Self Organized Criticality as a new paradigm of sleep regulation

描述（由申请人提供）：人类和动物经常表现出短暂的睡眠觉醒（觉醒），传统上认为这是由外部刺激或病理扰动引起的睡眠随机中断。然而，我们最近的研究结果表明，觉醒表现出复杂的时间组织和尺度不变的行为，其特征在于幂律概率分布的持续时间，而睡眠阶段的持续时间表现出指数行为。觉醒的这种复杂的尺度不变组织使得它们不太可能仅仅是对随机外部刺激的线性反应。迄今为止，在生理系统中还没有观察到由单一调节机制产生的标度不变过程和指数过程的共存。这种共存类似于表现出自组织临界性（SOC）的非平衡系统的动力学特征。因此，我们假设觉醒是睡眠调节的一个组成部分，可能是必要的，以维持和调节健康的睡眠，通过释放累积的兴奋，在监管神经元网络，SOC型的时间组织。为了解决这一假设，我们建议结合联合收割机数据从睡眠生理学和生物分子/遗传实验与现代概念从统计物理学和复杂网络的理论。利用SOC的框架，我们的具体目标是：（i）阐明导致在睡眠过程中觉醒的尺度不变组织的机制;（ii）揭示病理条件如何影响觉醒和睡眠阶段转换的SOC组织;（iii）获得新的和更敏感的睡眠障碍诊断标志物。我们将分析来自（i）健康人类受试者，和（ii）患有失眠症、嗜睡症、睡眠呼吸暂停和其他疾病的受试者;和（iii）来自健康野生型小鼠和大鼠的大型数据库。我们还将利用各种睡眠障碍的实验动物模型的数据，其中特定的睡眠相关的神经元组和脑区为目标，辨别神经生物学相互作用的关键要素可能是负责SOC复杂性的出现在系统水平的睡眠动力学。在睡眠动力学中建立SOC类型的复杂性将挑战目前占主导地位的基于稳态的睡眠调节范式，因为它表明需要在广泛的时间尺度上连续波动（觉醒）。神经元信号相互作用如何导致SOC型复杂性在系统水平上是未知的，我们将开发基于现代尺度不变网络理论的方法，以探索神经元网络拓扑结构在睡眠动力学中产生SOC的作用。 公共卫生相关性：从睡眠中短暂醒来（觉醒）传统上被视为睡眠中断，其时间动态以及潜在机制尚未得到很好的理解。我们最近发现，在健康的睡眠中，唤醒事件和睡眠阶段持续时间的时间组织表现出自组织临界性（SOC）行为，这在以前的综合生理系统中还没有报道过，并且不被当前基于稳态的睡眠动力学框架所解释。该提案的重点是通过利用生物分子和遗传动物实验的可用数据以及应用于动物模型和人类多导睡眠图记录数据的统计物理学的现代概念来确定导致SOC行为的基本控制机制，这将使我们能够在细胞水平上连接生化信号通路，通过睡眠和唤醒促进神经元的功能性神经元网络，与睡眠动力学在系统水平，并获得新的临床诊断和预后的睡眠障碍的标志物。

DESCRIPTION (provided by applicant): Humans and animals often exhibit brief awakenings from sleep (arousals), which are traditionally viewed as random disruptions of sleep caused by external stimuli or pathologic perturbations. However, our recent findings show that arousals exhibit complex temporal organization and scale-invariant behavior, characterized by a power-law probability distribution for their durations, while sleep stage durations exhibit exponential behavior. Such complex scale-invariant organization of the arousals makes it unlikely that they are merely a linear response to random external stimuli. The co-existence of both scale-invariant and exponential processes generated by a single regulatory mechanism has not been observed in physiological systems until now. Such co-existence resembles the dynamical features of non-equilibrium systems exhibiting self-organized criticality (SOC). Thus, we hypothesize that arousals are an integral part of sleep regulation and may be necessary to maintain and regulate healthy sleep by releasing accumulated excitations in the regulatory neuronal networks, following a SOC-type temporal organization. To address this hypothesis we propose to combine data from sleep physiology and bio-molecular/genetic experiments with modern concepts from statistical physics and the theory of complex networks. Utilizing the framework of SOC, our specific aim is: (i) to elucidate the mechanisms leading to scale-invariant organization of arousals during sleep; (ii) to uncover how pathologic conditions affect the SOC organization of arousals and sleep-stage transitions; (iii) to derive novel and more sensitive diagnostic markers of sleep disorders. We will analyze a large database from (i) healthy human subjects, and (ii) subjects with insomnia, narcolepsy, sleep apnea and other disorders; and (iii) from healthy wild type mice and rats. We will also utilize data from experimental animal models of various sleep disorders, where specific sleep-related neuronal groups and brain areas are targeted, to discern which key elements of the neurobiological interactions may be responsible for the emergence of SOC complexity in sleep dynamics at the system level. Establishing SOC-type complexity in sleep dynamics will challenge the current dominant homeostasis-based paradigm of sleep regulation, as it indicates the need of continuous fluctuations (arousals) over a broad range of time scales. How neuronal signaling interactions lead to SOC-type complexity at the system level is not known, and we will develop approaches based on the modern theory of scale-invariant networks to probe the role of the neuronal network topology in generating SOC in sleep dynamics. PUBLIC HEALTH RELEVANCE: Brief awakenings from sleep (arousals) are traditionally viewed as disruptions of sleep, and their temporal dynamics as well as the underlying mechanisms are not well understood. We have recently discovered that the temporal organization of arousal episodes and sleep-stage durations in healthy sleep exhibit a self-organized criticality (SOC) behavior, which has not been previously reported in integrated physiological systems, and is not accounted for by the current homeostasis-based framework of sleep dynamics. This proposal focuses on identifying the basic control mechanisms leading to SOC behavior by utilizing available data from bio-molecular and genetic animal experiments as well as modern concepts from statistical physics applied to data from animal models and human polysomnographic recordings, that will allow us to link biochemical signaling pathways at the cellular level, through functional neuronal networks of sleep- and wake-promoting neurons, with sleep dynamics at the system level, and to derive novel clinical diagnostic and prognostic markers of sleep disorders.