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: 8435430
• 负责人: NANCY L CHAMBERLIN
• 金额: $ 30.07万
• 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/8435430
• 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）的特点是睡眠期间上呼吸道反复塌陷。由此产生的窒息会引起立即的呼吸反应，包括中枢呼吸驱动的增加以及扩张肌的激活，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最大限度地提高患者呼吸唤醒的治疗方法。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，包括科利克熔丝 (KF)，在高碳酸血症呼吸唤醒中发挥关键作用。我们怀疑 KF 对于在高呼吸驱动（例如高碳酸血症）的情况下驱动舌、咽和喉中的一系列气道扩张肌很重要，并且有助于将气道扩张肌活动与​​通气努力产生的负压相匹配 以保证呼吸道通畅。我们假设谷氨酸能 PB-KF 神经元投射并激活上呼吸道运动和相应前运动核中的靶标，并且这些活动对于实现通气和上呼吸道扩张肌输出以响应高碳酸血症的正常增加是必要的。我们的具体目标包括使用一种转基因小鼠，其中 loxP sjtes 位于 2 型囊泡谷氨酸转运蛋白 (vglut2) 基因的侧翼，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) 进行局部转染，从而从 PB-KF 神经元中删除 vglut2，并测试其对未麻醉、自然睡眠的动物对高碳酸血症的呼吸唤醒反应的影响。此外，我们将使用常规逆行追踪结合 Fos 免疫组织化学来确定高碳酸血症激活的 PB-KF 神经元以及为 PB-KF 提供兴奋性输入的化学敏感神经元的解剖位置和神经连接。在体外切片中，我们将确定 KF 神经元是否具有本质上的化学敏感性。总之，这些实验将证明 PB-KF 神经元释放的谷氨酸在高碳酸血症呼吸反应中的功能作用以及相关神经元和靶标以及化学感应输入的来源。