Project 3 HMS - VA sub

项目 3 HMS - VA 子

• 批准号: 8794523
• 负责人: Robert W McCarley
• 金额: $ 33.06万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8794523
• 关键词: Acoustics; Address; Adult; Apnea; Arousal; Attention; Auditory; Brain; Brain Stem; Carbon Dioxide; Cardiovascular Diseases; Cells; Choline; Cognitive deficits; Complex; Data; Electroencephalography; Event; Excessive Daytime Sleepiness; Exposure to; Frequencies; Future; Glutamates; Health; High Frequency Oscillation; Human; Hypercapnia; Hypoxia; Impaired cognition; Lateral; Lead; Lesion; Life; Mediating; Metabolic Diseases; Modeling; Mus; Neurons; Neurotransmitters; Obstruction; Obstructive Sleep Apnea; Oxygen; Parvalbumins; Pathway interactions; Perception; Performance; Phenotype; Physiological; Play; Population; Research; Respiration Disorders; Response Latencies; Role; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Stimulus; Structure; Substantia Innominata; Symptoms; Techniques; Therapeutic; Transferase; Visceral; Wakefulness; Work; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; design; improved; indexing; neuromechanism; optogenetics; parabrachial nucleus; prevent; research study; respiratory; response; sensory stimulus; targeted treatment; therapy development; vesicular glutamate transporter 2; voltage

ABSTRACT Obstructive sleep apnea (OSA) is characterized by frequent arousals from sleep due to closure of the upper airway, producing hypercapnia (increased carbon dioxide levels) and hypoxia (decreased oxygen levels). The consequences of OSA include excessive daytime sleepiness, cognitive deficits, as well as respiratory, metabolic, and cardiovascular disorders. Despite its importance in OSA-induced arousals and sleep fragmentation, very little is known about the neural mechanisms that mediate arousals during OSA. Recent work indicates that the brainstem glutamatergic neurons of the parabrachial complex (PB), which receive visceral and respiratory input, are important for hypercapnic arousal. We hypothesize that the PB projections to the basal forebrain (BF), a region containing cortically projecting & wakefulness promoting neurons, mediate the cortical arousal response to the hypercapnia. Sleep apnea will be modeled in mice by exposure to hypercapnia during sleep, termed repetitive carbon dioxide-mediated arousals (RCA). Optogenetic techniques will be used to investigate the roles of three neurotransmitter-defined subpopulations of cortically-projecting BF neurons in apnea-induced arousals: GABAergic parvalbumin positive (PV), cholinergic, and glutamatergic neurons. For each identified BF neurotransmitter phenotype we will address the criteria of: 1) sufficiency for arousal by optogenetic excitation using Channelrhodopsin 2 (ChR2); 2) necessity for arousal by optogenetic inhibition of RCA using Archaerhodopsin (ArchT); and 3) relevance of our optogenetic findings to natural physiological conditions by recording the electrical activity of RCA -related BF neurons whose neurotransmitter phenotype has been defined by short latency excitation by ChR2. Each neuronal BF population will be evaluated as mice are exposed to RCA or acoustic stimuli; we predict both stimuli will arouse, as our data point to the BF as a final common pathway leading to cortical arousal from both visceral and external sensory stimuli. Our preliminary data point to PV GABergic neurons as the most important for RCA and acoustic arousals: 1) ChR2 excitation of BF PV neurons causes arousal and EEG activation including high frequency oscillations; 2) PV ArchT inhibition markedly prolongs the latency to RCA arousal; and 3) PV unit recordings show activation in concert with cortical activation. In contrast, ChR2 stimulation of BF cholinergic neurons shows more modulatory, less powerful and less immediate effects on cortical activation than PV neurons. We predict that glutamatergic BF neurons will play a role in promoting arousal, but not high frequency oscillations. If successful, these experiments would suggest that blocking BF activation, especially that from GABAergic PV neurons, would increase the cortical arousal threshold, and thus would treat the sleep fragmentation evident in apnea and responsible for many of the symptoms of OSA. Improved understanding of the neural mechanisms controlling cortical arousals in OSA will guide therapeutic treatment aiming to decrease cortical arousals while maintaining airway patency.

抽象的 阻塞性睡眠呼吸暂停 (OSA) 的特点是由于睡眠呼吸暂停而频繁从睡眠中惊醒。 上呼吸道，产生高碳酸血症（二氧化碳水平增加）和缺氧（氧气减少） 水平）。 OSA 的后果包括白天过度嗜睡、认知缺陷以及 呼吸系统、代谢和心血管疾病。尽管它在 OSA 引起的唤醒中很重要， 由于睡眠碎片化，人们对 OSA 期间介导觉醒的神经机制知之甚少。 最近的研究表明，臂旁复合体（PB）的脑干谷氨酸能神经元， 接受内脏和呼吸输入，对于高碳酸血症唤醒很重要。我们假设 PB 基底前脑 (BF) 的投射，该区域包含皮质投射和促进觉醒的区域 神经元，介导皮质对高碳酸血症的唤醒反应。睡眠呼吸暂停将在小鼠中建立模型 睡眠期间暴露于高碳酸血症，称为重复二氧化碳介导的唤醒（RCA）。 光遗传学技术将用于研究三种神经递质定义的亚群的作用 呼吸暂停引起的唤醒中皮质投射的 BF 神经元的变化：GABA 能小白蛋白阳性 (PV)， 胆碱能和谷氨酸能神经元。对于每个确定的 BF 神经递质表型，我们将解决 标准：1) 使用视紫红质通道蛋白 2 (ChR2) 进行光遗传学激发的充分性； 2）必要性 使用古视紫红质 (ArchT) 通过光遗传学抑制 RCA 来唤醒； 3）我们的相关性 通过记录 RCA 相关 BF 的电活动，对自然生理条件进行光遗传学研究 其神经递质表型由 ChR2 的短潜伏期激发定义的神经元。每个 当小鼠暴露于 RCA 或声刺激时，将评估神经元 BF 群体；我们预测两者 刺激将会被唤醒，因为我们的数据表明 BF 是导致皮质唤醒的最终共同途径 内脏和外部感觉刺激。我们的初步数据表明 PV GABergic 神经元是最重要的 对于 RCA 和声学唤醒很重要：1) BF PV 神经元的 ChR2 兴奋导致唤醒和脑电图 激活包括高频振荡； 2) PV ArchT抑制显着延长RCA潜伏期 唤醒； 3) PV 单元记录显示激活与皮质激活一致。相比之下，ChR2 BF 胆碱能神经元的刺激显示出更多的调节作用，不太强大且不太直接的影响 皮层激活程度高于 PV 神经元。我们预测谷氨酸能 BF 神经元将在促进 唤醒，但不是高频振荡。如果成功，这些实验表明阻断 BF 激活，尤其是 GABA 能 PV 神经元的激活，会增加皮质唤醒阈值，从而 可以治疗呼吸暂停中明显的睡眠碎片，并导致 OSA 的许多症状。 更好地了解控制 OSA 皮质唤醒的神经机制将指导治疗 治疗旨在减少皮质唤醒，同时保持气道通畅。