Hypothalamo-brainstem control of sleepiness and arousal

下丘脑脑干控制睡意和觉醒

• 批准号: 7529859
• 负责人: LESZEK K KUBIN
• 金额: $ 39.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529859
• 关键词: Adult; Affect; Agonist; American; Anterior; Arousal; Behavior; Bicuculline; Brain; Brain Stem; Brain region; Breathing; Carbachol; Cataplexy; Cell Nucleus; Cell physiology; Cells; Cholinergic Agonists; Circadian Rhythms; Condition; Disease; Disinhibition; Down-Regulation; Effectiveness; Funding; GABA Agonists; GABA Antagonists; GABA Receptor; GABA-A Receptor; Goals; Hypothalamic structure; Immunohistochemistry; In Vitro; Infusion procedures; Injection of therapeutic agent; Lead; Maintenance; Mediating; Messenger RNA; Microinjections; Modeling; Motor Neurons; Muscle; Neuraxis; Neurons; Neurotransmitters; Norepinephrine; Obstructive Sleep Apnea; Pathway interactions; Patients; Pattern; Peptides; Perfusion; Pharmaceutical Preparations; Phenotype; Play; Polymerase Chain Reaction; Polysomnography; Pontine structure; Population; Posterior Hypothalamus; Preparation; Process; Public Health; REM Sleep; Rattus; Regulation; Research; Respiratory System; Reverse Transcription; Role; Serotonin; Signal Transduction; Sleep; Sleep Deprivation; Slice; Slow-Wave Sleep; Source; Symptoms; Testing; Time; Tongue; Tracer; Up-Regulation; Wakefulness; base; circadian pacemaker; concept; gamma-Aminobutyric Acid; hypocretin; in vivo; instrument; mRNA Expression; noradrenergic; novel; pressure; prevent; programs; receptor; relating to nervous system; research study; respiratory; serotonin receptor; sleep regulation

DESCRIPTION (provided by applicant): Sleepiness is a major consequence of the obstructive sleep apnea syndrome (OSA), a debilitating disorder affecting 3-5% of adults. The long-term goal of this project is to determine the mechanisms responsible for detrimental effects of sleep loss on the central nervous system and respiratory control. We focus on the cellular processes resulting from sleep loss that occur in the perifornical (PF) region of the posterior hypothalamus because this region is involved in respiratory regulation and sleep. We found that, in rats, sleep loss leads to increased GABA receptor-mediated inhibition of wake-promoting cells in the PF region and that antagonism of this inhibition in the PF region activates hypoglossal (XII) motoneurons, which in OSA patients play an important role in the control of upper airway patency. We now propose to identify those hypothalamic cells in which sleep loss induces these changes and study the pathways that relay these effects to upper airway motoneurons. We hypothesize that hypothalamic neurons that have sleep deprivation-induced upregulation of certain subunits of GABA receptors contribute to the regulation of sleep and mediate hypothalamic excitatory effects on XII motoneurons. In Specific Aim (SA) 1, we shall use chronically instrumented, behaving rats to characterize the interaction between sleep deprivation and antagonism of GABA receptor-mediated inhibition in the PF region, as it occurs at the level of upper airway (genioglossal) muscles. In SA 2, we shall identify the patterns of GABA A receptor subunit mRNA expression in PF cells with different neurotransmitter phenotypes and axonal projections to XII motoneurons and wake-related brainstem neurons. In SA 3, we shall test whether activation of XII motoneurons elicited by disinhibition of PF neurons requires activation of orexin-containing PF neurons and whether it is mediated by brainstem serotonergic and/or noradrenergic neurons. In SA 4, we shall determine whether sleep deprivation and treatments of hypothalamic slices in vitro that neurochemically model sleep and wake conditions lead to distinct changes in mRNA levels for GABA receptor subunits in hypothalamic cells having different projections and neurotransmitter phenotypes. These studies will characterize the neural substrates of the "sleepiness signal," which include dynamic changes in GABA receptor-mediated inhibition. They will also define the role of hypothalamic inhibitory mechanisms in sleep loss-related changes in the control of the upper airway. Since both stimulants and sleep-promoting treatments are considered as adjunct therapies for OSA, our studies will provide the mechanistic basis for potential effectiveness of such treatments. PUBLIC HEALTH RELEVANCE: Sleepiness is a major consequence of the obstructive sleep apnea syndrome (OSA), a debilitating disorder affecting 3-5% of adult Americans. Sleep loss may exacerbate OSA symptoms, but the neural substrate(s) of the brain "sleepiness signal" are unknown. The goal of this project is to assess how selected brain regions and transmitters interact in their control of breathing under the condition of increased drive for sleep.

描述（由申请人提供）：嗜睡是阻塞性睡眠呼吸暂停综合征（OSA）的主要结果，这是一种使人衰弱的疾病，影响了3-5％的成年人。该项目的长期目标是确定导致睡眠流失对中枢神经系统和呼吸控制的有害影响的机制。我们专注于下丘脑后部森林（PF）区域中发生的睡眠损失导致的细胞过程，因为该区域参与了呼吸道调节和睡眠。我们发现，在大鼠中，睡眠丧失会导致GABA受体介导的PF区域中启动唤醒细胞的抑制作用，并且PF区域的这种抑制作用激活了OSA患者在OSA患者中起重要作用的降低（XII）运动神经元。现在，我们建议确定那些下丘脑细胞，其中睡眠损失引起这些变化并研究将这些作用传达给上呼吸道运动神经元的途径。我们假设患有睡眠剥夺的下丘脑神经元引起了某些GABA受体亚基的上调，这有助于调节睡眠并介导对XII运动神经元的下丘脑兴奋作用。在特定的目标（SA）1中，我们将使用长期仪器，表现大鼠来表征PF区域中GABA受体介导的抑制作用之间的相互作用，因为它发生在上呼吸道（Genioglossal）肌肉水平。在SA 2中，我们将确定具有不同神经递质表型的PF细胞中GABA A受体亚基mRNA表达的模式，以及对XII运动神经元和与尾流相关的脑干神经元的轴突投射。在SA 3中，我们将测试通过抑制PF神经元引发的XII运动神经元的激活是否需要激活含有Orexin的PF PF神经元，以及它是否是由脑干血清素能和/或去甲肾上腺素能神经元介导的。在SA 4中，我们将确定在体外的睡眠剥夺和下丘脑切片的治疗是否在神经化学上建模睡眠和唤醒状况会导致下丘脑细胞中具有不同投射和神经递质表型的MRNA水平的明显变化。这些研究将表征“嗜睡信号”的神经底物，其中包括GABA受体介导的抑制作用的动态变化。他们还将定义下丘脑抑制机制在睡眠损失相关的上呼吸道控制中的作用。由于兴奋剂和促进睡眠治疗都被认为是OSA的辅助疗法，因此我们的研究将为此类治疗的潜在有效性提供机械基础。 公共卫生相关性：嗜睡是阻塞性睡眠呼吸暂停综合症（OSA）的主要结果，这是一种使人衰弱的疾病，影响了3-5％的成年美国人。睡眠损失可能会加剧OSA症状，但大脑“嗜睡信号”的神经底物是未知的。该项目的目的是评估选定的大脑区域和发射器如何在睡眠驱动力增加的条件下控制呼吸。