Does Chronic Sleep Fragmentation Lead to Alzheimer's Disease in Young Wild-Type Mice?

Chronic sleep insufficiency is becoming a common issue in the young population nowadays, mostly due to life habits and work stress. Studies in animal models of neurological diseases reported that it would accelerate neurodegeneration progression and exacerbate interstitial metabolic waste accumulation in the brain. In this paper, we study whether chronic sleep insufficiency leads to neurodegenerative diseases in young wild-type animals without a genetic pre-disposition. To this aim, we modeled chronic sleep fragmentation (SF) in young wild-type mice. We detected pathological hyperphosphorylated-tau (Ser396/Tau5) and gliosis in the SF hippocampus. 18F-labeled fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET) further revealed a significant increase in brain glucose metabolism, especially in the hypothalamus, hippocampus and amygdala. Hippocampal RNAseq indicated that immunological and inflammatory pathways were significantly altered in 1.5-month SF mice. More interestingly, differential expression gene lists from stress mouse models showed differential expression patterns between 1.5-month SF and control mice, while Alzheimer's disease, normal aging, and APOEε4 mutation mouse models did not exhibit any significant pattern. In summary, 1.5-month sleep fragmentation could generate AD-like pathological changes including tauopathy and gliosis, mainly linked to stress, as the incremented glucose metabolism observed with PET imaging suggested. Further investigation will show whether SF could eventually lead to chronic neurodegeneration if the stress condition is prolonged in time.

Vivir endeudado. Las narcolepsias de Wasabi de Alan Pauls

The aim of this paper is to explore and to analyze the set of formal elements that makes up the time of Wasabi by Alan Pauls. The topic of debt is here understood as our starting point. There are three debts: one extratextual and two purely economic (contracted within fiction). Our hypothesis is that the three debts, linked together, are not only paid fictionally with the child born at the end of the text (analogy between art and life); nor only with the monstrosity of the cyst (link between body and writing), but with time. Narcolepsies, those chronic sleep disorders are, well looked at, temporary coins through which fiction collects the debt that the writer contracts with it.

Sleep and COVID-19. A Case Report of a Mild COVID-19 Patient Monitored by Consumer-Targeted Sleep Wearables

Since its first description in Wuhan, China, the novel Coronavirus (SARS-CoV-2) has spread rapidly around the world. The management of this major pandemic requires a close coordination between clinicians, scientists, and public health services in order to detect and promptly treat patients needing intensive care. The development of consumer wearable monitoring devices offers physicians new opportunities for the continuous monitoring of patients at home. This clinical case presents an original description of 55 days of SARS-CoV-2-induced physiological changes in a patient who routinely uses sleep-monitoring devices. We observed that sleep was specifically affected during COVID-19 (Total Sleep time, TST, and Wake after sleep onset, WASO), within a seemingly bidirectional manner. Sleep status prior to infection (e.g., chronic sleep deprivation or sleep disorders) may affect disease progression, and sleep could be considered as a biomarker of interest for monitoring COVID-19 progression. The use of habitual data represents an opportunity to evaluate pathologic states and improve clinical care.

Effect of Sleep Restriction on Cardiometabolic and Haemoinflammatory Parameters in Adult Male Wistar Rats

Background and Objective: While insufficient sleep remains an under-recognized public health issue across the globe, there is paucity and heterogeneity of data regarding its cardiometabolic and haemoinflammatory implications. We, therefore, aimed to evaluate the impact of chronic sleep restriction on cardiometabolic and haemoinflammatory parameters in rats. Materials and Methods: 16 male Wistar rats (aged 8-10 weeks) were randomly assigned into equal control or sleep restriction groups. Gentle handling was used to induce sleep restriction for six weeks. Fasting weight and blood sugar were obtained and lipids were analyzed using their respective Randox kits. Malondialdehyde (MDA) levels and catalase (CAT) and superoxide dismutase (SOD) activities were assayed. Full blood count and CD4+ T cell count were determined using automated analyzer. Data were analyzed using Student’s t-test, with level of significance set at P ≤ 0.05, via SPSS software. Results: Chronic sleep restriction caused significant initial weight loss, increase in feed consumption, and percentage increase in fasting blood sugar (FBS) (32% vs. 15%). We also noted the triglyceride-glucose (TyG) index of sleep-restricted rats to be significantly higher (6.22) than that of controls (5.62). In addition, a significant reduction in monocyte count, monocyte-lymphocyte ratio (MLR), and absolute CD4+ cell count among the sleep-restricted rats was observed. Conclusion: Our findings have provided objective evidence that, over the course of 6 weeks, 5 hours of sleep restriction had caused body weight gain, hyperglycaemia, insulin resistance, and impairment in immunoinflammatory status; hence, it could be a risk factor for developing cardiometabolic syndrome and immune-related disorders.

