0067 Chemogenetic Silencing of Hypoglossal Motor Neurons Creates a Model of Upper Airway Obstruction During Sleep. (27th April 2018)

• Record Type: Journal Article
• Authors: Fleury Curado, T A; Pho, H; Berger, S; Lee, R; Sennes, L; Schwartz, A R; Polotsky, V Y
• Is Part Of: Sleep. Volume 41(2018)Supplement 1
• Page Start: A27
• Page End: A28
• Publication Date: 2018-04-27
• Subjects: Sleep -- Physiological aspects -- Periodicals; Sleep disorders -- Periodicals; Sommeil -- Aspect physiologique -- Périodiques; Sommeil, Troubles du -- Périodiques; Sleep disorders; Sleep -- Physiological aspects; Sleep -- physiological aspects; Sleep Wake Disorders; Psychophysiology; Electronic journals; Periodicals; 616.8498
• DOI: 10.1093/sleep/zsy061.066
• Languages: English
• ISSNs: 0161-8105

Abstract

Abstract: Introduction: Obstructive Sleep Apnea (OSA) is a prevalent condition and a major cause of morbidity and mortality in Western Society. OSA contributes significantly to the development and progression of neurocognitive, metabolic, cardiovascular, and oncologic diseases. The loss of motor input to the tongue and specifically the genioglossus muscles during sleep is associated with pharyngeal collapsibility and the development of OSA. Efforts to develop pharmacotherapy have been hindered by a lack of animal models Methods: We applied chemogenetic method to reversibly silence neuromotor input to the genioglossal muscle (main upper airway dilator). G-protein coupled human cholinergic receptors engineered to recognize a specific ligand, clozapine-N-oxide (CNO), but no naturally occurring ligands were delivered by adeno-associated viral vectors (AAV5-hM4Di-mCherry, n=7) or sham virus (AAV5-GFP, n=4) bilaterally to the hypoglossal nucleus in lean mice. Four weeks after administration mice were treated with CNO (IP 1mg/kg) or Saline followed by sleep study; a week later treatments were alternated in a cross-over fashion and a second sleep study was performed. Inspiratory flow limitation was recognized by the presence of a plateau in mid-respiratory flow with increasing inspiratory effort; oxyhemoglobin desaturations were defined as desaturations ≥ 3% from baseline. Upon completion of the experiments mice were sacrificed for histology to confirm localization. Positive staining (mCherry or GFP) was detected in the hypoglossal nucleus in all mice confirming successful targeting. Results: In Gi treated mice CNO markedly increased the frequency of flow limitation in both NREM sleep (from 2.2% to 17.2% of all breaths) and REM sleep (from 26.2% to 40.3% of all breaths) compared to saline treatment, but there was no significant oxyhemoglobin desaturation. CNO or saline infusion did not change sleep parameters in sham treated mice. Conclusion: We conclude that lean mice with chemogenetically silenced hypoglossal motor neurons can be used as a rodent model of disordered breathing during sleep. Support (If Any): NIH: M016M161, AHA: 16POST31000017.