Sleep deprivation elevates, and sleep alleviates, oxidative stress in the brain.

睡眠不足会增加大脑的氧化应激，而睡眠会减轻这种应激。

• 批准号: 10391334
• 负责人: Jonathan P Wisor
• 金额: $ 33.47万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391334
• 关键词: Address; Adenine; Affect; Animals; Attenuated; Autopsy; Biochemical; Biochemical Markers; Biological Assay; Brain; Brain region; Buffers; Cell Respiration; Cells; Cerebral cortex; Cerebrum; Chemosensitization; Cognition; Consumption; Coupling; Data; Diagnostic; Dinucleoside Phosphates; Electroencephalogram; Electrophysiology (science); Equilibrium; Event; Excision; Extracellular Matrix; Fatigue; Frequencies; Glucose; High Frequency Oscillation; Histology; Interneurons; Maintenance; Measures; Mediating; Metabolic; Metabolism; Microscopy; Modification; Monitor; NADH; Neurobiology; Neurons; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Parvalbumins; Performance; Pharmacology; Polysomnography; Process; Protocols documentation; Regulation; Research; Rodent; Severities; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Slow-Wave Sleep; Structure; System; Temperature; Testing; Therapeutic Intervention; Time; Visual Cortex; Visual system structure; Wakefulness; Work; brain metabolism; cell type; cognitive performance; cognitive task; glucose metabolism; in vivo; innovation; insight; intravital microscopy; knock-down; link protein; neural circuit; neurochemistry; neuronal circuitry; oxidation; prevent; reconstitution; response; sensor; sleep onset; sleep quality; targeted treatment; visual plasticity

Abstract For reasons that remain unknown, sleep is essential for the reversal of deficits in cognition and performance that accumulate with increased severity during protracted wake. One of the most robust and reliable features of sleep is a reduction of cerebral metabolism, manifested by a decline in brain temperature and a decline in brain glucose and oxygen utilization, relative to wake. It stands to reason that the metabolic down state is essential for the restorative function of sleep, yet the biochemical basis for this relationship is uncertain. Oxidative metabolism of glucose fuels neuronal activity. Postmortem assays indicate that protracted wake produces an accumulation of oxidative stress in the brain. We hypothesize that reduced glucose utilization in sleep reverses a metabolically-driven shift in the redox status (the balance of oxidation and reduction reactions) of parvalbumin-positive neurons caused by the high metabolic demand of these cells in the waking brain. We further hypothesize that this function of sleep is facilitated in part by an extracellular matrix structure known as perineuronal nets, which serve to buffer against oxidative stress in metabolically vulnerable neurons. To address these hypotheses, we will perform a systemic pharmacological manipulations (the oxidation/reduction reaction substrate nicotinic adenine dinucleotide) known to affect the brain’s capacity to withstand oxidative stress. We will also assess perform brain region-specific depletion of perineuronal nets. We will assess the effects of these manipulations, and those of sleep/wake cycle manipulations, on cellular redox status markers, both in real- time in vivo using intravital microscopy, and post mortem by coupling oxidation assays with cell type-specific immunochemical markers and histochemical assessment of perineuronal net intensity. We will additionally measure the effects of the experimental manipulations on electroencephalographic markers for brain fatigue and sleep need. The anticipated results will establish a causal interrelationship between sleep/wake cycles and brain redox status, and will identify brain oxidation/reduction reactions as a target for both diagnostic inquiry and therapeutic intervention in the face of sleep insufficiency. 1

摘要 出于未知的原因，睡眠对于认知和表现方面的缺陷的逆转至关重要 在长时间清醒时严重程度会增加最强大、最可靠的 睡眠的特点是大脑代谢减少，表现为大脑温度下降， 脑葡萄糖和氧利用率下降，相对于清醒。很明显新陈代谢的下降 睡眠状态对睡眠的恢复功能至关重要，但这种关系的生化基础是 不确定葡萄糖的氧化代谢为神经元活动提供能量。尸检分析表明， 长时间的清醒会在大脑中产生氧化应激的积累。我们假设， 睡眠中的葡萄糖利用逆转了氧化还原状态的代谢驱动的转变（ 氧化和还原反应）的小清蛋白阳性神经元引起的高代谢 这些细胞在清醒的大脑中的需求。我们进一步假设睡眠的这种功能是 部分由称为神经元周网的细胞外基质结构促进， 缓冲代谢脆弱神经元的氧化应激。为了解决这些问题，我们 将进行全身药理学操作（氧化/还原反应底物烟碱 腺嘌呤二核苷酸），已知会影响大脑抵抗氧化应激的能力。我们亦会评估 执行大脑区域特异性的神经元周围网络的消耗。我们将评估这些影响 操纵，以及睡眠/觉醒周期操纵，对细胞氧化还原状态标志物，无论是在真实的- 使用活体显微镜观察体内时间，并通过与细胞类型特异性 免疫化学标记和组织化学评估神经元束膜净强度。我们还将 测量实验操作对脑疲劳脑电图标记物的影响 睡眠需要。预期的结果将建立睡眠/觉醒周期之间的因果关系 和脑氧化还原状态，并将确定脑氧化/还原反应作为两种诊断的目标， 在面对睡眠不足时进行调查和治疗干预。 1

项目成果

Effect of N-Acetylcysteine on Sleep: Impacts of Sex and Time of Day.

• DOI: 10.3390/antiox12051124
• 发表时间: 2023-05-19
• 期刊: ANTIOXIDANTS
• 影响因子: 7
• 作者: Bushana, Priyanka N.;Schmidt, Michelle A.;Chang, Kevin M.;Vuong, Trisha;Sorg, Barbara A.;Wisor, Jonathan P.
• 通讯作者: Wisor, Jonathan P.