Sleep, Cytokines and Infection

描述（由申请人提供）：感染对心理健康有负面影响。病人变得无精打采，经历认知缺陷和不适，对社会交往和其他日常活动失去兴趣。在感染期间中枢神经系统过程的显著变化是睡眠的改变。细胞因子，如白细胞介素(IL)-1、肿瘤坏死因子（TNF）和IL-6在感染期间上调。两种证据表明，感染引起的睡眠改变是由大脑中这些细胞因子的作用介导的。首先，大量研究表明，在没有免疫挑战的情况下，IL-1、TNF和IL-6调节生理性睡眠。第二，已经确定睡眠变化与这些细胞因子增加有关的实验模型。IL-1、TNF和IL-6参与睡眠调节，以及感染期间这些细胞因子上调时发生的睡眠改变，导致人们认为感染引起的睡眠改变是由大脑细胞因子介导的。尽管这似乎是合理的，并且基于经验证据，但尚未进行直接验证这一假设的研究。这个项目的基本目标是确定急性感染如何改变睡眠。为了实现这一目标，我们将使用临床相关的盲肠结扎和穿刺引起的感染、败血症小鼠模型。我们建议将实验重点放在细胞因子（IL-1， TNF, IL-6）作为感染诱导睡眠改变的介质上。我们将：1)确定感染改变睡眠的程度以及先前睡眠不足对感染反应的影响；2)量化感染期间脑细胞因子mRNA和蛋白的变化；3)回答“干扰大脑细胞因子的活动是否会影响感染引起的睡眠改变？”IL-1、TNF和IL-6在脓毒症中的外周作用一直是深入研究的主题，并且是已知的睡眠中枢调节因子。因此，有一个强有力的概念框架来研究睡眠和败血症之间的机制关系，以及涉及这两个过程的介质。我们提出的初步数据表明，急性外周感染后中枢神经系统功能的长期改变。我们证明了我们有能力确定小鼠睡眠-觉醒行为的多个方面，并以大脑中的细胞因子系统为目标。成功完成拟议的研究将为理解感染如何影响中枢神经系统功能提供关键信息，正如睡眠改变所证明的那样。

DESCRIPTION (provided by applicant): Infection negatively impacts mental health. Sick individuals become lethargic, experience cognitive deficits and malaise, and lose interest in social contact and other usual daily activities. Prominent among the changes in CNS processes during infection are alterations in sleep. Cytokines, such as interleukin (IL)-1, tumor necrosis factor (TNF), and IL-6 are upregulated during infection. Two lines of evidence suggest that infection-induced alterations in sleep are mediated by actions of these cytokines in brain. First, numerous studies indicate IL-1, TNF, and IL-6 regulate/modulate physiological sleep in the absence of immune challenge. Second, experimental models for which alterations in sleep have been determined are associated with increases in these same cytokines. The involvement of IL-1, TNF, and IL-6 in the regulation of sleep, and the alterations in sleep that occur during infections in which these cytokines are upregulated, have led to suggestions that infection-induced alterations of sleep are mediated by cytokines in brain. Although plausible, and based on empirical evidence, studies to directly test this hypothesis have not been conducted. The fundamental goal of this project is to determine how acute infections alter sleep. To achieve this goal we will use a clinically relevant murine model of infection, sepsis induced by cecal ligation and puncture. We propose experiments that focus on cytokines (IL-1, TNF, IL-6) as mediators of infection-induced alterations in sleep. We will: 1) determine the extent infection alters sleep and the impact of prior sleep loss on responses to infection; 2) quantify alterations in cytokine mRNA and protein in brain during infection; and 3) answer the question "Does interfering with cytokine actions in brain impact infection-induced alterations in sleep?" IL-1, TNF, and IL-6 have been the subject of intense investigation with respect to their peripheral roles in sepsis, and are known central regulators/modulators of sleep. As such, there is a strong conceptual framework within which to investigate the mechanistic relationships between sleep and sepsis, and mediators implicated in both processes. We present preliminary data that demonstrate long-term alterations in CNS function following acute peripheral infection. We demonstrate our ability to determine multiple facets of sleep-wake behavior of mice and to target cytokine systems in brain. Successful completion of the proposed studies will provide information critical to understanding how infection impacts CNS function, as evidenced by alterations in sleep.