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The association between sleep and the immune-endocrine system is well recognized, but the nature of that relationship is not well understood. Sleep fragmentation induces a pro-inflammatory response in peripheral tissues and brain, but it also activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing glucocorticoids (GCs) (cortisol in humans and corticosterone in mice). It is unclear whether this rapid release of glucocorticoids acts to potentiate or dampen the inflammatory response in the short term. The purpose of this study was to determine whether blocking or suppressing glucocorticoid activity will affect the inflammatory response from acute sleep fragmentation (ASF). Male C57BL/6J mice were injected i.p. with either 0.9% NaCl (vehicle 1), metyrapone (a glucocorticoid synthesis inhibitor, dissolved in vehicle 1), 2% ethanol in polyethylene glycol (vehicle 2), or mifepristone (a glucocorticoid receptor antagonist, dissolved in vehicle 2) 10 min before the start of ASF or no sleep fragmentation (NSF). After 24 h, samples were collected from brain (prefrontal cortex, hypothalamus, hippocampus) and periphery (liver, spleen, heart, and epididymal white adipose tissue (EWAT)). Proinflammatory gene expression (TNF-α and IL-1ß) was measured, followed by gene expression analysis. Metyrapone treatment affected pro-inflammatory cytokine gene expression during ASF in some peripheral tissues, but not in the brain. More specifically, metyrapone treatment suppressed IL-1ß expression in EWAT during ASF, which implies a pro-inflammatory effect of GCs. However, in cardiac tissue, metyrapone treatment increased TNF-α expression in ASF mice, suggesting an anti-inflammatory effect of GCs. Mifepristone treatment yielded more significant results than metyrapone, reducing TNF-α expression in liver (only NSF mice) and cardiac tissue during ASF, indicating a pro-inflammatory role. Conversely, in the spleen of ASF-mice, mifepristone increased pro-inflammatory cytokines (TNF-α and IL-1ß), demonstrating an anti-inflammatory role. Furthermore, irrespective of sleep fragmentation, mifepristone increased pro-inflammatory cytokine gene expression in heart (IL-1ß), pre-frontal cortex (IL-1ß), and hypothalamus (IL-1ß). The results provide mixed evidence for pro- and anti-inflammatory functions of corticosterone to regulate inflammatory responses to acute sleep loss.

Asunto(s)

Glucocorticoides , Metirapona , Ratones Endogámicos C57BL , Mifepristona , Privación de Sueño , Animales , Masculino , Metirapona/farmacología , Privación de Sueño/metabolismo , Privación de Sueño/tratamiento farmacológico , Ratones , Mifepristona/farmacología , Glucocorticoides/farmacología , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Corticosterona/sangre , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/genética

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STUDY OBJECTIVES: Menopause is associated with nighttime sleep fragmentation, declining estradiol, and impaired cognition. In a model of pharmacologically induced estradiol suppression mimicking menopause, we examined the impact of menopause-pattern sleep fragmentation on daytime neurobehavioral performance and sleepiness in premenopausal women. METHODS: Twenty premenopausal women completed two five-night inpatient studies in the mid-to-late follicular phase (estrogenized) and after pharmacological estradiol suppression (hypo-estrogenized). During each study, participants had an uninterrupted 8-hour sleep opportunity for two nights, followed by three nights where sleep was experimentally fragmented to mimic menopause-pattern sleep disturbance, and during which the sleep opportunity was extended to prevent shortening of the sleep duration. Neurobehavioral performance and subjective sleepiness were measured using the Psychomotor Vigilance Task and Karolinska Sleepiness Scale (KSS). RESULTS: Compared to unfragmented sleep, sleep fragmentation increased attentional lapses (+ 0.6 lapses, p < .05), slowed reaction time (+ 9.4 milliseconds, p < .01), and increased daytime sleepiness (+ 0.5 KSS score, p < .001). Estradiol suppression increased attentional lapses (+ 0.8; p < .001) and reaction time (+ 12.3, p < .01) but did not significantly affect daytime sleepiness. The effect of sleep fragmentation on neurobehavioral performance differed by estradiol state, such that the adverse effects of sleep fragmentation on attentional lapses (+ 0.9, trend p = .06) and reaction time (+ 15, p < .05) were observed only when estrogenized. CONCLUSIONS: Menopause-pattern sleep fragmentation and estradiol suppression worsened neurobehavioral performance and daytime sleepiness, even while sleep duration was not reduced. The adverse effects of sleep fragmentation in the context of an adequate sleep duration highlight the importance of sleep continuity as a vital aspect of good sleep health.

