16 research outputs found
How to study sleep apneas in mouse models of human pathology
No full textSleep apnea, the most widespread sleep-related breathing disorder (SBD), consists of recurrent episodes of breathing cessation during sleep. This condition can be classified as either central (CSA) or obstructive (OSA) sleep apnea, with the latest being the most common and toxic. Due to the complexity of living organisms, animal models and, particularly, mice still represent an essential tool for the study of SBD. In the present review we first discuss the methodological pros and cons in the use of whole-body plethysmography to coupling respiratory and sleep measurements and to characterize CSA and OSA in mice; then, we draw an updated and objective picture of the methods used so far in the study of sleep apnea in mice. Most of the studies present in the literature used intermittent hypoxia to mimic OSA in mice and to investigate consequent pathological correlates. On the contrary, few studies using genetic manipulation or high-fat diets investigated the pathogenesis or potential treatments of sleep apnea. To date, mice lacking orexins, hemeoxygenase-2, monoamine oxidase A, Phox2b or Cdkl5 can be considered validated mouse models of sleep apnea. Moreover, genetically- or diet-induced obese mice, and mice recapitulating Down syndrome were proposed as OSA models. In conclusion, our review shows that despite the growing interest in the field and the need of new therapeutical approaches, technical complexity and inter-study variability strongly limit the availability of validated mouse of sleep apnea, which are essential in biomedical research
Autonomic Mechanisms Of Blood Pressure Alterations During Sleep In Orexin/Hypocretin-Deficient Narcoleptic Mice
No full textSTUDY OBJECTIVES: increases in arterial pressure (AP) during sleep and smaller differences in AP between sleep and wakefulness have been reported in orexin (hypocretin)-deficient mouse models of narcolepsy type 1 (NT1) and confirmed in NT1 patients. We tested whether these alterations are mediated by parasympathetic or sympathetic control of the heart and/or resistance vessels in an orexin-deficient mouse model of NT1.METHODS: 13 orexin knock-out (ORX-KO) mice were compared with 12 congenic wild-type (WT) mice. The electroencephalogram, electromyogram, and AP of the mice were recorded in the light (rest) period during intraperitoneal infusion of atropine methyl nitrate, atenolol, or prazosin to block muscarinic cholinergic, beta1-adrenergic, or alpha1-adrenergic receptors, respectively, while saline was infused as control.RESULTS: AP significantly depended on a 3-way interaction among the mouse group (ORX-KO vs WT), the wake-sleep state, and the drug or vehicle infused. During the control vehicle infusion, ORX-KO had significantly higher AP values during REM sleep, smaller decreases in AP from wakefulness to either non-rapid-eye-movement (non-REM) sleep or REM sleep, and greater increases in AP from non-REM sleep to REM sleep compared to WT. These differences remained significant with atropine methyl nitrate, whereas they were abolished by prazosin and, except for the smaller AP decrease from wakefulness to REM sleep in ORX-KO, also by atenolol.CONCLUSIONS: sleep-related alterations of AP due to orexin deficiency significantly depend on alterations in cardiovascular sympathetic control in a mouse model of NT1
Modulation of sympathetic vasoconstriction is critical for the effects of sleep on arterial pressure in mice
No full textWhile values of arterial pressure during sleep are predictive of cardiovascular risk, the autonomic mechanisms underlying the cardiovascular effects of sleep remain poorly understood. Here, we assess the autonomic mechanisms of the cardiovascular effects of sleep in C57Bl/6J mice, taking advantage of a novel technique for continuous intraperitoneal infusion of autonomic blockers. Our results indicate that non-REM sleep decreases arterial pressure by decreasing sympathetic vasoconstriction, decreases heart rate by balancing parasympathetic activation and sympathetic withdrawal, and increases cardiac baroreflex sensitivity mainly by increasing fluctuations in parasympathetic activity. Our results also indicate that REM sleep increases arterial pressure by increasing sympathetic activity to the heart and blood vessels, and increases heart rate, at least in part, by increasing cardiac sympathetic activity. These results provide a framework for generating and testing hypotheses on cardiovascular derangements during sleep in mouse models and human patients
CDKL5 deficiency entails sleep apneas in mice
No full textA recently discovered neurodevelopmental disorder caused by the mutation of the cyclin-dependent kinase-like 5 gene (CDKL5) entails complex autistic-like behaviours similar to Rett syndrome, but its impact upon physiological functions remains largely unexplored. Sleep-disordered breathing is common and potentially life-threatening in patients with Rett syndrome; however, evidence is limited in children with CDKL5 disorder, and is lacking altogether in adults. The aim of this study was to test whether the breathing pattern during sleep differs between adult Cdkl5 knockout (Cdkl5-KO) and wild-type (WT) mice. Using whole-body plethysmography, sleep and breathing were recorded non-invasively for 8 h during the light period. Sleep apneas occurred more frequently in Cdkl5-KO than in WT mice. A receiver operating characteristic (ROC) analysis discriminated Cdkl5-KO significantly from WT mice based on sleep apnea occurrence. These data demonstrate that sleep apneas are a core feature of CDKL5 disorder and a respiratory biomarker of CDKL5 deficiency in mice, and suggest that sleep-disordered breathing should be evaluated routinely in CDKL5 patients
Accurate discrimination of the wake-sleep states of mice using non-invasive whole-body plethysmography
