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: 8925139
• 负责人: SIGRID C VEASEY
• 金额: $ 44.59万
• 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/8925139
• 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; 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; 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

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）：美国劳动力中很大一部分从事夜班工作。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稳态会导致轮班工人嗜睡，但可能无法完全解释症状和后果。我们最近发现，暴露于连续三个夜班的睡眠/觉醒模式的小鼠会出现蓝斑神经元（LCn）中线粒体蛋白的氧化应激和过度乙酰化，以及LCn的部分丧失，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，经过 4 天的恢复期后，重新暴露于相同睡眠/觉醒模式的小鼠表现出氧化应激增加和 LCn 进一步损失。我们假设，反复暴露于睡眠不足，如间歇性夜班工作，会导致进行性代谢失调和某些清醒活跃神经元（包括 LCn）的神经元丢失，并且随着频繁、反复暴露于夜班睡眠不足，不可逆的觉醒损伤变得明显。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质，然后确定反复睡眠不足引起的 LCn 损伤的分子机制，模拟夜班工作。为此，我们发现了涉及 1 型和 3 型去乙酰化酶（SirT1 和 SirT3）的 LCn 对重复睡眠中断的潜在适应不良反应。我们发现 SirT3 作为 LCn 中重要的适应性代谢传感器和调节器来响应短期觉醒，但这种适应性信号会随着反复的睡眠缺失而失效，并且 LCn 也会丢失。此前我们发现大脑 SirT1 的急性缺失会迅速加速 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，反复睡眠不足会消耗 LCn SirT1，同时增加 LCn 中的脂褐质。使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，并确定激活 Sirt1-SirT3 通路在轮班工作睡眠缺失模型中预防神经损伤和觉醒障碍的治疗潜力。