Asunto(s)

Atención , Estradiol , Premenopausia , Desempeño Psicomotor , Privación de Sueño , Humanos , Femenino , Estradiol/sangre , Privación de Sueño/fisiopatología , Privación de Sueño/complicaciones , Adulto , Premenopausia/fisiología , Atención/efectos de los fármacos , Atención/fisiología , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Somnolencia , Adulto Joven , Persona de Mediana Edad

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INTRODUCTION: The association between quality sleep and improved cognition is well reported in literature. However, very few studies have been undertaken to evaluate the impact of poor sleep on educational outcomes in Indigenous Australian children. OBJECTIVES: The objective of this review was to explore the association between sleep and educational outcomes of Indigenous children. METHODS: For this systematic review, a literature search covering research articles in academic databases and grey literature sources was conducted to retrieve studies published until March 2022. Eight online e-databases (PubMed, Ovid MEDLINE, CINAHL, SCOPUS, HealthinfoNet, PsycINFO, Cochrane and Google Scholar) were searched for data extraction and two appraisal tools (NIH and CREATE) were used for quality assessment. Studies that explored any aspect of sleep health in relation to educational/academic outcomes in school going Indigenous Australian children aged 5-18 were included in this study. All review articles and studies that focused on physical/ mental disabilities or parent perceptions of sleep and educational outcomes were excluded. A convergent integrated approach was used to collate and synthesize information. RESULTS: Only three studies (two cross-sectional and one longitudinal) met the eligibility criteria out of 574 articles. The sample size ranged from 21-50 of 6 to 13 year old children. A strong relationship was indicated between sleep quantity and educational outcomes, in two of the three studies. One study related the sleep fragmentation/shorter sleep schedules of short sleep class and early risers with poorer reading (B = -30.81 to -37.28, p = 0.006 to 0.023), grammar (B = -39.79 to -47.89, p = 0.012-0.013) and numeracy (B = -37.93 to -50.15, p = 0.003 to 0.022) skills compared with long sleep and normative sleep class whereas another reported no significant relation between sleep and educational outcomes. CONCLUSION: The review highlights the need for more research to provide evidence of potentially modifiable factors such as sleep and the impact these may have on academic performance.

Asunto(s)

Nativos de Hawái y Otras Islas del Pacífico , Humanos , Niño , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Australia , Adolescente , Sueño , Preescolar , Femenino , Masculino , Escolaridad , Aborigenas Australianos e Isleños del Estrecho de Torres

RESUMEN

OBJECTIVE: To compare the effect of stage 3 fragmentation and the paradoxical phase of night sleep on melatonin (MT) secretion, and to evaluate the effects of changes in autonomic balance and activation reactions that occur in the orthodox and paradoxical phases of sleep. MATERIAL AND METHODS: Fifteen healthy men participated in three sessions: with stage 3 fragmentation, with fragmentation of paradoxical sleep, and in a control experiment in which sleep was not disturbed. In each experiment, 7 saliva samples were collected in the evening, at night and in the morning and the MT content was determined. Heart rate variability was analyzed using an electrocardiogram and autonomic balance was assessed. RESULTS: Sleep fragmentation was accompanied by activation reactions and reduced the duration of stage 3 and paradoxical phase sleep by 50% and 51% in the corresponding sessions. Fragmentation of paradoxical sleep also led to an increase in the duration of night wakefulness. Sleep disturbances caused an increase in MT secretion in the second half of the night and in the morning, especially pronounced in sessions with fragmentation of paradoxical sleep, in which upon awakening MT was 1.8 times higher than in the control. Stage 3 fragmentation was accompanied by increased sympathetic activation, while fragmentation of paradoxical sleep did not cause autonomic shifts. The subjects were divided into 2 clusters: with high and low MT in night and morning saliva samples. In all sessions, subjects with high MT had 1.7-2 times longer duration of night wakefulness; in sessions with fragmentation, they had significantly more activations in the paradoxical phase of sleep. CONCLUSION: Night sleep disturbances cause an increase in MT secretion, especially pronounced during the fragmentation of the paradoxical phase. An increase in MT levels does not depend on changes in autonomic balance and is apparently associated with activation of the serotonergic system, which accompanies disturbances in the depth and continuity of sleep.

