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: 8634591
• 负责人: NANCY L CHAMBERLIN
• 金额: $ 36.66万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8634591
• 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呼吸道反复塌陷。随之而来的窒息会引起即刻的呼吸反应，包括中枢呼吸驱动增加和气道扩张肌的激活，我们称之为呼吸唤醒，与疾病的严重程度直接相关。我们的最终目标是找到治疗方法，最大限度地唤醒患者的呼吸。我们的策略是确定呼吸觉醒的神经机制。我们假设臂旁核(PB)的组成部分，包括Kolliker-Fuse(KF)，在高碳酸血症的呼吸觉醒中起关键作用。我们怀疑，在高呼吸驱动条件下，如高碳酸血症，KF对驱动舌、咽和喉部的一系列呼吸道扩张肌肉很重要，并有助于使气道扩张肌肉的活动与呼吸机产生的负压相匹配。 以确保呼吸道通畅。我们假设，谷氨酸能PB-KF神经元投射并激活上主干运动和相应运动前核团中的靶点，这些活动是实现呼吸和上呼吸道扩张器肌肉输出对高碳酸血症反应的正常增加所必需的。我们的具体目标包括使用一种转基因小鼠，在该小鼠中，loxP基因位于囊泡型谷氨酸转运体2(Vlut2)基因的两侧，该基因包含在PB-KF神经元中。我们将使用病毒衍生的载体(/\AV-cre)来局部转基因并随后从PB-KF神经元中删除vlu2，并测试其对未麻醉的自然睡眠动物高碳酸血症引起的呼吸觉醒反应的影响。此外，我们将使用传统的逆行追踪结合Fos免疫组织化学方法来确定高碳酸血症激活的PB-KF神经元和为PB-KF提供兴奋性输入的化学敏感性神经元的解剖位置和神经联系。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，这些实验将展示从PB-KF神经元释放谷氨酸在高碳酸血症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。