Role of the Parabrachial Complex in Respiratory Arousal

臂旁复合体在呼吸唤醒中的作用

• 批准号: 8243533
• 负责人: NANCY L CHAMBERLIN
• 金额: $ 38.26万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243533
• 关键词: Ablation; Acute; Affect; Animals; Arousal; Asphyxia; Automobile Driving; Blood gas; Brain region; Breathing; Cardiovascular system; Cell Nucleus; Clinical; Complex; Deformity; Dilator; Disease; Ensure; Environmental air flow; Face; Genes; Genetic; Glutamate Transporter; Glutamates; Goals; Hypercapnia; Hypercapnic respiratory failure; Immunohistochemistry; In Situ Hybridization; In Vitro; Knowledge; Larynx; Lateral; Lead; Location; Mediating; Microinjections; Modeling; Motor; Motor Neurons; Mus; Muscle; Muscle Tonus; Neurons; Obstructive Sleep Apnea; Output; Pathology; Pathway interactions; Patients; Pharyngeal structure; Play; Prosencephalon; Recurrence; Reflex action; Respiratory Diaphragm; Respiratory Muscles; Role; Severities; Severity of illness; Site; Sleep; Sleep Apnea Syndromes; Slice; Source; Techniques; Testing; Tongue; Transgenic Mice; Trazodone; Trigeminal System; Virus; Work; airway obstruction; defense response; neuromechanism; neuromuscular; parabrachial nucleus; pressure; prevent; recombinase; relating to nervous system; research study; respiratory; response; vector

Obstructive sleep apnea (OSA) is characterized by recurrent collapse of the upper airway during sleep. The consequent asphyxia provokes immediate respiratory responses that comprise increased central respiratory drive as well as activation of ainway dilator muscles, which we term respiratory arousal and is directly related to the severity of the disease. Our ultimate goal is to find treatments to maximize respiratory arousal in patients. Our strategy is to determine the neural mechanisms for respiratory arousal. We hypothesize that components of the parabrachial nucleus (PB), including the Kolliker-Fuse (KF), play a key role in hypercapnic respiratory arousal. We suspect that the KF is important for driving an array of airway dilatory muscles in the tongue, pharynx and larynx under conditions of high respiratory drive such as hypercapnia and aides in matching airway dilator muscle activity to the negative pressure generated by ventilatory effort to ensure airway patency. We hypothesize that glutamatergic PB-KF neurons project to and activate targets in the upper ainway motor and respective premotor nuclei and that these activities are necessary to achieve normal increases in ventilatory and upper airway dilator muscle output in response to hypercapnia. Our specific aims include using a genetically modified mouse in which loxP sjtes flank the gene for the vesicular glutamate transporter type 2 (vglut2), the one contained in PB-KF neurons. We will us a virally-derived vector (/\AV-cre) to focally transfect and consequently delete vglut2 from PB-KF neurons and test the effects on respiratory arousal responses to hypercapnia in unanesthetized, naturally sleeping animals. In addition, we will use conventional retrograde tracing in combination with Fos immunohistochemistry to determine the anatomical location and neural connections of the PB-KF neurons activated by hypercapnia and the chemosensitive neurons that provide excitatory input to the PB-KF. In in vitro slices we will determine if KF neurons are intrinsically chemosensitive. In all, these experiments will demonstrate the functional role for glutamate release from PB-KF neurons in respiratory responses to hypercapnia as well as the relevant neurons and targets and the sources of chemosensory input.

阻塞性睡眠呼吸暂停（OSA）的特征是睡眠期间上气道的反复塌陷。随后的窒息引起立即的呼吸反应，包括增加的中枢呼吸驱动以及气道扩张肌的激活，我们称之为呼吸觉醒，并与疾病的严重程度直接相关。我们的最终目标是找到最大限度地唤醒患者呼吸的治疗方法。我们的策略是确定呼吸唤醒的神经机制。我们假设臂旁核（PB）的组成部分，包括Kolliker-Kollyte（KF），在高碳酸呼吸觉醒中起着关键作用。我们怀疑KF对于在高呼吸驱动（例如高碳酸血症）条件下驱动舌、咽和喉中的气道扩张肌阵列是重要的，并且有助于使气道扩张肌活动与呼吸努力产生的负压相匹配 以确保气道通畅。我们假设，pbamatergic PB-KF神经元项目，并激活上气道运动和相应的运动前核的目标，这些活动是必要的，以实现正常的增加，呼吸道和上气道扩张肌输出响应高碳酸血症。我们的具体目标包括使用基因修饰的小鼠，其中loxP sjtes侧翼的囊泡谷氨酸转运蛋白2型（vapor 2），PB-KF神经元中包含的基因。我们将使用病毒衍生的载体（IAV-cre）来局灶性地阻断并因此从PB-KF神经元中删除vEGF 2，并测试对未麻醉的自然睡眠动物中高碳酸血症的呼吸唤醒反应的影响。此外，我们将使用传统的逆行追踪结合Fos免疫组化，以确定高碳酸血症激活的PB-KF神经元的解剖位置和神经连接，以及向PB-KF提供兴奋性输入的化学敏感神经元。在体外切片中，我们将确定KF神经元是否具有内在的化学敏感性。总之，这些实验将证明从PB-KF神经元释放谷氨酸在对高碳酸血症的呼吸反应中的功能作用，以及相关的神经元和靶点以及化学感觉输入的来源。