Asunto(s)

Melatonina , Saliva , Privación de Sueño , Sueño REM , Humanos , Melatonina/metabolismo , Masculino , Sueño REM/fisiología , Adulto , Saliva/metabolismo , Saliva/química , Privación de Sueño/fisiopatología , Privación de Sueño/metabolismo , Sueño de Onda Lenta/fisiología , Adulto Joven , Frecuencia Cardíaca/fisiología , Sistema Nervioso Autónomo/fisiopatología , Sistema Nervioso Autónomo/metabolismo , Vigilia/fisiología

RESUMEN

BACKGROUND: Obstructive sleep apnea (OSA) is associated with multiple comorbidities, including diabetes. Its development is preceded by alterations in the initial phase of carbohydrate metabolism characterized by insulin resistance. This study aims to evaluate the role of intermittent hypoxia and sleep fragmentation characteristic of OSA on the risk of insulin resistance among apneic patients without diabetes. METHODOLOGY: 92 consecutive patients with OSA without evidence of diabetes were recruited. Overnight video polysomnography was performed and, the following morning, fasting blood glucose, insulin and glycosylated hemoglobin were determined. Insulin resistance was measured using the HOMA-IR index. RESULTS: Insulin resistance was present in 52.2% of OSA patients. In these subjects, insulin resistance was independently associated to the apnea index during REM sleep (adjusted odds ratio [aOR] 1.09; 95% CI, 1.03 to 1.16; p = 0.004), desaturation index (aOR 1.08; 95% CI: 1.04 to 1.13; p = 0.027), and sleep time with oxygen saturation below 90% (aOR 1.04; 95% CI 1.00 to 1.08; p = 0.049). Furthermore, the HOMA-IR level was also directly related to the desaturation index (standardized regression coefficient [B] = 0.514, p < 0.001) and to the apnea index during REM sleep (B = 0.344, p = 0.002). CONCLUSIONS: Intermittent hypoxia and disturbances in REM sleep emerge as main contributors to insulin resistance in OSA patients yet to experience diabetes onset.

Asunto(s)

Resistencia a la Insulina , Polisomnografía , Apnea Obstructiva del Sueño , Humanos , Apnea Obstructiva del Sueño/fisiopatología , Apnea Obstructiva del Sueño/epidemiología , Resistencia a la Insulina/fisiología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Hipoxia/fisiopatología , Glucemia/metabolismo , Privación de Sueño/fisiopatología , Privación de Sueño/epidemiología , Privación de Sueño/complicaciones

RESUMEN

Traumatic brain injury (TBI) causes a prolonged inflammatory response in the central nervous system (CNS) driven by microglia. Microglial reactivity is exacerbated by stress, which often provokes sleep disturbances. We have previously shown that sleep fragmentation (SF) stress after experimental TBI increases microglial reactivity and impairs hippocampal function 30 days post-injury (DPI). The neuroimmune response is highly dynamic the first few weeks after TBI, which is also when injury induced sleep-wake deficits are detected. Therefore, we hypothesized that even a few weeks of TBI SF stress would synergize with injury induced sleep-wake deficits to promote neuroinflammation and impair outcome. Here, we investigated the effects of environmental SF in a lateral fluid percussion model of mouse TBI. Half of the mice were undisturbed, and half were exposed to 5 h of SF around the onset of the light cycle, daily, for 14 days. All mice were then undisturbed 15-30 DPI, providing a period for SF stress recovery (SF-R). Mice exposed to SF stress slept more than those in control housing 7-14 DPI and engaged in more total daily sleep bouts during the dark period. However, SF stress did not exacerbate post-TBI sleep deficits. Testing in the Morris water maze revealed sex dependent differences in spatial reference memory 9-14 DPI with males performing worse than females. Post-TBI SF stress suppressed neurogenesis-related gene expression and increased inflammatory signaling in the cortex at 14 DPI. No differences in sleep behavior were detected between groups during the SF stress recovery period 15-30 DPI. Microscopy revealed cortical and hippocampal IBA1 and CD68 percent-area increased in TBI SF-R mice 30 DPI. Additionally, neuroinflammatory gene expression was increased, and synaptogenesis-related gene expression was suppressed in TBI-SF mice 30 DPI. Finally, IPA canonical pathway analysis showed post-TBI SF impaired and delayed activation of synapse-related pathways between 14 and 30 DPI. These data show that transient SF stress after TBI impairs recovery and conveys long-lasting impacts on neuroimmune function independent of continuous sleep deficits. Together, these finding support that even limited exposure to post-TBI SF stress can have lasting impacts on cognitive recovery and regulation of the immune response to trauma.

