Respiratory-Related Outputs of Glutamatergic, Hypercapnia-Responsive Parabrachial Neurons in Mice

In patients with obstructive sleep apnea, airway obstruction during sleep produces hypercapnia, which in turn activates respiratory muscles that pump air into the lungs (e.g., the diaphragm) and that dilate and stabilize the upper airway (e.g., the genioglossus). We hypothesized that these responses are facilitated by glutamatergic neurons in the parabrachial complex (PB) that respond to hypercapnia and project to premotor and motor neurons that innervate the diaphragm and genioglossus muscles. To test this hypothesis, we combined c-Fos immunohistochemistry with in situ hybridization for vGluT2 or GAD67 or with retrograde tracing from the ventrolateral medullary region that contains phrenic premotor neurons, the phrenic motor nucleus in the C3-C5 spinal ventral horn, or the hypoglossal motor nucleus. We found that hypercapnia (10% CO2 for 2 hours) activated c-Fos expression in neurons in the external lateral, lateral crescent (PBcr), and Kolliker-Fuse (KF) PB subnuclei and that most of these neurons were glutamatergic and virtually none -aminobutyric acidergic. Numerous CO2-responsive neurons in the KF and PBcr were labeled after retrograde tracer injection into the ventrolateral medulla or hypoglossal motor nuclei, and in the KF after injections into the spinal cord, making them candidates for mediating respiratory-facilitatory and upper-airway-stabilizing effects of hypercapnia. J. Comp. Neurol. 523:907-920, 2015. (c) 2014 Wiley Periodicals, Inc.