Sleep loss impairment of arousal and cognition: role of the basal forebrain

睡眠不足对觉醒和认知的损害：基底前脑的作用

• 批准号: 9206087
• 负责人: ROBERT E STRECKER
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206087
• 关键词: Accidents; Adenosine; Adverse effects; Affect; American; Arousal; Attention; Auditory; Basic Science; Behavioral; Bilateral; Binding; Brain; Cells; Choline; Chronic; Chronic Insomnia; Clinical; Cognition; Coma; Data; Diabetes Mellitus; Disease; Drowsiness; Electroencephalogram; Emergency Situation; Excessive Daytime Sleepiness; Fire - disasters; Frequencies; Goals; Health; Heart Diseases; Housing; Human; Impaired cognition; Impairment; Incidence; Individual; Lesion; Link; Measures; Mediation; Mediator of activation protein; Medical; Mental disorders; Methods; Military Personnel; Modeling; Movement; Mus; Neurons; Neurotransmitters; Parvalbumins; Pattern; Physiological; Population; Post-Traumatic Stress Disorders; Productivity; Psyche structure; Regulation; Research; Response Latencies; Role; Safety; Sensory; Short-Term Memory; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep Wake Cycle; Sleep disturbances; Sleeplessness; Stimulus; Symptoms; Testing; Time; Traffic accidents; Transferase; Veterans; Wakefulness; Work; Workplace; alertness; auditory stimulus; basal forebrain; basal forebrain cholinergic neurons; base; cell type; cholinergic; cholinergic neuron; chronic pain; cognitive performance; cognitive process; common symptom; experimental study; improved; novel; object recognition; optogenetics; public health relevance; response; sensory stimulus; shift work; symptom treatment; therapeutic development; therapy development; vigilance

 DESCRIPTION (provided by applicant): Sleep loss leads to impaired cognitive performance and excessive daytime sleepiness. These symptoms of sleep loss are now recognized as major contributors to accident rates and decreased workplace productivity. Mice will be used to model two types of human sleep loss that produce daytime sleepiness and cognitive impairments: 1) Total sleep deprivation, which can occur due to vocational demands such as shift work or emergency work, and, 2) Sleep fragmentation, a pattern of sleep disturbance seen in many clinical disorders including sleep apnea. Sleep fragmentation disrupts the continuity of sleep and interferes with the restorative effects of sleep. Despite the fact that total sleep time is not greatly reduced by sleep fragmentation, we hypothesize that the physiological and behavioral consequences of sleep fragmentation will be similar to those of total sleep deprivation. The overall goal of this proposa is to understand the role of basal forebrain (BF) neurons in sleep loss induced deficits in wakefulness and vigilance. To accomplish this goal, mice will be used to test the hypothesis that BF GABAergic parvalbumin (PV) and cholinergic - positive neurons enhance wakefulness/alertness, attention, and cortical activation. Both BF PV and cholinergic neurons are hypothesized to be arousal promoting via their cortical projections. Hence, we predict that activation of these arousal promoting BF neurons can reduce sleep-loss induced impairments. Based on preliminary data, we further hypothesize that BF PV neurons will more potently enhance wakefulness, attention, and cortical activation relative to BF cholinergic neurons; PV neurons are also predicted to more effectively reduce the impairments in these measures observed in sleep deprived mice. Abundant evidence indicates that the BF contains cortically projecting and wakefulness promoting neurons that are important for cortical activation and wakefulness (e.g., large non-specific cell body lesions in BF produce a coma-like state). However, only recently have optogenetic methods been available to precisely determine the role of neurotransmitter specific neurons in the brain. Optogenetic inhibition of BF neurons in Aim 1 is predicted to simulate the effects of sleep loss, demonstrating the necessity of BF PV and cholinergic neurons in the sleep loss induced impairments. Aim 2 will determine if: a) excitation of BF neurons is sufficient to enhance wakefulness, attention, and cortical activation in non sleep deprived mice, and, b) excitation of BF neurons will reduce sleep loss induced impairments in wakefulness, attention, and cortical activation. Aim 3 will measure the single unit activity of optogenetically identified BF neurons to confirm that their discharge pattern is consistent with their proposed physiological role in the regulation of natural sleep and wakefulness, and in the mediation of the cortical activity responses to sensory stimuli. The following preliminary data support these hypotheses and predictions: 1. Inhibition of PV neurons reduces measures of wakefulness, attention in the novel object recognition task, and evoked cortical activation; thus, the effects of inhibition of BF PV neurons closely resemble the effects f sleep loss on these measures. 2. Excitation of BF PV neurons produces wakefulness and cortical activation and BF PV unit activity is increased during wakefulness. Compared to BF PV neurons, excitation of cholinergic neurons appears to produce a more modulatory, slower and less powerful behavioral and physiological response. If successful, the experiments proposed will demonstrate mechanistic links between BF unit activity, cortical activation, wakefulness/arousal, and attention. Thus, these findings will guide the development of therapeutic interventions targeting the subcortical arousal promoting neurons to treat the consequences of sleep disorders which are prevalent in the Veteran population.