RESUMEN

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea (OSA) is poorly explained by standard clinical sleep architecture metrics. We hypothesized that reduced sleep stage continuity mediates this connection independently from standard sleep architecture metrics. METHODS: 1,907 patients with suspected OSA with daytime sleepiness complaints underwent in-lab diagnostic polysomnography and next-day Multiple Sleep Latency Test (MSLT). Sleep architecture was evaluated with novel sleep-stage continuity quantifications (mean sleep stage duration and probability of remaining in each sleep stage), and conventional metrics (total N1, N2, N3 and REM times; and sleep onset latency). Multivariate analyses were utilized to identify variables associated with moderate EDS (5 ≤ mean daytime sleep latency (MSL) ≤ 10 minutes) and severe EDS (MSL < 5 minutes). RESULTS: Compared to those without EDS, participants with severe EDS had lower N3 sleep continuity (mean N3 period duration 10.4 vs 13.7 minutes, p<0.05), less N3 time (53.8 vs 76.5 minutes, p<0.05); greater total sleep time (374.0 vs 352.5 minutes, p<0.05) and greater N2 time (227.5 vs 186.8 minutes, p<0.05). After adjusting for standard sleep architecture metrics using multivariate logistic regression, decreased mean wake and N3 period duration, and the decreased probability of remaining in N2 and N3 sleep remained significantly associated with severe EDS, while the decreased probability of remaining in wake and N2 sleep were associated with moderate EDS. CONCLUSIONS: Patients with OSA with EDS experience lower sleep continuity, noticeable especially during N3 sleep and wake. Sleep-stage continuity quantifications assist in characterizing the sleep architecture and are associated with objective daytime sleepiness highlighting the need for more detailed evaluations of sleep quality.

RESUMEN

INTRODUCTION: The effects of sleep-wake behavior on perceived fatigability and cognitive abilities when performing daily activities have not been investigated across levels of cognitive reserve (CR). METHODS: CR Index Questionnaire (CRIq) data were collected and subjected to moderated mediation analysis. RESULTS: In amnestic mild cognitive impairment (aMCI; n = 41), CR moderated sleep-related impairments (SRIs), and fatigability at low CR (CRIq < 105.8, p = 0.004) and mean CR (CRIq = 126.9, p = 0.03) but not high CR (CRIq > 145.9, p = 0.65) levels. SRI affected cognitive abilities mediated by fatigability at low CR (p < 0.001) and mean CR (p = 0.003) levels. In healthy controls (n = 13), SRI in fatigability did not alter cognitive abilities across CR levels; controls had higher leisure scores than patients with aMCI (p = 0.003, effect size = 0.93). DISCUSSION: SRI can amplify impaired cognitive abilities through exacerbation of fatigability in patients with aMCI with below-mean CR. Therefore, improving sleep-wake regulation and leisure activities may protect against fatigability and cognitive decline. HIGHLIGHTS: Clinical fatigue and fatigability cannot be alleviated by rest. Clinical fatigability disrupts daily activities during preclinical Alzheimer's. High cognitive reserve mitigates sleep-wake disturbance effects. High cognitive reserve attenuates clinical fatigability effects on daily functioning. Untreated obstructive sleep apnea potentiates Alzheimer's pathology in the brain.

Asunto(s)

Disfunción Cognitiva , Reserva Cognitiva , Fatiga , Humanos , Masculino , Femenino , Reserva Cognitiva/fisiología , Anciano , Fatiga/fisiopatología , Disfunción Cognitiva/fisiopatología , Encuestas y Cuestionarios , Sueño/fisiología , Trastornos del Sueño-Vigilia/fisiopatología , Pruebas Neuropsicológicas/estadística & datos numéricos , Actividades Cotidianas , Anciano de 80 o más Años

RESUMEN

Accumulating evidence shows that most chronic neurological diseases have a link with sleep disturbances, and that patients with chronically poor sleep undergo an accelerated cognitive decline. Indeed, a single-night of sleep deprivation may increase metabolic waste levels in cerebrospinal fluid. However, it remains unknown how chronic sleep disturbances in isolation from an underlying neurological disease may affect the glymphatic system. Clearance of brain interstitial waste by the glymphatic system occurs primarily during sleep, driven by multiple oscillators including arterial pulsatility, and vasomotion. Herein, we induced sleep fragmentation in young wildtype mice and assessed the effects on glymphatic activity and cognitive functions. Chronic sleep fragmentation reduced glymphatic function and impaired cognitive functions in healthy mice. A mechanistic analysis showed that the chronic sleep fragmentation suppressed slow vasomotion, without altering cardiac-driven pulsations. Taken together, results of this study document that chronic sleep fragmentation suppresses brain metabolite clearance and impairs cognition, even in the absence of disease.

