Sleep, Cytokines and Infection

描述(申请人提供)：感染对心理健康有负面影响。患病的人会变得昏昏欲睡，出现认知缺陷和不适，对社交和其他日常活动失去兴趣。在感染期间中枢神经系统进程的变化中，突出的是睡眠变化。白介素1、肿瘤坏死因子和白介素6等细胞因子在感染过程中表达上调。两条证据表明，感染引起的睡眠变化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，在没有免疫攻击的情况下，IL-1、肿瘤坏死因子和IL-6调节/调节生理睡眠。其次，已经确定睡眠变化的实验模型与这些相同的细胞因子的增加有关。IL-1、TNF和IL-6参与了睡眠的调节，以及在这些细胞因子上调的感染过程中发生的睡眠变化，导致了感染诱导的睡眠变化是由大脑中的细胞因子介导的。尽管这似乎有道理，而且是基于经验证据，但还没有进行过直接检验这一假设的研究。这个项目的基本目标是确定急性感染是如何改变睡眠的。为了实现这一目标，我们将使用一种临床相关的小鼠感染模型，即盲肠结扎和穿孔引起的败血症。我们建议进行实验，重点研究细胞因子(IL-1、肿瘤坏死因子、IL-6)作为感染引起的睡眠改变的介体。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)量化感染期间大脑中细胞因子mRNA和蛋白质的变化；以及3)回答“干扰大脑中的细胞因子活动是否会影响感染引起的睡眠改变？”白介素1、肿瘤坏死因子和白介素6在脓毒症中的外周作用一直是密集研究的对象，它们是已知的睡眠中枢调节/调节因子。因此，有一个强有力的概念框架来研究睡眠和脓毒症之间的机械关系，以及与这两个过程有关的介体。我们提供的初步数据显示急性外周感染后中枢神经系统功能的长期变化。我们展示了我们能够确定小鼠睡眠-觉醒行为的多个方面，并针对大脑中的细胞因子系统。拟议研究的成功完成将为理解感染如何影响中枢神经系统功能提供关键信息，如睡眠变化所证明的那样。

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.