Shift Work Sleep Loss: Locus Coeruleus Neuron Senescence and Degeneration

描述(由申请人提供)：美国劳动力中有很高比例的人从事夜班工作。这些人患与疲劳相关的职业伤害、抑郁症和慢性疲劳综合症的风险更大。然而，人们对轮班工作困倦和疲劳背后的神经机制知之甚少。昼夜节律失调和睡眠动态平衡是轮班工人困倦的原因，但可能不能完全解释症状和后果。我们最近发现，暴露在连续三个夜班的睡眠/觉醒模式下的小鼠出现蓝斑神经元(LCN)线粒体蛋白的氧化应激和高乙酰化，以及LCN的部分丢失，LCN是保持最佳警觉性和大脑健康所必需的神经元。值得注意的是，在4天的恢复期后，再次暴露在同样的睡眠/唤醒模式下的小鼠显示出更多的氧化应激和进一步的LCN丢失。我们假设，反复暴露于睡眠缺失，就像间歇性夜班工作一样，会导致包括LCN在内的特定觉醒活动神经元的渐进性代谢失调和神经元丢失，并且随着频繁、重复地暴露于夜班睡眠丧失，不可逆转的觉醒障碍变得明显。这项拟议的研究将确定反复暴露于轮班工作睡眠中断的渐进性质，然后确定反复睡眠丧失导致LCN损伤的分子机制，模拟夜班工作。为此，我们已经确定了涉及Sirtuins类型1和3(SirT1和SirT3)的LCN患者对反复睡眠中断的潜在适应不良反应。我们发现SirT3在LCN中作为一种重要的适应性代谢感受器和调节器来应对短期觉醒，但这种适应性信号会随着反复的睡眠丢失而失效，LCN也就丢失了。以前我们发现，大脑SirT1的急性丢失会迅速加速LCN中脂褐素的积累。脂褐素是不可逆转的氧化应激的来源。现在我们发现，反复睡眠不足耗尽了LCN SirT1，同时增加了LCN中的脂褐素。利用独特的条件性转基因小鼠品系和基因治疗，我们将研究慢性间歇性睡眠缺失中LCN损伤的机制，并确定激活Sirt1-SirT3途径在预防轮班工作睡眠缺失模型中神经损伤和觉醒障碍方面的治疗潜力。

DESCRIPTION (provided by applicant): A high percentage of the American workforce performs night shift work. These individuals have greater risk of fatigue-related occupational injuries, depression and chronic fatigue syndrome. Yet, little is known of the neural mechanisms underlying shift work sleepiness and fatigue. Circadian misalignment and sleep homeostasis contribute to sleepiness in shift workers, but may not fully explain symptomatology and consequences. We recently discovered that mice exposed to a sleep/wake pattern modeling three consecutive night shifts develop oxidative stress and hyperacetylation of mitochondrial proteins in locus coeruleus neurons (LCn) and partial loss of LCn, neurons essential for optimal alertness and brain health. Remarkably, mice re-exposed to this same sleep/wake pattern after a 4-day recovery period show increased oxidative stress and further LCn loss. We hypothesize that repeated exposures to sleep loss, as in intermittent night shift work, result in progressive metabolic dyshomeostasis and neuron loss in select wake-active neurons, including LCn, and that with frequent, repeated exposures to night shift sleep loss, irreversible wake impairments become evident. The proposed studies will determine the progressive nature of repeated exposures to shift work sleep disruption and then identify the molecular mechanisms underlying LCn injury with repeated sleep loss, modeling night shift work. To this end, we have identified potentially maladaptive responses to repeated sleep disruption in LCn involving sirtuins type 1 and 3 (SirT1 and SirT3). We find that SirT3 serves as an essential adaptive metabolic sensor and regulator in LCn in response to short-term wakefulness, yet this adaptive signal fails with repeated sleep loss, and LCn are lost. Previously we discovered that acute loss of brain SirT1 rapidly accelerates lipofuscin accumulation in LCn. Lipofuscin presents a source of irreversible oxidative stress. Now we find that repeated sleep loss depletes LCn SirT1 while increasing lipofuscin in LCn. Using unique conditional transgenic mice strains and gene therapy, we will examine the mechanisms underlying LCn injury in chronic intermittent sleep loss and determine the therapeutic potential for activating the Sirt1-SirT3 pathway in preventing neural injury and wake impairments in a model of shift work sleep loss.