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Encéfalo , Sistema Glinfático , Privación de Sueño , Animales , Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología , Ratones , Encéfalo/metabolismo , Sistema Glinfático/metabolismo , Sistema Glinfático/fisiopatología , Masculino , Ratones Endogámicos C57BL , Cognición/fisiología

RESUMEN

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

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Trastorno del Espectro Autista , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Proteínas del Tejido Nervioso , Tálamo , Animales , Tálamo/metabolismo , Tálamo/patología , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Ratones , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/patología , Lamotrigina/farmacología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Canalopatías/genética , Canalopatías/metabolismo , Canalopatías/patología , Humanos , Modelos Animales de Enfermedad , Masculino , Neuronas/metabolismo , Femenino , Ratones Endogámicos C57BL , Mutación/genética , Sueño/fisiología , Sueño/efectos de los fármacos , Sueño/genética , Canales de Potasio

RESUMEN

Sleep fragmentation (SF) is a common sleep problem experienced during the perioperative period by older adults, and is associated with postoperative cognitive dysfunction (POCD). Increasing evidence indicates that delta-wave activity during non-rapid eye movement (NREM) sleep is involved in sleep-dependent memory consolidation and that hippocampal theta oscillations are related to spatial exploratory memory. Recovery sleep (RS), a self-regulated state of sleep homeostasis, enhances delta-wave power and memory performance in sleep-deprived older mice. However, it remains unclear whether RS therapy has a positive effect on cognitive changes following SF in older mouse models. Therefore, this study aimed to explore whether preoperative RS can alleviate cognitive deficits in aged mice with SF. A model of preoperative 24-h SF combined with exploratory laparotomy-induced POCD was established in 18-month-old mice. Aged mice were treated with preoperative 6-h RS following SF and postoperative 6-h RS following surgery, respectively. The changes in hippocampus-dependent cognitive function were investigated using behavioral tests, electroencephalography (EEG), local field potential (LFP), magnetic resonance imaging, and neuromorphology. Mice that underwent 24-h SF combined with surgery exhibited severe spatial memory impairment; impaired cognitive performance could be alleviated by preoperative RS treatment. In addition, preoperative RS increased NREM sleep; enhanced EEG delta-wave activity and LFP theta oscillation in the hippocampal CA1; and improved hippocampal perfusion, microstructural integrity, and neuronal damage. Taken together, these results provide evidence that preoperative RS may ameliorate the severity of POCD aggravated by SF by enhancing delta slow-wave activity and hippocampal theta oscillation, and by ameliorating the reduction in regional cerebral blood flow and white matter microstructure integrity in the hippocampus.

Asunto(s)

Región CA1 Hipocampal , Ritmo Delta , Complicaciones Cognitivas Postoperatorias , Privación de Sueño , Ritmo Teta , Animales , Privación de Sueño/fisiopatología , Privación de Sueño/complicaciones , Ratones , Ritmo Teta/fisiología , Masculino , Ritmo Delta/fisiología , Región CA1 Hipocampal/fisiopatología , Ratones Endogámicos C57BL , Electroencefalografía/métodos , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Sueño/fisiología , Envejecimiento/fisiología

RESUMEN

Sleep fragmentation (SF) can increase inflammation and production of reactive oxygen species (ROS), leading to metabolic dysfunction. SF is associated with inflammation of adipose tissue and insulin resistance. Several studies have suggested that melatonin may have beneficial metabolic effects due to activating AMP-activated protein kinase (AMPK). However, it is unclear whether melatonin affects the AMPK signaling pathway in SF-induced metabolic dysfunction. Therefore, we hypothesize that SF induces metabolic impairment and inflammation in white adipose tissue (WAT), as well as altered intracellular homeostasis. We further hypothesize that these conditions could be improved by melatonin treatment. We conducted an experiment using adult male C57BL/6 mice, which were divided into three groups: control, SF, and SF with melatonin treatment (SF+Mel). The SF mice were housed in SF chambers, while the SF+Mel mice received daily oral melatonin. After 12 weeks, glucose tolerance tests, insulin tolerance tests, adipose tissue inflammation tests, and AMPK assessments were performed. The SF mice showed increased weight gain, impaired glucose regulation, inflammation, and decreased AMPK in WAT compared to the controls. Melatonin significantly improved these outcomes by mitigating SF-induced metabolic dysfunction, inflammation, and AMPK downregulation in adipose tissue. The therapeutic efficacy of melatonin against cardiometabolic impairments in SF may be due to its ability to restore adipose tissue homeostatic pathways.