No full textA major limitation in the study of sleep breathing disorders in mouse models of pathology is the need to combine whole-body plethysmography (WBP) to measure respiration with electroencephalography/electromyography (EEG/EMG) to discriminate wake-sleep states. However, murine wake-sleep states may be discriminated from breathing and body movements registered by the WBP signal alone. Our goal was to compare the EEG/EMG-based and the WBP-based scoring of wake-sleep states of mice, and provide formal guidelines for the latter. EEG, EMG, blood pressure and WBP signals were simultaneously recorded from 20 mice. Wake-sleep states were scored based either on EEG/EMG or on WBP signals and sleep-dependent respiratory and cardiovascular estimates were calculated. We found that the overall agreement between the 2 methods was 90%, with a high Cohen's Kappa index (0.82). The inter-rater agreement between 2 experts and between 1 expert and 1 naïve sleep investigators gave similar results. Sleep-dependent respiratory and cardiovascular estimates did not depend on the scoring method. We show that non-invasive discrimination of the wake-sleep states of mice based on visual inspection of the WBP signal is accurate, reliable and reproducible. This work may set the stage for non-invasive high-throughput experiments evaluating sleep and breathing patterns on mouse models of pathophysiology
Artificial protein and its applications
No full textThe present invention relates to a synthetic peptide comprising the following elements from the N-terminus to the C-terminus:
a) a first cell-penetrating peptide or functional fragments or derivatives, or biologically active variants thereof and
b) a second peptide with agonist activity of OR1 and OR2 receptors or functional fragments or derivatives, or biologically active variants thereof
Detection of central and obstructive sleep apneas in mice: A new surgical and recording protocol
No full text: Sleep apnea is a common respiratory disorder in humans and consists of recurrent episodes of cessation of breathing or decrease in airflow during sleep. Sleep apnea can be classified as central or obstructive, based on its origin. Central sleep apnea results from an impaired transmission of the signal for inspiration from the brain to inspiratory muscles, while obstructive sleep apnea occurs in the presence of an obstruction of the upper airways during inspiration. This condition leads to repetitive episodes of reduced oxygen and elevated carbon dioxide levels in the bloodstream, which entail both direct and indirect adverse effects on vital organs, especially the brain and heart. Basic research on animal models has been instrumental in advancing the understanding of disease mechanisms and pathophysiology, and in expediting the development of targeted therapies in several medical fields. Among animal models, mice are the mammalian species of choice for functional genomics of integrative functions such as sleep. Mice have long been known to show sleep apneas, but the classification of sleep apneas as central or obstructive in mice is technically challenging due to the small size of these animals. Here we present a method aimed at identifying central and obstructive sleep apneas in mice. This method involves the surgical implantation of electrodes for recording the electroencephalogram and nuchal muscle electromyogram, which are the gold standard to study the wake-sleep cycle, and for recording the diaphragm electromyogram, which allows the detection of diaphragm contraction. The method also includes the simultaneous recording of the above-mentioned biological signals and breathing inside a whole-body plethysmograph and the data analysis allows to score wake-sleep states and to detect sleep apneas and categorize them into central and obstructive events
Pilot Study of the Effects of Chronic Intracerebroventricular Infusion of Human Anti-IgLON5 Disease Antibodies in Mice
No full textBackground: Anti-IgLON5 disease is a rare late-onset neurological disease associated with autoantibodies against IgLON5, neuronal accumulation of phosphorylated Tau protein (p-Tau), and sleep, respiratory, and motor alterations. Purpose: We performed a pilot study of whether the neuropathological and clinical features of anti-IgLON5 disease may be recapitulated in mice with chronic intracerebroventricular infusion of human anti-IgLON5 disease IgG (Pt-IgG). Methods: Humanized transgenic hTau mice expressing human Tau protein and wild-type (WT) control mice were infused intracerebroventricularly with Pt-IgG or with antibodies from a control subject for 14 days. The sleep, respiratory, and motor phenotype was evaluated at the end of the antibody infusion and at least 30 days thereafter, followed by immunohistochemical assessment of p-Tau deposition. Results: In female hTau and WT mice infused with Pt-IgG, we found reproducible trends of diffuse neuronal cytoplasmic p-Tau deposits in the brainstem and hippocampus, increased ventilatory period during sleep, and decreased inter-lick interval during wakefulness. These findings were not replicated on male hTau mice. Conclusion: The results of our pilot study suggest, but do not prove, that chronic ICV infusion of mice with Pt-IgG may elicit neuropathological, respiratory, and motor alterations. These results should be considered as preliminary until replicated in larger studies taking account of potential sex differences in mice
Cardiorespiratory control during sleep in orexin deficient mice
No full textAim of this thesis was to study specific aspects of cardiorespiratory control during sleep in orexin- deficient (ORX-KO) mice. In particular, we explored the autonomic mechanisms of cardiovascular control during sleep in ORX-KO mice, and we investigated the role of orexins (ORXs) in breathing regulation and disturbances during sleep, as a function of Ta (ambient temperature).
