Obstructive sleep apnea (OSA) is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. There is no pharmacotherapy for OSA. There is an urgent need for therapeutics that reverse neuromuscular defects in upper airway function. Our efforts have focused on leptin, an adipocyte-produced hormone, which suppresses appetite, increases metabolic rate, and up-regulates control of breathing. We have previously reported that obese mice develop OSA, which was treated by leptin. Our preliminary results show that (1) leptin receptor (LepRb) deficient db/db mice develop OSA, which was abolished by intracerebroventricular (ICV) leptin after expression of LepRb in the dorsomedial hypothalamus (db/db-LepRb- DMH mice); (2) OSA improved in diet induced obese (DIO) LepRb-Cre mice upon activation of excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) expressed in LepRb+ neurons of the nucleus of the solitary tract (NTS); (3) hypoglossal motoneurons do not express LepRb, but LepRb+ neurons project to the hypoglossal nucleus and photogenetic stimulation of LepRb+ synapses increased hypoglossal motoneuron activity in LepRb-ChR2 mice; (4) LepRb+ neurons in DMH and NTS are melanocortin 4 receptor (MCR4) positive. Our hypothesis is that leptin acts on LepRb+ neurons in DMH and NTS to maintain upper airway patency during sleep.
Specific Aim 1 will test the hypothesis that activation of LepRb+ neurons in the DMH alleviates upper airway obstruction and OSA. We propose that (A) selective stimulation of LepRb+ DMH neurons by ICV leptin in db/db-LepRb-DMH mice and by activation of excitatory DREADDs in DIO LepRb-Cre mice will improve upper airway patency and treat OSA; (B) knockout of LepRb+ in DMH neurons by Cre recombinase in DIO LepRb flox/flox mice and inhibition of these neurons in DIO LepRb-Cre mice expressing inhibitory DREADDs will decrease upper airway patency and aggravate OSA; (C) effects of leptin on OSA in db/db-LepRb-DMH mice will be attenuated by MC4R blockers.
Specific Aim 2 will examine mechanisms of leptin?s action in the NTS on OSA in vivo and will be designed as SA1 A-C with exception that our interventions will target NTS.
Specific Aim 3 will examine synaptic connections between LepRb+ neurons, originating from both the DMH and NTS, that project to and synapse upon hypoglossal motoneurons. We propose that both DMH and NTS LepRb+ neurons connect to hypoglossal motoneurons and that optogenetic stimulation of (A) DMH- and (B) NTS LepRb-channelrhodopsin (ChR2) expressing neurons and fibers activates hypoglossal motoneurons. In SA1-2, we will employ a full arrays of physiological measurements developed in our laboratory including polysomnograms, dynamic MR imaging, and pharyngeal collapsibility measurements in obese male and female mice. In SA3, selective expression of optogenetic tools in targeted LepRb neuronal populations will be employed in combination with patch clamp electrophysiology in brain slices ex vivo. Our proposal will identify leptin-dependent mechanisms which can be targeted for treatment of OSA.
Obstructive sleep apnea, a recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep, does not have effective treatment, except poorly tolerated continuous positive airway pressure. We have previously shown that a fat tissue produced hormone leptin acts in the brain to treat sleep apnea. This proposal will examine different sites in the brain where leptin works to relieve upper airway obstruction and identify specific leptin receptor expressing neurons as therapeutic targets in obstructive sleep apnea.
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| Pham, Luu V; Schwartz, Alan R; Polotsky, Vsevolod Y (2018) Integrating loop gain into the understanding of obstructive sleep apnoea mechanisms. J Physiol 596:3819-3820 |
| Fleury Curado, Thomaz; Pho, Huy; Berger, Slava et al. (2018) Sleep-disordered breathing in C57BL/6J mice with diet-induced obesity. Sleep 41: |
| Holingue, Calliope; Wennberg, Alexandra; Berger, Slava et al. (2018) Disturbed sleep and diabetes: A potential nexus of dementia risk. Metabolism 84:85-93 |
| Berger, Slava; Pho, Huy; Fleury-Curado, Thomaz et al. (2018) Intranasal Leptin Relieves Sleep Disordered Breathing in Mice with Diet Induced Obesity. Am J Respir Crit Care Med : |
| Berger, Slava; Polotsky, Vsevolod Y (2018) Leptin and Leptin Resistance in the Pathogenesis of Obstructive Sleep Apnea: A Possible Link to Oxidative Stress and Cardiovascular Complications. Oxid Med Cell Longev 2018:5137947 |
| Drager, Luciano F; Tavoni, Thauany M; Silva, Vanessa M et al. (2018) Obstructive sleep apnea and effects of continuous positive airway pressure on triglyceride-rich lipoprotein metabolism. J Lipid Res 59:1027-1033 |
| Fleury Curado, Thomaz; Oliven, Arie; Sennes, Luiz U et al. (2018) Neurostimulation Treatment of OSA. Chest 154:1435-1447 |
| Fleury Curado, Thomaz A; Pho, Huy; Dergacheva, Olga et al. (2018) Silencing of Hypoglossal Motoneurons Leads to Sleep Disordered Breathing in Lean Mice. Front Neurol 9:962 |
| Pham, Luu V; Miele, Catherine H; Schwartz, Noah G et al. (2017) Cardiometabolic correlates of sleep disordered breathing in Andean highlanders. Eur Respir J 49: |
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