Asunto(s)

Resistencia a la Insulina , Melatonina , Masculino , Animales , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Melatonina/uso terapéutico , Privación de Sueño/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Aumento de Peso , Inflamación/metabolismo , Glucosa , Homeostasis

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Sleep disorders have emerged as a widespread public health concern, primarily due to their association with an increased risk of developing cardiovascular diseases. Our previous research indicated a potential direct impact of insufficient sleep duration on cardiac remodeling in children and adolescents. Nevertheless, the underlying mechanisms behind the link between sleep fragmentation (SF) and cardiac abnormalities remain unclear. In this study, we aimed to investigate the effects of SF interventions at various life stages on cardiac structure and function, as well as to identify genes associated with SF-induced cardiac dysfunction. To achieve this, we established mouse models of chronic SF and two-week sleep recovery (SR). Our results revealed that chronic SF significantly compromised left ventricular contractile function across different life stages, leading to alterations in cardiac structure and ventricular remodeling, particularly during early life stages. Moreover, microarray analysis of mouse heart tissue identified two significant modules and nine hub genes (Ddx60, Irf9, Oasl2, Rnf213, Cmpk2, Stat2, Parp14, Gbp3, and Herc6) through protein-protein interaction analysis. Notably, the interactome predominantly involved innate immune responses. Importantly, all hub genes lost significance following SR. The second module primarily consisted of circadian clock genes, and real-time PCR validation demonstrated significant upregulation of Arntl, Dbp, and Cry1 after SF, while subsequent SR restored normal Arntl expression. Furthermore, the expression levels of four hub genes (Ddx60, Irf9, Oasl2, and Cmpk2) and three circadian clock genes (Arntl, Dbp, and Cry1) exhibited correlations with structural and functional echocardiographic parameters. Overall, our findings suggest that SF impairs left ventricular contractile function and ventricular remodeling during early life stages, and this may be mediated by modulation of the innate immune response and circadian rhythm. Importantly, our findings suggest that a short period of SR can alleviate the detrimental effects of SF on the cardiac immune response, while the influence of SF on circadian rhythm appears to be more persistent. These findings underscore the importance of good sleep for maintaining cardiac health, particularly during early life stages.

Asunto(s)

Ritmo Circadiano , Inmunidad Innata , Privación de Sueño , Función Ventricular Izquierda , Animales , Ratones , Privación de Sueño/genética , Inmunidad Innata/genética , Ritmo Circadiano/genética , Masculino , Función Ventricular Izquierda/genética , Contracción Miocárdica/genética , Ratones Endogámicos C57BL , Remodelación Ventricular/genética , Regulación de la Expresión Génica

RESUMEN

Sleep timing is controlled by intrinsic homeostatic and circadian components. The circadian component controls the chronotype, which is defined by the propensity to sleep at a particular clock time. However, sleep timing can be significantly affected by external factors such as the morning alarm clock. In this study, we analysed the timing of deep and REM sleep as well as the composition of REM sleep using Fitbit sleep staging in young healthy adults (n = 59) under real-life conditions. Sleep stage percentiles were correlated with the timing of total sleep in time after sleep onset for the homeostatic component and in clock time for the circadian component. Regarding the circadian component, the phase of total sleep is most strongly associated with the phases of early deep sleep and REM sleep. Furthermore, a stronger phase relationship between deep and REM sleep with total sleep is associated with greater consolidation of REM sleep. Chronotype-dependent sleep loss correlates negatively with the strength of the phase relationship between deep sleep and total sleep. In conclusion, the interaction of the circadian component of sleep timing with the timing of sleep stages is associated with REM sleep quality. In particular, the interaction of the circadian component of sleep timing with deep sleep seems to be more vulnerable to external factors.

