive deficits. DEX activated astrocytic α2Aadrenoceptors and inhibited astrocytic complement C3 release to attenuate synapse elimination through microglial phagocytosis. DEX restored synaptic connections and reversed cognitive deficits induced by CSR.ConclusionsThe results demonstrate that complement pathway activation associated with synapse elimination contributes to sleep loss-related cognitive deficits and that dexmedetomidine protects against sleep deprivation-induced complement activation. Dexmedetomidine holds potential for preventing cognitive deficits associated with sleep loss, which warrants further study.