Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling
Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling
复制标题
DOI：
10.1016/j.cub.2006.02.023
复制
发表时间：
2006-03-21
期刊：
影响因子：
9.2
通讯作者：
Hastings, MH
中科院分区：
文献类型：
--
作者：
Maywood, ES;Reddy, AB;Hastings, MH
哺乳动物的昼夜节律计时是由转录/翻译后反馈环路驱动的[1]，这些环路在外周组织和视交叉上核（SCN）的昼夜节律起搏器中都很活跃。 SCN 神经元之间这些分子环的自发同步是其起搏器作用的主要要求，并将其与周围组织区分开来，后者需要外在的 SCN 依赖性线索来施加细胞同步 [2, 3]。血管活性肠多肽 (VIP) 是一种内在的 SCN 因子，参与 SCN 神经元的急性激活和电同步 [4, 5] 以及行为节律的协调 [6]。通过对整个 SCN 切片培养物中细胞昼夜节律基因表达的实时成像，我们首次证明编码 VIP 的 VPAC(2) 受体的 Vipr2 基因对于维持单个 SCN 神经元内的分子计时以及同步嵌入完整的器官典型电路中的 SCN 神经元之间的分子计时是必需的。此外，我们证明去极化和第二种 SCN 神经肽、胃泌素释放肽 (GRP) 都可以急剧增强和同步 Vipr2-/- SCN 神经元的分子计时。然而，瞬时激活和同步的 Vipr2-/- 细胞在缺乏 VIP 信号传导的情况下无法维持同步。因此，神经肽能神经元间信号传导赋予 SCN 一个典型的特性：单个神经元的细胞内分子发条装置的自发同步。
Circadian timekeeping in mammals is driven by transcriptional/posttranslational feedback loops [1] that are active within both peripheral tissues and the circadian pacemaker of the suprachiasmatic nuclei (SCN). Spontaneous synchronization of these molecular loops between SCN neurons is a primary requirement of its pacemaker role and distinguishes it from peripheral tissues, which require extrinsic, SCN-dependent cues to impose cellular synchrony [2, 3]. Vasoactive intestinal polypeptide (VIP) is an intrinsic SCN factor implicated in acute activation and electrical synchronization of SCN neurons [4, 5] and coordination of behavioral rhythms [6]. Using real-time imaging of cellular circadian gene expression across entire SCN slice cultures, we show for the first time that the Vipr2 gene encoding the VPAC(2) receptor for VIP is necessary both to maintain molecular timekeeping within individual SCN neurons and to synchronize molecular timekeeping between SCN neurons embedded within intact, organotypical circuits. Moreover, we demonstrate that both depolarization and a second SCN neuropeptide, gastrin-releasing peptide (GRP), can acutely enhance and synchronize molecular timekeeping in Vipr2-/- SCN neurons. Nevertheless, transiently activated and synchronized Vipr2-/- cells cannot sustain synchrony in the absence of VIP-ergic signaling. Hence, neuropeptidergic interneuronal signaling confers a canonical property upon the SCN: spontaneous synchronization of the intracellular molecular clockworks of individual neurons.