RESUMEN

Migraine and sleep disorders are common co-morbidities. Patients frequently link their sleep to migraine attacks suggesting a potential causal relationship between these conditions. However, whether migraine pain promotes or disrupts sleep or whether sleep disruption can increase the risk of migraine remains unknown. We assessed the potential impact of periorbital allodynia, a measure consistent with migraine-like pain, from multiple preclinical models on sleep quantity and quality. Additionally, we evaluated the possible consequences of sleep deprivation in promoting susceptibility to migraine-like pain. Following the implantation of electroencephalogram/electromyography electrodes to record sleep, mice were treated with either single or repeated systemic injections of nitroglycerin at the onset of their active phase (i.e. nocturnal awake period). Neither single nor repeated nitroglycerin affected the total sleep time, non-rapid eye movement sleep, rapid eye movement sleep, sleep depth or other measures of sleep architecture. To account for the possible disruptive effects of the surgical implantation of electroencephalogram/electromyography electrodes, we used immobility recordings as a non-invasive method for assessing sleep-wake behaviour. Neither single nor repeated nitroglycerin administration during either the mouse sleep (i.e. daylight) or active (i.e. night) periods influenced immobility-defined sleep time. Administration of an inflammatory mediator mixture onto the dura mater at either sleep or active phases also did not affect immobility-defined sleep time. Additionally, inhalational umbellulone-induced migraine-like pain in restraint-stressed primed mice did not alter immobility-defined sleep time. The possible influence of sleep disruption on susceptibility to migraine-like pain was evaluated by depriving female mice of sleep over 6 h with novel objects, a method that does not increase circulating stress hormones. Migraine-like pain was not observed following acute sleep deprivation. However, in sleep-deprived mice, subthreshold doses of systemic nitroglycerin or dural calcitonin gene-related peptide induced periorbital cutaneous allodynia consistent with migraine-like pain. Our data reveal that while migraine-like pain does not significantly disrupt sleep, sleep disruption increases vulnerability to migraine-like pain suggesting that a therapeutic strategy focused on improving sleep may diminish migraine attacks.

RESUMEN

STUDY OBJECTIVES: Lyme arthritis is a common late-stage complication of infection by Borrelia burgdorferi, the agent of Lyme disease. Patients with Lyme arthritis report increased levels of sleep disturbance associated with pain. Using a mouse model of experimental Lyme arthritis, we investigated the effect of disrupted sleep on the development and resolution of joint inflammation. METHODS: Lyme arthritis-susceptible C3H/HeJ mice (n = 10/group) were infected with B. burgdorferi and were left either alone (control) or subjected to sleep fragmentation (SF). Arthritis development or resolution were monitored. The impact of SF on immune and inflammatory parameters such as arthritis severity scores, anti-borrelia antibody production, and bacterial clearance was measured. We also determined the effect of SF on arthritis resolution in C3H mice deficient in leukotriene (LT) B4 signaling (BLT1/2-/-) who display delayed Lyme arthritis resolution. RESULTS: SF had no significant impact on Lyme arthritis development or inflammatory parameters regardless of whether SF treatment began 1 week prior to or congruent with infection. However, initiation of SF at the peak of arthritis resulted in a significant delay in arthritis resolution as measured by joint edema, arthritis severity scores, and decreased bacterial clearance from the joint. This was accompanied by significant changes in joint cytokine transcription levels (e.g., increased TNFα and decreased IL-4). SF has no significant impact on Lyme arthritis resolution in the BLT1/2-/- mice. CONCLUSIONS: Poor sleep, especially near the peak of arthritis inflammation, may delay initiation of resolution programs possibly through altering cytokine production and host immune responses, leading to defects in spirochete clearance and prolonged disease.

Asunto(s)

Artritis , Enfermedad de Lyme , Humanos , Animales , Ratones , Privación de Sueño , Ratones Endogámicos C3H , Enfermedad de Lyme/complicaciones , Enfermedad de Lyme/microbiología , Inflamación , Citocinas

RESUMEN

Sleep fragmentation (SF), which refers to discontinuous and fragmented sleep, induces cognitive impairment and anxiety-like behavior in mice. However, whether SF can affect motor capability in healthy young wild-type mice and the underlying mechanisms remain unknown. We performed seven days of sleep fragmentation (SF 7d) interventions in young wild-type male mice. While SF mice experienced regular sleep disruption between Zeitgeber time (ZT) 0-12, control mice were allowed to have natural sleep (NS) cycles. Homecage analysis and conventional behavioral tests were conducted to assess the behavioral alterations in behavioral patterns in general and motor-related behaviors. Sleep structures and the power spectrum of electroencephalograms (EEGs) were compared between SF 7d and NS groups. Neuronal activation was measured using c-Fos immunostaining and quantified in multiple brain regions. SF of 7 days significantly decreased bouts of rearing and sniffing and the duration of rearing and impaired motor coordination. An increase in the total sleep time and a decrease in wakefulness between ZT12-24 was found in SF 7d mice. In SF 7d mice, EEG beta1 power was increased in rapid eye movement (REM) sleep while theta power was decreased during wakefulness. SF 7d resulted in significant suppression in c-Fos (+) cell counts in the motor cortex and hippocampus but an increase in c-Fos (+) cell counts in the substantia nigra pars compacta (SNc). In summary, SF 7d suppressed explorative behaviors and impaired motor coordination as compared to NS. EEG power and altered neuronal activity detected by c-Fos staining might contribute to the behavioral changes.