 描述（由申请人提供）： 睡眠不足会导致认知能力受损和白天过度嗜睡，这些睡眠不足的症状现在被认为是导致事故率和工作效率下降的主要原因，小鼠将被用来模拟两种类型的人类睡眠不足，这些睡眠不足会导致白天嗜睡和认知障碍。 ：1) 完全睡眠不足，可能是由于轮班工作或紧急工作等职业需求而发生，以及 2) 睡眠碎片化，这是一种在许多临床疾病中出现的睡眠障碍模式，包括睡眠呼吸暂停。尽管睡眠碎片化并不会大大减少总睡眠时间，但我们认为碎片化睡眠的生理和行为后果将与完全睡眠剥夺相似。该提案的目的是了解基底前脑 (BF) 神经元在睡眠不足引起的觉醒和警觉性缺陷中的作用。为了实现这一目标，将使用小鼠来测试 BF GABA 能小清蛋白 (PV) 和 BF 神经元的假设。胆碱能阳性神经元增强觉醒/警觉性、注意力和皮质激活，BF PV 和胆碱能神经元都通过其皮质投射而被剥夺促进唤醒的作用，因此，我们预测这些促进唤醒的 BF 神经元的激活可以减少诱发的睡眠丧失。根据初步数据，我们进一步注意到，相对于 BF 胆碱能神经元，BF PV 神经元将更有效地增强觉醒、注意力和皮质激活；还预测可以更有效地减少在睡眠剥夺小鼠中观察到的这些措施的损伤。大量证据表明，BF 含有皮质投射和觉醒促进神经元，这些神经元对皮质激活和觉醒很重要（例如 BF 中的大非特异性细胞体病变）。产生类似昏迷的状态）然而，直到最近才可以使用光遗传学方法来精确确定 Aim 1 中 BF 神经元的光遗传学抑制作用。模拟睡眠缺失的影响，证明 BF PV 和胆碱能神经元在睡眠缺失引起的损伤中的必要性，目标 2 将确定：a) BF 神经元的兴奋是否足以增强非睡眠剥夺的觉醒、注意力和皮质激活。小鼠，b) BF 神经元的兴奋将减少睡眠缺失引起的觉醒、注意力和皮质激活损伤。目标 3 将测量光遗传学鉴定的 BF 神经元的单个单位活动，以确认它们的活性。放电模式与它们在调节自然睡眠和觉醒以及介导对感觉刺激的皮层活动反应减少中所提出的生理作用一致，以下初步数据支持这些假设和预测： 1.PV 神经元测量的抑制。觉醒、新物体识别任务中的注意力以及诱发的皮质激活；因此，BF PV 神经元的抑制作用与睡眠缺失对这些指标的影响非常相似。 2. BF PV 神经元的兴奋会产生觉醒和皮质激活。与 BF PV 神经元相比，BF PV 单元的活动在清醒时会增加，胆碱能神经元的兴奋似乎会产生更多的调节性、更慢且更弱的行为和生理反应。如果成功，所提出的实验将证明 BF 单元活动之间的机制联系。因此，这些发现将指导针对皮质下唤醒促进神经元的治疗干预措施的开发，以治疗退伍军人中普遍存在的睡眠障碍的后果。