Shift Work Sleep Loss: Locus Coeruleus Neuron Senescence and Degeneration

轮班工作睡眠不足：蓝斑神经元衰老和变性

• 批准号: 9121592
• 负责人: SIGRID C VEASEY
• 金额: $ 45.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-09 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121592
• 关键词: Accidents; Acetylation; Acute; Age; American; Antioxidants; Apoptosis; Biological Assay; Blood Vessels; Brain; Chronic; Chronic Fatigue Syndrome; Circadian Rhythms; Exposure to; Fatigue; Health; Homeostasis; Impairment; Individual; Injury; Life; Lipofuscin; Mental Depression; Metabolic; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mouse Strains; Mus; Nature; Nerve Degeneration; Neurobiology; Neuronal Injury; Neurons; Occupational injury; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pattern; Personal Satisfaction; Phenotype; Play; Prevention; Production; Recovery; Research; Residual state; Risk; Role; Safety; Signal Transduction; Sirtuins; Sleep; Sleep Deprivation; Source; Therapeutic; Time; Transgenic Mice; Up-Regulation; Wakefulness; Work; alertness; behavior test; brain health; disturbance in affect; experience; feeding; gene therapy; improved; injured; locus ceruleus structure; nerve injury; neuromechanism; neuron loss; novel therapeutics; premature; prevent; response; senescence; sensor; shift work; symptomatology

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.

描述（由申请人提供）：美国劳动力的高比例进行夜班工作。这些人有更大的风险与疲劳有关的职业伤害，抑郁症和慢性疲劳综合症。然而，很少有人知道的神经机制轮班工作嗜睡和疲劳。昼夜节律失调和睡眠稳态有助于倒班工人的嗜睡，但可能不能完全解释睡眠学和后果。我们最近发现，暴露于模拟连续三个夜班的睡眠/觉醒模式的小鼠在蓝斑神经元（LCn）中产生氧化应激和线粒体蛋白的过度乙酰化，以及LCn的部分损失，这些神经元对最佳警觉性和大脑健康至关重要。值得注意的是，在4天恢复期后再次暴露于相同睡眠/觉醒模式的小鼠显示出增加的氧化应激和进一步的LCn损失。我们假设反复暴露于睡眠丧失，如在间歇性夜班工作中，导致进行性代谢平衡障碍和选择的唤醒活性神经元（包括LCn）的神经元丢失，并且随着频繁重复暴露于夜班睡眠丧失，不可逆的唤醒损伤变得明显。拟议的研究将确定反复暴露于轮班工作睡眠中断的渐进性，然后确定LCn损伤与反复睡眠丧失的分子机制，模拟夜班工作。为此，我们已经确定了潜在的适应不良反应，反复睡眠中断LCn涉及sirtuins类型1和3（SirT 1和SirT 3）。我们发现SirT 3作为LCn中响应短期觉醒的重要适应性代谢传感器和调节器，但这种适应性信号随着反复睡眠丧失而失效，LCn丢失。以前，我们发现大脑SirT 1的急性丢失迅速加速LCn中脂褐素的积累。脂褐素是不可逆氧化应激的来源。现在我们发现，反复的睡眠不足会消耗LCn SirT 1，同时增加LCn中的脂褐素。使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丧失中LCn损伤的潜在机制，并确定激活Sirt 1-SirT 3通路在轮班工作睡眠丧失模型中预防神经损伤和觉醒障碍的治疗潜力。