Rodent models of sleep apnea

Davis, Eric M.; O’Donnell, Christopher P.

doi:10.1016/j.resp.2013.05.022

Cited by 57 publications

(63 citation statements)

References 66 publications

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“…Leptin and orexin receptors are in the brainstem, both peptides influence metabolism, and anatomic connections occur that could influence autonomic output and respiratory drive (Haxhiu et al, 2003; Shirasaka et al, 2003). Pauses occur in the leptin receptor deficient mouse, the ob/ob mouse, a strain arising as a spontaneous mutation out of the B6 strain (Davis and O'Donnell, 2013). OX1R is involved in the modulation of central chemosensitivity (Corcoran et al, 2010), as is the leptin receptor (O'Donnell et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Rodent models of sleep apnea can provide information on pathways for rhythmogenesis and have been used as a platform by others to explore drug therapy (Davis and O'Donnell, 2013). Apneas in rodents in the unanesthetized state are classified as central apnea; and as we have shown, there can be apneas in not only NREM and REM sleep, but wakefulness as well.…”

Section: Discussionmentioning

confidence: 99%

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Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse

Moore

Akladious

et al. 2014

Respiratory Physiology & Neurobiology

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Background The hypothesis was that an orexin 2 receptor (OX2R) agonist would prevent sleep-related disordered breathing. Methods In C57BL/6J (B6) mice, body plethysmography was performed with and without EEG monitoring of state (wakefulness, NREM and REM sleep). Outcome was apnea rate/hr during sleep-wake states at baseline and with an intracerebroventricular administration of vehicle, 4nMol of agonist OBDL, and 4nMol of an antagonist, TCS OX2 29. Results A significant reduction (p=0.035; f=2.99) in apneas/hour occurred, especially with the agonist. Expressed as a function of the change from baseline, there was a significant difference among groups in Wake (p=0.03, f=3.8), NREM (p=0.003, f= 6.98) and REM (p=0.03, f= 3.92) with the agonist reducing the rate of apneas during sleep from 29.7± 4.7 (M+/− SEM) to 7.3±2.4 during sleep (p=0.001). There was also a reduction in apneas during wakefulness. Administration of the antagonist did not increase event rate over baseline levels. Conclusions The B6 mouse is a preclinical model of wake-and sleep-disordered breathing, and the orexin receptor agonist at a dose of 4nMol given intracerebroventricularly will reduce events in sleep and also wakefulness.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse

Moore

Akladious

et al. 2014

Respiratory Physiology & Neurobiology

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“…I ntermittent hypoxia during sleep (IH) is one of the hallmarks of obstructive sleep apnea (OSA) and induces a wide range of morbid consequences, including excessive daytime sleepiness and cognitive, mood, and neurobehavioral deficits (1)(2)(3)(4)(5)(6), as well as cardiovascular dysfunction (7)(8)(9)(10). IH also imposes adverse metabolic consequences, such as hyperlipidemia and insulin resistance, even in lean mice, along with structural and cellular remodeling of adipose tissue (11)(12)(13)(14)(15)(16)(17)(18).…”

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confidence: 99%

Resveratrol Attenuates Intermittent Hypoxia-Induced Macrophage Migration to Visceral White Adipose Tissue and Insulin Resistance in Male Mice

et al. 2014

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Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea.

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“…More common, however, is the use of natural rodent models in research on sleep-related central apneic events in which the respiratory rhythm transiently stops without a concurrent flow limitation. This is beyond the scope of this article and has been reviewed elsewhere (96). …”

Section: Neural Control Of the Upper Airway In Sleep-disordered Breatmentioning

confidence: 99%

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

Kubin

2016

Comprehensive Physiology

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Upper airway muscles subserve many essential for survival orofacial behaviors, including their important role as accessory respiratory muscles. In the face of certain predisposition of craniofacial anatomy, both tonic and phasic inspiratory activation of upper airway muscles is necessary to protect the upper airway against collapse. This protective action is adequate during wakefulness, but fails during sleep which results in recurrent episodes of hypopneas and apneas, a condition known as the obstructive sleep apnea syndrome (OSA). Although OSA is almost exclusively a human disorder, animal models help unveil the basic principles governing the impact of sleep on breathing and upper airway muscle activity. This article discusses the neuroanatomy, neurochemistry, and neurophysiology of the different neuronal systems whose activity changes with sleep-wake states, such as the noradrenergic, serotonergic, cholinergic, orexinergic, histaminergic, GABAergic and glycinergic, and their impact on central respiratory neurons and upper airway motoneurons. Observations of the interactions between sleep-wake states and upper airway muscles in healthy humans and OSA patients are related to findings from animal models with normal upper airway, and various animal models of OSA, including the chronic-intermittent hypoxia model. Using a framework of upper airway motoneurons being under concurrent influence of central respiratory, reflex and state-dependent inputs, different neurotransmitters, and neuropeptides are considered as either causing a sleep-dependent withdrawal of excitation from motoneurons or mediating an active, sleep-related inhibition of motoneurons. Information about the neurochemistry of state-dependent control of upper airway muscles accumulated to date reveals fundamental principles and may help understand and treat OSA.

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Rodent models of sleep apnea

Cited by 57 publications

References 66 publications

Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse

Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse

Resveratrol Attenuates Intermittent Hypoxia-Induced Macrophage Migration to Visceral White Adipose Tissue and Insulin Resistance in Male Mice

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

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