Causes and consequences of hyperexcitation in central clock neurons.
Causes and consequences of hyperexcitation in central clock neurons.
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DOI：
10.1371/journal.pcbi.1003196
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发表时间：
2013
影响因子：
4.3
通讯作者：
Forger DB
中科院分区：
文献类型：
--
作者：
Diekman CO;Belle MD;Irwin RP;Allen CN;Piggins HD;Forger DB
在视交叉上核（SCN）的神经元中观察到超兴奋状态，包括去极化阻滞和去极化低振幅膜振荡（DLAMO），视交叉上核（SCN）是哺乳动物昼夜节律（~24小时）时钟的中心部位。这种过度兴奋的原因和后果尚未确定。在这里，我们探索单个离子电流如何促成这些超兴奋状态，以及超兴奋如何影响 SCN 神经元内的分子昼夜节律计时。我们开发了 SCN 神经元电活动的数学模型，并通过实验验证了其关于 DLAMO 依赖于突触后 L 型钙电流的预测。该模型预测，过度兴奋状态会导致细胞内钙浓度升高，从而触发时钟基因的转录。该模型还预测，某些离子电流的昼夜节律控制可以诱发超兴奋状态。将它们整合到一个综合模型中，我们展示了膜电位和钙浓度如何提供快速反馈，从而增强细胞内生物钟的节律性。这项工作提出了电活动在昼夜节律计时中的新作用，并表明超兴奋状态提供了将膜电动力学与细胞核转录激活联系起来的通用机制。哺乳动物的行为和生理的日常节律是由一组神经元协调的，这些神经元构成了中央昼夜节律（~24 小时）时钟。时钟神经元包含分子反馈回路，导致时钟相关基因的节律表达。过去二十年来，在了解分子生物钟的遗传基础方面已经取得了很大进展。然而，分子钟和时钟神经元的主要输出（它们的电活动）之间的关系仍不清楚。在这里，我们使用时钟神经元在一天中的某个时间进入的不寻常电状态的计算模型来探索这种关系。我们预测这种状态会导致时钟神经元内钙离子浓度升高，从而激活时钟基因的转录。我们证明这种额外的反馈可以促进 24 小时基因表达节律。因此，我们认为电活动不仅仅是时钟的输出，而且是核心昼夜节律计时机制的一部分，在健康和疾病中发挥着重要作用。
Hyperexcited states, including depolarization block and depolarized low amplitude membrane oscillations (DLAMOs), have been observed in neurons of the suprachiasmatic nuclei (SCN), the site of the central mammalian circadian (∼24-hour) clock. The causes and consequences of this hyperexcitation have not yet been determined. Here, we explore how individual ionic currents contribute to these hyperexcited states, and how hyperexcitation can then influence molecular circadian timekeeping within SCN neurons. We developed a mathematical model of the electrical activity of SCN neurons, and experimentally verified its prediction that DLAMOs depend on post-synaptic L-type calcium current. The model predicts that hyperexcited states cause high intracellular calcium concentrations, which could trigger transcription of clock genes. The model also predicts that circadian control of certain ionic currents can induce hyperexcited states. Putting it all together into an integrative model, we show how membrane potential and calcium concentration provide a fast feedback that can enhance rhythmicity of the intracellular circadian clock. This work puts forward a novel role for electrical activity in circadian timekeeping, and suggests that hyperexcited states provide a general mechanism for linking membrane electrical dynamics to transcription activation in the nucleus. Daily rhythms in the behavior and physiology of mammals are coordinated by a group of neurons that constitute the central circadian (∼24-hour) clock. Clock neurons contain molecular feedback loops that lead to rhythmic expression of clock-related genes. Much progress has been made in the past two decades to understand the genetic basis of the molecular circadian clock. However, the relationship between the molecular clock and the primary output of clock neurons—their electrical activity—remains unclear. Here, we explore this relationship using computational modeling of an unusual electrical state that clock neurons enter at a certain time of day. We predict that this state causes high concentration of calcium ions inside clock neurons, which activates transcription of clock genes. We demonstrate that this additional feedback promotes 24-hour gene expression rhythms. Thus, we propose that electrical activity is not just an output of the clock, but also part of the core circadian timekeeping mechanism that plays an important role in health and disease.
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影响因子：
3.5
作者：
Diekman, Casey O.;Forger, Daniel B.
通讯作者：
Forger, Daniel B.
DOI：
10.1016/j.cub.2011.09.027
发表时间：
2011-11-08
期刊：
Current biology : CB
影响因子：
--
作者：
Depetris-Chauvin A;Berni J;Aranovich EJ;Muraro NI;Beckwith EJ;Ceriani MF
通讯作者：
Ceriani MF
影响因子：
3.5
作者：
Cheng, Hai-Ying M.;Alvarez-Saavedra, Matias;Obrietan, Karl
通讯作者：
Obrietan, Karl
影响因子：
16.2
作者：
Ikeda, M;Sugiyama, T;Allen, CN
通讯作者：
Allen, CN
连接SCN中的神经活动和分子振荡。
影响因子：
34.7
作者：
Colwell, Christopher S.
通讯作者：
Colwell, Christopher S.