Asunto(s)

Conducta Exploratoria , Privación de Sueño , Masculino , Animales , Ratones , Sueño , Ansiedad , Recuento de Células , Proteínas Proto-Oncogénicas c-fos

RESUMEN

STUDY OBJECTIVES: Mounting evidence indicated the correlation between sleep and cerebral small vessel disease (CSVD). However, little is known about the exact causality between poor sleep and white matter injury, a typical signature of CSVD, as well as the underlying mechanisms. METHODS: Spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats were subjected to sleep fragmentation (SF) for 16 weeks. The effects of chronic sleep disruption on the deep white matter and cognitive performance were observed. RESULTS: SHR were validated as a rat model for CSVD. Fragmented sleep induced strain-dependent white matter abnormalities, characterized by reduced myelin integrity, impaired oligodendrocytes precursor cells (OPC) maturation and pro-inflammatory microglial polarization. Partially reversible phenotypes of OPC and microglia were observed in parallel following sleep recovery. CONCLUSIONS: Long-term SF-induced pathological effects on the deep white matter in a rat model of CSVD. The pro-inflammatory microglial activation and the block of OPC maturation may be involved in the mechanisms linking sleep to white matter injury.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Sustancia Blanca , Ratas , Animales , Privación de Sueño , Ratas Endogámicas SHR , Sueño , Ratas Endogámicas WKY , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/patología

RESUMEN

STUDY OBJECTIVES: Hypnograms contain a wealth of information and play an important role in sleep medicine. However, interpretation of the hypnogram is a difficult task and requires domain knowledge and "clinical intuition." This study aimed to uncover which features of the hypnogram drive interpretation by physicians. In other words, make explicit which features physicians implicitly look for in hypnograms. METHODS: Three sleep experts evaluated up to 612 hypnograms, indicating normal or abnormal sleep structure and suspicion of disorders. ElasticNet and convolutional neural network classification models were trained to predict the collected expert evaluations using hypnogram features and stages as input. The models were evaluated using several measures, including accuracy, Cohen's kappa, Matthew's correlation coefficient, and confusion matrices. Finally, model coefficients and visual analytics techniques were used to interpret the models to associate hypnogram features with expert evaluation. RESULTS: Agreement between models and experts (Kappa between 0.47 and 0.52) is similar to agreement between experts (Kappa between 0.38 and 0.50). Sleep fragmentation, measured by transitions between sleep stages per hour, and sleep stage distribution were identified as important predictors for expert interpretation. CONCLUSIONS: By comparing hypnograms not solely on an epoch-by-epoch basis, but also on these more specific features that are relevant for the evaluation of experts, performance assessment of (automatic) sleep-staging and surrogate sleep trackers may be improved. In particular, sleep fragmentation is a feature that deserves more attention as it is often not included in the PSG report, and existing (wearable) sleep trackers have shown relatively poor performance in this aspect.

Asunto(s)

Electroencefalografía , Privación de Sueño , Humanos , Electroencefalografía/métodos , Reproducibilidad de los Resultados , Polisomnografía/métodos , Sueño , Fases del Sueño

RESUMEN

Psychological stress poses a risk for sleep disturbances. Importantly, trauma-exposed individuals who develop posttraumatic stress disorder (PTSD) frequently report insomnia and recurrent nightmares. Clinical studies have provided insight into the mechanisms of these sleep disturbances. We review polysomnographic findings in PTSD and identify analogous measures that have been made in animal models of PTSD. There is a rich empirical and theoretical literature on rapid eye movement sleep (REMS) substrates of insomnia and nightmares, with an emphasis on REMS fragmentation. For future investigations of stress-induced sleep changes, we recommend a focus on tonic, phasic and other microarchitectural REMS measures. Power spectral density analysis of the sleep EEG should also be utilized. Animal models with high construct validity can provide insight into gender and time following stressor exposure as moderating variables. Ultimately, preclinical studies with translational potential will lead to improved treatment for stress-related sleep disturbances.