Shift Work Sleep Loss: Locus Coeruleus Neuron Senescence and Degeneration

描述（由申请人提供）：美国有很高比例的劳动力从事夜班工作。这些人患与疲劳有关的职业伤害、抑郁和慢性疲劳综合症的风险更大。然而，人们对倒班工作导致困倦和疲劳的神经机制知之甚少。昼夜节律失调和睡眠稳态导致轮班工作者嗜睡，但可能不能完全解释症状和后果。我们最近发现，小鼠暴露于连续三个夜班的睡眠/觉醒模式下，蓝斑神经元（LCn）的线粒体蛋白出现氧化应激和超乙酰化，LCn部分丧失，而LCn是最佳警觉性和大脑健康所必需的神经元。值得注意的是，小鼠在4天的恢复期后再次暴露于相同的睡眠/觉醒模式，显示出氧化应激增加和进一步的LCn损失。我们假设，反复暴露于睡眠不足，如在间歇性夜班工作中，导致进行性代谢不平衡和包括LCn在内的特定清醒活跃神经元的神经元损失，并且频繁、反复暴露于夜班睡眠不足，不可逆转的清醒损伤变得明显。拟议的研究将确定反复暴露于轮班工作睡眠中断的进行性性质，然后通过模拟夜班工作，确定反复睡眠不足导致的LCn损伤的分子机制。为此，我们已经确定了LCn中涉及sirtuins 1型和3型（SirT1和SirT3）的反复睡眠中断的潜在适应性不良反应。我们发现SirT3在LCn中作为一个重要的自适应代谢传感器和调节器来响应短期清醒，然而这种自适应信号随着反复的睡眠缺失而失效，LCn丢失。先前我们发现脑SirT1的急性丧失会迅速加速脂褐素在LCn中的积累。脂褐素是不可逆氧化应激的一个来源。现在我们发现反复的睡眠缺失会消耗LCn SirT1，同时增加LCn中的脂褐素。利用独特的条件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，并确定在轮班工作睡眠缺失模型中激活Sirt1-SirT3通路预防神经损伤和觉醒障碍的治疗潜力。

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.