Sleeping sickness/cytokine effects on biological clock

描述（由申请人提供）： 昏睡病，或非洲锥虫病，是一种由细胞外寄生虫布氏锥虫（T。B.）。这种疾病的特征是睡眠-觉醒周期的明显碎片化。在拟议的项目中，将使用慢性昏睡病大鼠实验模型来研究血液疾病对昼夜节律系统的影响。感染T. B.显示出昼夜节律紊乱的明显迹象这些干扰包括片段化的睡眠-觉醒模式、激素释放的改变以及视交叉上核（SCN）内在节律活动的失调，视交叉上核是哺乳动物大脑中驱动昼夜节律的主要起搏器。因此，实验性昏睡病构成了一种独特的睡眠障碍模型，可用于研究介导睡眠-觉醒周期紊乱的病理生理机制。这些紊乱的潜在机制可能涉及某些炎性细胞因子，这些细胞因子在血液中以高浓度释放并在大脑中表达作为对感染的反应。我们将在锥虫感染的大鼠SCN进行电生理记录，以检查实验性昏睡病是否改变了体内SCN和体外起搏神经元的昼夜节律功能。此外，我们将采用报告基因技术来监测昏睡病大鼠SCN神经元中“时钟基因”的昼夜节律表达的改变，以及这些改变是否可以在没有锥虫衍生分子的情况下恢复。此外，我们将研究促炎细胞因子，特别是干扰素-γ和肿瘤坏死因子-α，如何影响SCN神经元的神经元活动，突触活动和“时钟基因”表达，以检查细胞因子对昼夜节律的影响。干扰素-γ是特别感兴趣的，因为我们最近发现，它的受体表达的腹外侧SCN的神经元元素。

DESCRIPTION (provided by applicant): Sleeping sickness, or African trypanosomiasis, is an infectious blood disease caused by the extracellular parasite Trypanosoma brucei (T. b.). The disease is characterized by a marked fragmentation of the sleep-wake cycle. For the proposed project, an experimental chronic rat model of sleeping sickness will be used to study the effects of a blood disease on the circadian system. Rats infected with T. b. display clear signs of a disturbed circadian regulation. These disturbances include a fragmented sleep-wake pattern, alterations in hormonal release, and a dysregulation of the intrinsic rhythmic activity in the suprachiasmatic nuclei (SCN), the principal pacemaker in the mammalian brain driving circadian rhythms. Experimental sleeping sickness therefore constitutes a unique model of a sleep disorder that can be used in order to study pathophysiological mechanisms mediating disturbances in the sleep-wake cycle. The mechanisms underlying these disturbances may involve certain inflammatory cytokines, which are released in high concentrations in the blood and expressed in the brain as a response to the infection. We will perform electrophysiological recordings in the SCN from trypanosome-infected rats to examine if experimental sleeping sickness alters the circadian SCN function in vivo and in pacemaker neurons in vitro. In addition, we will employ reporter gene technology to monitor alterations of the circadian expression of 'clock genes' in SCN neurons from rats with sleeping sickness, and if these alterations can be restored in the absence of trypanosome-derived molecules. Further, we will study how pro-inflammatory cytokines, in particular interferon-gamma and tumor necrosis factor-alpha, affect the neuronal activity, synaptic activity and 'clock gene' expression of SCN neurons to examine the impact of cytokines on circadian rhythms. Interferon-gamma is of particular interest since we have recently found that its receptor is expressed on neuronal elements in the ventrolateral SCN.