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: 8921583
• 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/8921583
• 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; Development; Diabetes Mellitus; Disease; Electroencephalogram; Emergency Situation; Excessive Daytime Sleepiness; Fire - disasters; Frequencies; Goals; Health; Heart Diseases; House mice; 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; Therapeutic Intervention; 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; improved; novel; object recognition; optogenetics; public health relevance; research study; response; sensory stimulus; shift work; symptom treatment; 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场所生产率下降的主要原因。小鼠将被用来建立两种类型的人类睡眠缺失的模型，这两种类型会导致白天嗜睡和认知障碍：1)完全睡眠剥夺，这可能是由于轮班工作或紧急工作等职业需求而发生的；以及2)睡眠碎片，这是许多临床疾病中常见的一种睡眠障碍模式，包括睡眠呼吸暂停。睡眠碎片会扰乱睡眠的连续性，干扰睡眠的恢复效果。尽管睡眠碎片化不会大大减少总睡眠时间，但我们假设睡眠碎片化的生理和行为后果将类似于完全睡眠剥夺的结果。本研究的总体目标是了解基底前脑(BF)神经元在睡眠缺失引起的觉醒和警觉性缺陷中的作用。为了实现这一目标，将用小鼠检验BF GABA能小白蛋白(PV)和胆碱能阳性神经元增强觉醒/警觉、注意力和皮质激活的假设。BF PV和胆碱能神经元都被认为是通过其皮质投射促进觉醒的。因此，我们预测，激活这些促进觉醒的BF神经元可以减少睡眠缺失引起的损伤。基于初步数据，我们进一步假设，与BF胆碱能神经元相比，BF PV神经元将更有效地增强觉醒、注意力和皮质激活；PV神经元也被预测将更有效地减少在睡眠剥夺小鼠中观察到的这些措施中的损害。大量证据表明，BF含有促进皮层投射和觉醒的神经元，这些神经元对皮质激活和觉醒非常重要(例如，BF中大型的非特异性细胞体损伤会产生昏迷样状态)。然而，直到最近才有了光遗传学方法来精确确定神经递质特定神经元在大脑中的作用。对AIM 1中BF神经元的光遗传抑制进行了预测，以模拟睡眠缺失的影响，证明了BF PV和胆碱能神经元在睡眠缺失所致损伤中的必要性。目的2将确定：a)BF神经元的兴奋是否足以增强非睡眠剥夺小鼠的觉醒、注意力和皮质激活，以及b)BF神经元的兴奋是否将减少睡眠缺失引起的觉醒、注意力和皮质激活的损害。目的3将测量光遗传学识别的BF神经元的单个单位活动，以确认它们的放电模式与它们在调节自然睡眠和觉醒以及在调节皮层活动对感觉刺激的反应中的生理作用是一致的。以下初步数据支持这些假说和预测：1.抑制PV神经元减少了觉醒、注意力在新的物体识别任务中的测量，以及诱发的皮质激活；因此，抑制BF PV神经元的影响与睡眠丧失对这些测量的影响非常相似。2.兴奋BF-PV神经元产生觉醒和皮层激活，清醒时BF-PV单位活动增加。与BF PV神经元相比，胆碱能神经元的兴奋似乎产生了更具调节性、更慢和更弱的行为和生理反应。如果成功，这些实验将证明BF单位活动、大脑皮层激活、觉醒/唤醒和注意力之间的机械联系。因此，这些发现将指导针对皮质下促进神经元的治疗干预措施的发展，以治疗在退伍军人中普遍存在的睡眠障碍的后果。