Gastrin-releasing peptide mediates light-like resetting of the Suprachiasmatic nucleus circadian pacemaker through cAMP response element-binding protein and Per1 activation
Gastrin-releasing peptide mediates light-like resetting of the Suprachiasmatic nucleus circadian pacemaker through cAMP response element-binding protein and Per1 activation
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DOI：
10.1523/jneurosci.1109-07.2007
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发表时间：
2007-10-31
影响因子：
5.3
通讯作者：
McMahon, Douglas G.
中科院分区：
文献类型：
--
作者：
Gamble, Karen L.;Allen, Gregg C.;McMahon, Douglas G.
哺乳动物主要的昼夜节律起搏器——下丘脑视交叉上核（SCN）的昼夜节律性，是由昼夜节律钟基因之间的转录和翻译反馈回路维持的。SCN起搏器的光重置涉及时钟基因Period1 （Per1）和Period2 （Per2）的诱导和不同细胞群之间的通信。胃泌素释放肽（GRP）定位于SCN腹侧视网膜受体区，可能从那里在SCN网络内传递光重置信号。在这里，我们在行为和细胞水平上测试了GRP作为scn内光信号的假设作用，我们还测试了GRP的作用是否依赖于cAMP反应元件结合蛋白（CREB）途径和Per1的激活。在体内显微注射GRP到Per1:：绿色荧光蛋白（GFP）小鼠的SCN区域在深夜诱导整个SCN的Per1:: GFP，包括有限的精氨酸抗利尿素免疫反应（AVP-IR）神经元群。阻断棘突介导的河河毒素通讯不会破坏Per1::GFP的诱导，但会减少AVP-IR神经元的诱导。体外应用GRP导致Per1:: gfp诱导的神经元的峰值频率持续增加。用反义寡脱氧核苷酸阻断内源性Per1抑制grp诱导的峰值频率增加。此外，用诱饵寡核苷酸抑制creb介导的基因激活可以阻断grp诱导的SCN切片中PER2:：荧光素酶节律的相移。综上所述，这些结果表明，GRP在SCN网络中通过spike依赖性和spike非依赖性机制传递相位重置信号，而CREB通路和Per1的激活是介导SCN神经元GRP重置下游事件的关键步骤。
Circadian rhythmicity in the primary mammalian circadian pacemaker, the suprachiasmatic nucleus ( SCN) of the hypothalamus, is maintained by transcriptional and translational feedback loops among circadian clock genes. Photic resetting of the SCN pacemaker involves induction of the clock genes Period1 ( Per1) and Period2 ( Per2) and communication among distinct cell populations. Gastrin-releasing peptide ( GRP) is localized to the SCN ventral retinorecipient zone, from where it may communicate photic resetting signals within the SCN network. Here, we tested the putative role of GRP as an intra-SCN light signal at the behavioral and cellular levels, and we also tested whether GRP actions are dependent on activation of the cAMP response element-binding protein ( CREB) pathway and Per1. In vivo microinjections of GRP to the SCN regions of Per1:: green fluorescent protein ( GFP) mice during the late night induced Per1:: GFP throughout the SCN, including a limited population of arginine vasopressin-immunoreactive ( AVP-IR) neurons. Blocking spike-mediated communication with tetrodotoxin did not disrupt overall Per1::GFP induction but did reduce induction within AVP-IR neurons. In vitro GRP application resulted in persistent increases in the spike frequency of Per1:: GFP-induced neurons. Blocking endogenous Per1 with antisense oligodeoxynucleotides inhibited GRP-induced increases in spike frequency. Furthermore, inhibition of CREB-mediated gene activation with decoy oligonucleotides blocked GRP-induced phase shifts of PER2:: luciferase rhythms in SCN slices. Altogether, these results indicate that GRP communicates phase resetting signals within the SCN network via both spike-dependent and spike-independent mechanisms, and that activation of the CREB pathway and Per1 are key steps in mediating downstream events in GRP resetting of SCN neurons.