Department of Veterinary Comparative Anatomy, Pharmacology and Physiology, Sleep and Performance Research Center, Washington State University, Spokane, WA 99210-1945, USA.
Sleep. 2011 Oct 1;34(10):1335-45. doi: 10.5665/SLEEP.1274.
Sleep loss triggers changes in inflammatory signaling pathways in the brain and periphery. The mechanisms that underlie these changes are ill-defined. The Toll-like receptor 4 (TLR4) activates inflammatory signaling cascades in response to endogenous and pathogen-associated ligands known to be elevated in association with sleep loss. TLR4 is therefore a possible mediator of some of the inflammation-related effects of sleep loss. Here we describe the baseline electroencephalographic sleep phenotype and the biochemical and electroencephalographic responses to sleep loss in TLR4-deficient mice.
DESIGN, MEASUREMENTS AND RESULTS: TLR4-deficient mice and wild type controls were subjected to electroencephalographic and electromyographic recordings during spontaneous sleep/wake cycles and during and after sleep restriction sessions of 3, 6, and 24-h duration, during which sleep was disrupted by an automated sleep restriction system. Relative to wild type control mice, TLR4-deficient mice exhibited an increase in the duration of the primary daily waking bout occurring at dark onset in a light/dark cycle. The amount of time spent in non-rapid eye movement sleep by TLR4-deficient mice was reduced in proportion to increased wakefulness in the hours immediately after dark onset. Subsequent to sleep restriction, EEG measures of increased sleep drive were attenuated in TLR4-deficient mice relative to wild-type mice. TLR4 was enriched 10-fold in brain cells positive for the cell surface marker CD11b (cells of the monocyte lineage) relative to CD11b-negative cells in wild type mouse brains. To assess whether this population was affected selectively by TLR4 knockout, flow cytometry was used to count F4/80- and CD45-positive cells in the brains of sleep deprived and time of day control mice. While wild-type mice exhibited a significant reduction in the number of CD11b-positive cells in the brain after 24-h sleep restriction, TLR4-deficient mice did not.
These data demonstrate that innate immune signaling pathways active in the monocyte lineage, including presumably microglia, detect and mediate in part the cerebral reaction to sleep loss.
睡眠缺失会引发大脑和外周炎症信号通路的改变。这些变化的机制尚不清楚。Toll 样受体 4（TLR4）可识别内源性和病原体相关配体，并激活炎症信号级联反应，这些配体与睡眠缺失有关，其水平会升高。因此，TLR4 可能是睡眠缺失引起的一些炎症相关效应的介导者。本文描述了 TLR4 缺陷型小鼠的基础脑电图睡眠表型，以及它们在睡眠缺失时的生化和脑电图反应。
设计、测量和结果：TLR4 缺陷型小鼠和野生型对照小鼠在自发睡眠/觉醒周期以及在 3、6 和 24 小时持续时间的睡眠限制期间进行脑电图和肌电图记录，在睡眠限制期间，通过自动睡眠限制系统破坏睡眠。与野生型对照小鼠相比，TLR4 缺陷型小鼠在明暗周期中黑暗开始时主要的每日清醒期持续时间增加。TLR4 缺陷型小鼠的非快速眼动睡眠时间随着黑暗开始后立即增加的觉醒时间成比例减少。睡眠限制后，与野生型小鼠相比，TLR4 缺陷型小鼠的脑电图测量结果表明睡眠驱动力增加。TLR4 在大脑细胞中高度富集，其细胞表面标志物 CD11b（单核细胞谱系的细胞）的丰度是 CD11b 阴性细胞的 10 倍。为了评估该细胞群是否被 TLR4 敲除选择性影响，采用流式细胞术计数睡眠剥夺和时间控制小鼠大脑中 F4/80 和 CD45 阳性细胞的数量。尽管野生型小鼠在 24 小时睡眠限制后大脑中 CD11b 阳性细胞的数量显著减少，但 TLR4 缺陷型小鼠没有。
这些数据表明，单核细胞谱系中活跃的先天免疫信号通路，包括推测的小胶质细胞，部分检测并介导了大脑对睡眠缺失的反应。