To unravel the mechanisms of ORX-dependent cardiovascular changes during sleep, we recorded electroencephalogram, electromyogram and arterial pressure (AP) in 13 male ORX-KO mice and 12 wild-type (WT) mice during intraperitoneal infusions of selective autonomic blockers. To investigate the role of ORXs in breathing as function of sleep states and Ta, we studied 9 male ORX-KO and 8 WT mice at two different Ta (30°C, 20°C) in a whole-body plethysmography chamber.
ORX-KO mice had higher AP values during rapid-eye-movement sleep (REMS), smaller decreases in AP from wakefulness (W) to both non-rapid-eye-movement sleep (NREMS) or REMS, and greater increases in AP from NREMS to REMS, compared to WT. These differences were abolished by prazosin and, also by atenolol, except for the transition from W to REMS, in ORX-KO mice. No significant differences were found in respiratory regulation during sleep between WT and ORX-KO mice, except for sigh occurrence rate, which was increased at Ta=20°C, compared with Ta=30°C, only in WT mice. In both groups, the occurrence rate of sleep apneas in NREMS was significantly reduced at Ta=20°C.
We demonstrated that changes in cardiovascular sympathetic control mediate sleep-related alterations of AP showed by ORX-KO mice, compared to WT mice. Moreover, we demonstrated that the sleep apnea occurrence rate critically depends on Ta, and that ORXs have not a main role in sleep-breathing regulation as a function of Ta
Mice overexpressing lamin B1 in oligodendrocytes recapitulate the age-dependent motor signs, but not the early autonomic cardiovascular dysfunction of autosomal-dominant leukodystrophy (ADLD)
No full textAutosomal dominant leukodystrophy (ADLD) is a rare adult-onset demyelinating disease caused by overexpression of lamin B1, a nuclear lamina filament. Early autonomic dysfunction involving the cardiovascular system before progressive somatic motor dysfunction is a striking feature of most cases of ADLD. In the Plp-FLAG-LMNB1 transgenic mouse model, lamin B1 overexpression in oligodendrocytes elicits somatic motor dysfunction and neuropathology akin to ADLD. Here, we investigate whether Plp-FLAG-LMNB1 mice also develop autonomic cardiovascular dysfunction before or after somatic motor dysfunction. We find that Plp-FLAG-LMNB1 mice have preserved cardiovascular responses to changes in wake-sleep state and ambient temperature and normal indexes of autonomic modulation at 37–42 weeks of age despite a progressive somatic motor dysfunction, which includes impairments of walking ability (the ability to walk on a narrow path was impaired in 80% of mice at 34–38 weeks of age) and subtle breathing derangements. Only late in the development of the disease phenotype did Plp-FLAG-LMNB1 mice develop a structural deficit of sympathetic noradrenergic fibers, with a 38% decrease in fiber profiles in the kidneys at 44–47 weeks of age. We demonstrate that while the Plp-FLAG-LMNB1 mouse model recapitulates the age-dependent motor dysfunction of ADLD, it does not show signs of early autonomic cardiovascular dysfunction, raising the possibility that oligodendrocyte dysfunction may not be sufficient to cause the full spectrum of clinical features present in ADLD
