Role of the Parabrachial Complex in Respiratory Arousal

阻塞性睡眠呼吸暂停（OSA）的特点是在睡眠中反复出现上呼吸道塌陷。随后的窒息引起立即的呼吸反应，包括中枢呼吸驱动的增强以及气道扩张肌的激活，我们称之为呼吸觉醒，这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，最大限度地提高患者的呼吸唤醒。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）的成分，包括Kolliker-Fuse (KF)，在高碳酸血症呼吸唤醒中起关键作用。我们推测KF对于在高呼吸驱动（如高碳酸血症）条件下驱动舌头、咽和喉部的一系列气道扩张肌很重要，并有助于将气道扩张肌活动与通气努力产生的负压相匹配

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.