Activation of Leptin‐Receptor‐Expressing Neurons in the Dorsomedial Hypothalamus Increases Hypercapcnic Ventilatory Response and Relieves Obstructive Sleep Apnea in Obese Mice

Obesity leads to obstructive sleep apnea (OSA), characterized by loss of upper airway muscle tone during sleep leading to carbon dioxide retention and intermittent hypoxemia. OSA leads to high neurocognitive, cardiovascular, and oncologic morbidity and mortality. There is no effective pharmacotherapy for OSA. We have previously shown that an adipose-produce hormone leptin acts in the brain to abolish hypoventilation and upper airway obstruction during sleep, and, therefore may be a promising therapeutic in obese patients with OSA. Our previous data also suggest that leptin stimulates breathing acting on the leptin receptor (LEPRb ) positive neurons in the dorsomedial hypothalamus (DMH), but not in the medulla. Herein, we tested the hyphotesis that leptin stimulates control of breathing and improves upper airway patency during sleep acting on LEPRb positive DMH neurons and their projections to serotonergic neurons in raphe.In this study, we examined the contribution of LEPRb positive neurons in the DMH to control of breathing and upper airway function during sleep in diet-induced obese mice.We expressed designer receptors exclusively activated by designer drugs (DREADD) selectively in the LEPRb positive neurons of the DMH of Leprb -Cre-GFP mice with diet-induced obesity (DIO) and examined the effect of DREADD ligand, J60, on breathing during sleep.Chemogenetic activation of LEPRb positive DMH neurons increased inspiratory flow, respiratory rate, and minute ventilation during REM sleep, without significant changes in sleep architecture. The effect was particularly pronounced during inspiratory flow limitation, which suggest that upper airway obstruction during REM sleep was relieved. Activation of LEPRb positive DMH neurons with a DREADD ligand, J60, increased the hypercapnic ventilatory response and this response was blunted by a serotonin receptor antagonist, methysergide. In vitroexperiments revealed that DMH LEPRb neurons project to the serotonergic neurons in the dorsal raphe and that optogenetic stimulation of DMH LEPRb neurons evoked excitatory post-synaptic currents in ChR2 expressing neurons.Leptin up-regulates the hypercapnic ventilatory response and upper airway patency during sleep acting on LEPRb neurons in the DMH. Respiratory effects of leptin are likely mediated via projections of these neurons to the dorsal raphe.