Sleeping sickness/cytokine effects on biological clock

点击翻译按钮获取中文摘要

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.