Project 2: Orexin Signaling and Hypoventilation

PROJECT SUMMARY This Project focuses on improving breathing in mouse models of Obesity Hypoventilation syndrome (OHS) and Opioid-Induced Respiratory Depression (OIRD) as these disorders are relatively common causes of hypoventilation and have very high mortality. OHS occurs in people with severe obesity and is manifest as hypoventilation during wakefulness and especially during sleep. Opiates also reduce ventilation, and about 6% of Americans take prescription opioids which can cause hypoventilation and worsen sleep apnea and other respiratory disorders. Considering these staggering impacts, there is a large and unmet need to develop better therapies for these hypoventilation disorders. Several lines of evidence indicate that increasing orexin signaling through the orexin receptors should be a highly effective therapy for people with OHS and OIRD. The orexin neurons excite all key brainstem regions regulating ventilation. In addition, orexin knockout mice have a blunted response to hypercarbia, and orexin receptor antagonists reduce the response to hypercarbia. We hypothesize that increased activity of the orexin neurons and orexin agonists will improve breathing in mouse models of OHS and OIRD via lower brainstem respiratory circuits. As a model of OHS, we will use mice with diet-induced obesity which are severely obese and have hypoventilation with a reduced hypercapnic ventilatory response. In addition, we will study mice treated with morphine as a model of OIRD. These Aims seek to determine the role of orexin signaling in the responses to hypercapnia and OIRD. This Project synergizes well with Projects 1, 3, and 4 that seek to enhance ventilatory responses to hypercapnia and OIRD in mice, and Project 5 which seeks to identify pharmacological methods to improve hypoventilation in people, especially with OIRD. The first Aim is to determine if the orexin neurons are necessary for the HCVR and OIRD with morphine in a novel mouse model. Second, we will define the location and molecular identity of orexin-responsive neurons in the brainstem using in situ hybridization, calcium imaging and RNAseq, in collaboration with the Electrophysiology and Molecular Biology Cores. The third Aim is to test if the orexin neurons are sufficient to improve the response to hypercapnia and OIRD. Finally, we will test of an orexin agonist improves the HCVR and OIRD and then map the brainstem regions through which this occurs. Collectively, these experiments should demonstrate that orexin signaling improves hypoventilation in mouse models of OHS and OIRD, and that orexin agonists have potential for improving these disorders.