Sleep and Performance Research Center, Washington State University, Spokane, WA, USA.
Prog Brain Res. 2011;193:39-47. doi: 10.1016/B978-0-444-53839-0.00003-X.
Cytokines such as tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL1β) play a role in sleep regulation in health and disease. TNFα or IL1β injection enhances non-rapid eye movement sleep. Inhibition of TNFα or IL1β reduces spontaneous sleep. Mice lacking TNFα or IL1β receptors sleep less. In normal humans and in multiple disease states, plasma levels of TNFα covary with EEG slow wave activity (SWA) and sleep propensity. Many of the symptoms induced by sleep loss, for example, sleepiness, fatigue, poor cognition, enhanced sensitivity to pain, are elicited by injection of exogenous TNFα or IL1β. IL1β or TNFα applied unilaterally to the surface of the cortex induces state-dependent enhancement of EEG SWA ipsilaterally, suggesting greater regional sleep intensity. Interventions such as unilateral somatosensory stimulation enhance localized sleep EEG SWA, blood flow, and somatosensory cortical expression of IL1β and TNFα. State oscillations occur within cortical columns. One such state shares properties with whole animal sleep in that it is dependent on prior cellular activity, shows homeostasis, and is induced by TNFα. Extracellular ATP released during neuro- and gliotransmission enhances cytokine release via purine type 2 receptors. An ATP agonist enhances sleep, while ATP antagonists inhibit sleep. Mice lacking the P2X7 receptor have attenuated sleep rebound responses after sleep loss. TNFα and IL1β alter neuron sensitivity by changing neuromodulator/neurotransmitter receptor expression, allowing the neuron to scale its activity to the presynaptic neurons. TNFα's role in synaptic scaling is well characterized. Because the sensitivity of the postsynaptic neuron is changed, the same input will result in a different network output signal and this is a state change. The top-down paradigm of sleep regulation requires intentional action from sleep/wake regulatory brain circuits to initiate whole-organism sleep. This raises unresolved questions as to how such purposeful action might itself be initiated. In the new paradigm, sleep is initiated within networks and local sleep is a direct consequence of prior local cell activity. Whole-organism sleep is a bottom-up, self-organizing, and emergent property of the collective states of networks throughout the brain.
细胞因子，如肿瘤坏死因子-α（TNFα）和白细胞介素-1β（IL1β），在健康和疾病中的睡眠调节中发挥作用。TNFα 或 IL1β 的注射增强非快速眼动睡眠。TNFα 或 IL1β 的抑制减少自发性睡眠。缺乏 TNFα 或 IL1β 受体的小鼠睡眠较少。在正常人类和多种疾病状态下，血浆 TNFα 水平与 EEG 慢波活动（SWA）和睡眠倾向相关。例如，睡眠剥夺引起的许多症状，如嗜睡、疲劳、认知能力下降、对疼痛的敏感性增强，都是由外源性 TNFα 或 IL1β 的注射引起的。IL1β 或 TNFα 单侧施加于皮质表面会导致 EEG SWA 同侧的状态依赖性增强，表明区域睡眠强度更大。单侧体感刺激等干预措施会增强局部睡眠 EEG SWA、血流和体感皮质中 IL1β 和 TNFα 的表达。状态振荡发生在皮质柱内。其中一种状态与整个动物睡眠具有相同的特性，即它依赖于先前的细胞活动，表现出自稳态，并由 TNFα 诱导。神经递质和神经胶质传递过程中释放的细胞外 ATP 通过嘌呤 2 型受体增强细胞因子的释放。ATP 激动剂增强睡眠，而 ATP 拮抗剂抑制睡眠。缺乏 P2X7 受体的小鼠在睡眠剥夺后睡眠反弹反应减弱。TNFα 和 IL1β 通过改变神经调质/神经递质受体的表达来改变神经元的敏感性，使神经元能够根据突触前神经元的活动来调整其活动。TNFα 在突触缩放中的作用已得到很好的描述。由于突触后神经元的敏感性发生变化，相同的输入将导致不同的网络输出信号，这是一种状态变化。睡眠调节的自上而下范式需要睡眠/觉醒调节脑回路的有意动作来启动整个生物体的睡眠。这就提出了一个悬而未决的问题，即这种有目的的行动本身是如何开始的。在新范式中，睡眠是在网络中启动的，局部睡眠是先前局部细胞活动的直接结果。整个生物体的睡眠是大脑中整个网络的集体状态的自下而上、自我组织和涌现的属性。
