0061 Orexin Neuron Chemoactivation Improves the Ventilatory Response to Hypercapnia in a Mouse Model of Obesity Hypoventilation Syndrome

Abstract Introduction Obesity Hypoventilation Syndrome (OHS) is characterized by impaired respiratory mechanics due to increased upper airway resistance, decreased chest wall compliance, and impaired central ventilatory drive to CO2. Consequently, OHS patients develop chronic daytime hypercapnia that worsens during sleep when ventilatory drive is reduced. Current treatments for OHS are limited, warranting investigation of new therapies. Orexin neurons control wake/sleep behavior and project to brainstem respiratory centers to regulate breathing. We hypothesized that chemoactivation of orexin neurons would improve the hypercapnic ventilatory response (HCVR) in diet induced obesity (DIO) mice, a model of OHS. Methods We studied DIO orexin-cre mice which were fed a 60% high fat diet and lean orexin-cre mice which were fed normal chow. We stereotaxically injected the orexin field with AAV8-hsyn-DIO-hM3Dq-mCherry and surgically implanted EEG/EMG headstages. We measured respiratory activity across quiet wake, NREM, and REM sleep using whole body plethysmography chambers integrated with EEG/EMG. We exposed mice to ascending hypercapnia mixtures of 0, 3, 5, 8% CO2, with 50% oxygen, balanced with nitrogen (one hour of each gas). Results About 42% of the orexin neurons expressed hM3Dq-mCherry. Treatment with CNO (0.3 mg/kg IP) increased the latency to enter REM sleep. With saline, DIO mice showed a blunted HCVR compared to lean mice. In lean mice, chemoactivation of the orexin neurons increased the frequency, tidal volume, and minute ventilation at moderate to high levels of CO2 during quiet wakefulness and NREM sleep. Importantly, in DIO mice, chemoactivation increased tidal volume and minute ventilation across all CO2 levels during quiet wake and NREM sleep. Conclusion These findings demonstrate that activation of the orexin neurons improves the hypercapnic ventilatory response in a mouse model of OHS. These results suggest that enhancing orexin signaling may improve hypoventilation in Obesity Hypoventilation Syndrome. Support (if any) NIH HL149630 and Harvard Medical School Dean’s Postdoctoral Fellowship