Project 3 HMS - VA sub

项目 3 HMS - VA 子

• 批准号: 9304306
• 负责人: Robert W McCarley
• 金额: $ 31.21万
• 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/9304306
• 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; Loudness; Mediating; Metabolic Diseases; Modeling; Mus; Neurons; Neurotransmitters; Obstruction; Obstructive Sleep Apnea; Oxygen; Parvalbumins; Pathway interactions; Perception; Performance; Periodicity; 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; cholinergic; design; experimental study; improved; indexing; neuromechanism; optogenetics; parabrachial nucleus; 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）的特征是由于关闭而经常出现睡眠的唤醒 上呼吸道，产生高碳酸盐（二氧化碳水平升高）和缺氧（氧气降低） 级别）。 OSA的后果包括白天过度嗜睡，认知缺陷以及 呼吸道，代谢和心血管疾病。尽管它在OSA引起的唤醒和 睡眠碎片化，对介导OSA期间唤醒的神经机制知之甚少。 最近的工作表明，旁皮复合体（PB）的脑干谷氨酸能神经元，该神经元 接受内脏和呼吸输入，对于高囊泡唤醒很重要。我们假设PB 对基础前脑（BF）的预测，该区域包含皮质投射和唤醒的区域 神经元，介导皮质唤醒反应对高碳酸盐。睡眠呼吸暂停将通过小鼠建模 在睡眠期间暴露于高碳酸盐，称为重复的二氧化碳介导的唤醒（RCA）。 光遗传技术将用于研究三个神经递质定义亚群的作用 呼吸暂停诱导的唤醒中皮质注射的BF神经元：Gabaergic Parvalbumin阳性（PV）， 胆碱能和谷氨酸能神经元。对于每个已鉴定的BF神经递质表型，我们将解决 ：1）使用通道Ropopsin 2（CHR2）通过光遗传激发唤醒的标准； 2）必要 使用Archaerhopopsin（Archt）对RCA进行光遗传学抑制作用； 3）我们的相关性 通过记录与RCA相关的BF的电活动，对天然生理条件的光遗传学发现 神经递质表型的神经元已通过CHR2的短潜伏期激发来定义。每个 由于小鼠暴露于RCA或声学刺激，将评估神经元的BF群体；我们预测两者 刺激将引起唤起，因为我们的数据指向BF是最终的公共途径，导致两者的皮质唤醒 内脏和外部感觉刺激。我们的初步数据指向PV GABERGIC神经元最大的数据 对于RCA和声学唤醒的重要性：1）BF PV神经元的CHR2激发引起唤醒和脑电图 激活包括高频振荡； 2）PV ArchT抑制明显延长了RCA的潜伏期 唤醒3）PV单元记录显示与皮质激活协同的激活。相反，Chr2 BF胆碱能神经元的刺激表现出更大的调节性，功能较小，直接影响较少 皮质激活比PV神经元。我们预测谷氨酸能BF神经元将在促进中发挥作用 唤醒，但没有高频振荡。如果成功，这些实验将表明阻止BF 激活，尤其是从GABA能PV神经元中的激活，会增加皮质唤醒阈值，从而增加 将处理呼吸暂停中明显的睡眠碎片化，并负责OSA的许多症状。 对OSA中控制皮质唤醒的神经机制的了解，可以指导治疗 旨在减少皮质唤醒的治疗，同时保持气道通畅。