七氟醚麻醉后的MAPK/ERK-CREB通路变化及睡眠节律紊乱机制

Postoperative delirium is usually accompanied by sleep-rhythm disturbance, but the mechanisms underlying the disturbance of sleep-rhythm, and its relationship with POD are not clearly understood. It has been shown that melatonin and its receptor pathway are considered as the basis of neuroendocrine, regulating the sleep/wake circles, which gated by biological clock gene. We previously found that sevoflurane exposure altered rhythmicity of melatonin secretion and MT1/MT2 expression, suggesting the feedback loop among melatonin secretion rhythmicity, melatonin receptor pathway and biological clock gene is the key contributor in sevoflurane-induced disturbance of sleep-rhythm and memory deficits. This study is thus designed to investigate the dynamic effect of sevoflurane exposure on sleep rhythmicity and its relationship with biological clock gene baml1、clock、per1 levels in aged rats. In addition， to further explore the relationship between biological rhythm and memory performance, MAPK/ERK-CREB pathway, a known downstream signaling pathway for melatonin receptor, will be intervened. The results of the present study may reveal the molecular mechanism for how the sleep rhythm system potentially effect cognitive after sevoflurane anesthesia, and provide a new experimental basis for preventing POD.

术后谵妄（POD）常伴有睡眠节律的改变，而睡眠节律紊乱的机制及其与POD的关系尚不明确。研究表明，褪黑素及其受体（MT1/MT2）通路是调节睡眠-觉醒周期的神经内分泌基础，且均受到生物钟节律基因的调控。我们前期研究发现：麻醉后褪黑素分泌节律及受体表达水平出现明显波动，因此推测褪黑素分泌节律变化及受体通路与生物钟基因形成反馈环路在麻醉手术所致睡眠紊乱及脑功能障碍起关键作用。本研究拟观察七氟醚麻醉对老龄大鼠睡眠节律的影响，并探究其与褪黑素及生物钟基因baml1、clock、per1表达节律的关系；在此基础上，通过干预褪黑素受体下游信号传导通路MAPK/ERK-CREB，观察七氟醚麻醉后其节律性变化，进一步探讨生物节律与记忆的关系。研究结果将揭示七氟醚麻醉后睡眠节律相关作用通路对认知影响的分子机制，为防治术后谵妄提供新的实验依据。

术后谵妄（POD）常伴有睡眠节律的改变，而睡眠节律紊乱的机制及其与POD的关系尚不明确。研究表明，褪黑素及其受体（MT1/MT2）通路是调节睡眠-觉醒周期的神经内分泌基础，且均受到生物钟节律基因的调控。我们前期研究发现：麻醉后褪黑素分泌节律及受体表达水平出现明显波动，因此推测褪黑素分泌节律变化及受体通路与生物钟基因形成反馈环路在麻醉手术所致睡眠紊乱及脑功能障碍起关键作用。本研究观察到1）七氟醚麻醉及手术可引起老龄小鼠谵妄样行为及睡眠-觉醒节律改变，并且引起SCN区MT1表达水平上调及生物钟基因baml1、clock、Cry1相位移动。在此基础上，我们通过进一步干预褪黑素受体下游信号传导通路ERK-CREB，发现p-ERK/ERK、p-CREB/CREB水平在术后第1天下降。外源性褪黑素给予可缓解上述症状。研究结果揭示七氟醚麻醉手术后出现的谵妄样行为及睡眠节律变化可能与褪黑素受体，节律基因及其下游下游信号通路ERK-CREB行成的反馈环路相关。