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 i nclude 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.
The findings from these studies will delineate brain regions that directly influence the severity of OSA. The ultimate goal of our work is to develop treatments for OSA and other conditions that involve hypoventilation during sleep.
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