Global parameter search reveals design principles of the mammalian circadian clock.
Global parameter search reveals design principles of the mammalian circadian clock.
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全局参数搜索揭示了哺乳动物昼夜节律时钟的设计原理。
DOI：
10.1186/1752-0509-2-22
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发表时间：
2008-02-29
影响因子：
--
通讯作者：
Herzel H
中科院分区：
文献类型：
--
作者：
Locke JC;Westermark PO;Kramer A;Herzel H
几乎所有的生物都进化出了昼夜节律（约24小时）时钟，它在昼夜循环中精确地控制着生理和行为过程。哺乳动物产生这些~24小时节律的视交叉上核（SCN）由数千个神经元组成。每个神经元包含一个产生分子振荡的基因调控网络，单个神经元的振荡通过细胞间耦合（可能是通过神经递质）同步。尽管这一基本机制目前已被接受，并在数学模型中得到了概括，但关于SCN设计原则的几个基本问题仍然知之甚少。例如，SCN的一个显著特性是，在“时差”型实验后，即当光/暗（LD）周期突然提前或延迟几个小时时，SCN节律的阶段会迅速重置。在这里，我们描述了先前构建的SCN简化模型的广泛参数优化，以进一步了解其设计原则。通过检查参数优化的前50个解决方案，我们表明神经递质在产生分子昼夜节律中的作用是极其重要的。此外，我们表明，当神经递质驱动耦合阻尼振荡器系统的节奏时，它表现出非常稳健的同步，并且更容易被光/暗周期所束缚。我们还能够在模拟中重现“时差”类型实验后的快速节奏重置。我们的工作表明，对哺乳动物时钟的参数空间进行仔细的探索，即使是一个极其简化的模型，也可以揭示意想不到的行为和重要的预测。我们的研究结果表明，神经递质反馈回路在哺乳动物时钟的稳健性和相位重置特性中起着至关重要的作用，即使在单个神经元水平上也是如此。
Virtually all living organisms have evolved a circadian (~24 hour) clock that controls physiological and behavioural processes with exquisite precision throughout the day/night cycle. The suprachiasmatic nucleus (SCN), which generates these ~24 h rhythms in mammals, consists of several thousand neurons. Each neuron contains a gene-regulatory network generating molecular oscillations, and the individual neuron oscillations are synchronised by intercellular coupling, presumably via neurotransmitters. Although this basic mechanism is currently accepted and has been recapitulated in mathematical models, several fundamental questions about the design principles of the SCN remain little understood. For example, a remarkable property of the SCN is that the phase of the SCN rhythm resets rapidly after a 'jet lag' type experiment, i.e. when the light/dark (LD) cycle is abruptly advanced or delayed by several hours. Here, we describe an extensive parameter optimization of a previously constructed simplified model of the SCN in order to further understand its design principles. By examining the top 50 solutions from the parameter optimization, we show that the neurotransmitters' role in generating the molecular circadian rhythms is extremely important. In addition, we show that when a neurotransmitter drives the rhythm of a system of coupled damped oscillators, it exhibits very robust synchronization and is much more easily entrained to light/dark cycles. We were also able to recreate in our simulations the fast rhythm resetting seen after a 'jet lag' type experiment. Our work shows that a careful exploration of parameter space for even an extremely simplified model of the mammalian clock can reveal unexpected behaviours and non-trivial predictions. Our results suggest that the neurotransmitter feedback loop plays a crucial role in the robustness and phase resetting properties of the mammalian clock, even at the single neuron level.
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影响因子：
64.8
作者：
Cheng, MY;Bullock, CM;Zhou, QY
通讯作者：
Zhou, QY
DOI：
10.1073/pnas.0604511103
发表时间：
2006-07-11
影响因子：
11.1
作者：
Gallego, Monica;Eide, Erik J.;Forger, Daniel B.
通讯作者：
Forger, Daniel B.
影响因子：
3.4
作者：
Gonze, D;Bernard, S;Herzel, H
通讯作者：
Herzel, H
影响因子：
3.4
作者：
King, VM;Chahad-Ehlers, S;Hastings, MH
通讯作者：
Hastings, MH
影响因子：
3.4
作者：
Becker-Weimann, S;Wolf, J;Kramer, A
通讯作者：
Kramer, A