Terazono Hideyuki, Mutoh Tatsushi, Yamaguchi Shun, Kobayashi Masaki, Akiyama Masashi, Udo Rhyuta, Ohdo Shigehiro, Okamura Hitoshi, Shibata Shigenobu
Department of Pharmacology and Brain Science, School of Human Sciences, Waseda University, Tokorozawa, Saitama 359-1192, Japan.
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6795-800. doi: 10.1073/pnas.0936797100. Epub 2003 May 16.
A main oscillator in the suprachiasmatic nucleus (SCN) conveys circadian information to the peripheral clock systems for the regulation of fundamental physiological functions. Although polysynaptic autonomic neural pathways between the SCN and the liver were observed in rats, whether activation of the sympathetic nervous system entrains clock gene expression in the liver has yet to be understood. To assess sympathetic innervation from the SCN to liver tissue, we investigated whether injection of adrenaline/noradrenaline (epinephrine/norepinephrine) or sympathetic nerve stimulation could induce mPer gene expression in mouse liver. Acute administration of adrenaline or noradrenaline increased mPer1 but not mPer2 expression in the liver of mice in vivo and in hepatic slices in vitro. Electrical stimulation of the sympathetic nerves or adrenaline injection caused an elevation of bioluminescence in the liver area of transgenic mice carrying mPer1 promoter-luciferase. Under a light-dark cycle, destruction of the SCN flattened the daily rhythms of not only mPer1, mPer2, and mBmal1 genes but also noradrenaline content in the liver. Daily injection of adrenaline, administered at a fixed time for 6 days, recovered oscillations of mPer2 and mBmal1 gene expression in the liver of mice with SCN lesion on day 7. Sympathetic nerve denervation by 6-hydroxydopamine flattened the daily rhythm of mPer1 and mPer2 gene expression. Thus, on the basis of the present results, activation of the sympathetic nerves through noradrenaline and/or adrenaline release was a factor controlling the peripheral clock.
视交叉上核（SCN）中的主振荡器将昼夜节律信息传递给外周生物钟系统，以调节基本生理功能。尽管在大鼠中观察到了SCN与肝脏之间的多突触自主神经通路，但交感神经系统的激活是否会影响肝脏中生物钟基因的表达仍有待明确。为了评估从SCN到肝脏组织的交感神经支配，我们研究了注射肾上腺素/去甲肾上腺素（肾上腺素/去甲肾上腺素）或交感神经刺激是否能诱导小鼠肝脏中mPer基因的表达。急性给予肾上腺素或去甲肾上腺素可增加体内小鼠肝脏和体外肝切片中mPer1的表达，但不会增加mPer2的表达。对交感神经进行电刺激或注射肾上腺素会导致携带mPer1启动子-荧光素酶的转基因小鼠肝脏区域的生物发光增强。在明暗周期下，破坏SCN不仅会使mPer1、mPer2和mBmal1基因的昼夜节律变平，还会使肝脏中的去甲肾上腺素含量变平。在第7天，每天在固定时间注射肾上腺素，持续6天，可恢复SCN损伤小鼠肝脏中mPer2和mBmal1基因表达的振荡。用6-羟基多巴胺进行交感神经去神经支配会使mPer1和mPer2基因表达的昼夜节律变平。因此，根据目前的结果，通过去甲肾上腺素和/或肾上腺素释放激活交感神经是控制外周生物钟的一个因素。
