Respiratory-related outputs of glutamatergic, hypercapnia-responsive parabrachial neurons in mice

J Comp Neurol. 2015 Apr 15;523(6):907-20. doi: 10.1002/cne.23720. Epub 2015 Jan 14.


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 Kölliker-Fuse (KF) PB subnuclei and that most of these neurons were glutamatergic and virtually none γ-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.

Keywords: AB_2341545; AB_518147; AB_631250; c-Fos; carbon dioxide; diaphragm; hypoglossal; phrenic; respiratory.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Cholera Toxin / metabolism
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Glutamic Acid / metabolism*
  • Hypercapnia / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Neurons / physiology*
  • Neural Pathways / physiology*
  • Parabrachial Nucleus / cytology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Respiration / immunology*
  • Vesicular Glutamate Transport Protein 2 / genetics
  • Vesicular Glutamate Transport Protein 2 / metabolism


  • Proto-Oncogene Proteins c-fos
  • Vesicular Glutamate Transport Protein 2
  • Glutamic Acid
  • Cholera Toxin
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • Calcitonin Gene-Related Peptide