Effects of Chronic Intermittent Hypoxia and Chronic Sleep Fragmentation on Gut Microbiome, Serum Metabolome, Liver and Adipose Tissue Morphology

Chronic intermittent hypoxia (CIH) and chronic sleep fragmentation (CSF) are two cardinal pathological features of obstructive sleep apnea (OSA). Dietary obesity is a crucial risk intermediator for OSA and metabolic disorders. Gut microbiota affect hepatic and adipose tissue morphology under conditions of CIH or CSF through downstream metabolites. However, the exact relationship is unclear. Herein, chow and high-fat diet (HFD)-fed mice were subjected to CIH or CSF for 10 weeks each and compared to normoxia (NM) or normal sleep (NS) controls. 16S rRNA amplicon sequencing, untargeted liquid chromatography-tandem mass spectrometry, and histological assessment of liver and adipose tissues were used to investigate the correlations between the microbiome, metabolome, and lipid metabolism under CIH or CSF condition. Our results demonstrated that CIH and CSF regulate the abundance of intestinal microbes (such as Akkermansia mucinphila, Clostridium spp., Lactococcus spp., and Bifidobacterium spp.) and functional metabolites, such as tryptophan, free fatty acids, branched amino acids, and bile acids, which influence adipose tissue and hepatic lipid metabolism, and the level of lipid deposition in tissues and peripheral blood. In conclusion, CIH and CSF adversely affect fecal microbiota composition and function, and host metabolism; these findings provide new insight into the independent and synergistic effects of CIH, CSF, and HFD on lipid disorders.

Polyamine elevation and nitrogen stress are toxic hallmarks of chronic sleep loss in Drosophila melanogaster

Chronic sleep loss profoundly impacts health in ways coupled to metabolism; however, much existing literature links sleep and metabolism only on acute timescales. To explore the impact of chronically reduced sleep, we conducted unbiased metabolomics on heads from three Drosophila short-sleeping mutants. Common features included elevated ornithine and polyamines; and lipid, acyl-carnitine, and TCA cycle changes suggesting mitochondrial dysfunction. Biochemical studies of overall, circulating, and excreted nitrogen in sleep mutants demonstrate a specific defect in eliminating nitrogen, suggesting that elevated polyamines may function as a nitrogen sink. Both supplementing polyamines and inhibiting their synthesis with RNAi regulated sleep in control flies. Finally, both polyamine-supplemented food and high-protein feeding were highly toxic to sleep mutants, suggesting their altered nitrogen metabolism is maladaptive. Together, our results suggest polyamine accumulation specifically, and nitrogen stress in general, as potential mechanisms linking chronic sleep loss to adverse health outcomes.

510 - EFFECT OF SLEEP DEPRIVATION ON SOCIAL RESILIENCE THROUGH ΔFOSB ACTIVATION

Introduction:Stress can have a variety of detrimental effects on humans. From depression and anxiety to schizophrenia, stress plays a factor in the development of these diseases through neurochemical changes in the brain and elevated levels of hormones. Among the geriatric population, decreased sleep levels are known to be a frequent issue; insomnia rates among the senior population are much higher in frequency compared to any other age group. Sleep deprivation also leads to major consequences in the brain and sleep disruption is linked to neuropsychological illness; however, the specific mechanisms involved in these effects are not understood. This study focuses on the resilient effects of ΔFosB, a protein known to mediate resilience to stress and the direct effect of sleep deprivation on ΔFosB expression in areas known to mediate resilience to social stress. We hypothesize that ΔFosB may be part of the mechanism through which sleep alters resilience to social stress.Methods:Mice were sleep-deprived for an eight-hour period for five days. After sleep deprivation they were subject to social defeat and underwent avoidance testing. The brains of these mice were removed, and immunohistochemistry analysis was conducted to determine ∆FosB expression in various sections of the brain.Results:The preliminary findings of this study indicates that sleep is altered in resilient animals and that sleep deprivation may lead to increased resilience to social defeat. The most significant decrease in ∆FosB expression was found in the prelimbic cortex, a change associated with resilience, and which was observed after chronic sleep deprivation. Contrarily, there was also an increase of ∆FosB expression in the nucleus accumbens.Conclusion:These findings indicate that changes in ∆FosB activation in the brain is a significant factor for promoting resilient behavior in situations of social stress. In particular, a decrease in ∆FosB activation in the PLC plays a role in explaining how sleep deprivation contributes to decreased social resilience in situations of social stress.

Narcolepsy with cataplexy is caused by epigenetic silencing of hypocretin neurons

Narcolepsy with cataplexy is a chronic sleep disorder characterized by hypocretin deficiency. The condition is believed to result from autoimmune destruction of hypocretin (HCRT) neurons, although direct evidence is lacking and mere Hcrt gene inactivation causes full-blown narcolepsy in mice. Here we show that the expression of another hypothalamic neuropeptide, QRFP, is lost in mouse models with HCRT cell-ablation, but tends to be even increased in Hcrt gene knockout mice, suggesting that QRFP expression can be used as a proxy for the presence or absence of HCRT neurons. Similar to Hcrt knockout mice, narcolepsy patients show intact hypothalamic QRFP expression, and cerebrospinal fluid levels of QRFP peptide are increased, suggesting their HCRT neurons are intact. We show that the human HCRT gene promoter is methylation-sensitive in vitro, and is hypermethylated in the hypothalamus of patients selectively at a putative PAX5:ETS1 binding site within the proximal HCRT promoter. Ets1-KO mice display downregulated Hcrt expression, while pax5-ets1 knockdown in zebrafish causes decreased hcrt expression, decreased activity and sleep fragmentation, similar to narcolepsy patients. Our results suggest that HCRT neurons are alive, but epigenetically silenced, in the hypothalamus of narcolepsy patients, opening the possibility to reverse or cure narcolepsy.