Chronic Sleep Fragmentation Research Articles

Acetate enables metabolic fitness and cognitive performance during sleep disruption

Sleep is essential for overall health, and its disruption is linked to increased risks of metabolic, cognitive, and cardiovascular dysfunctions; however, the molecular mechanisms remain poorly understood. This study investigated how sleep disturbances contribute to metabolic imbalance and cognition impairment using a chronic sleep fragmentation (SF) mouse model. SF mice exhibited impaired cognition, glucose metabolism, and insulin sensitivity compared with controls. We identified increased acetate levels in hypothalamic astrocytes as a defensive response in SF mice. Through acetate infusion or astrocyte-specific Acss1 deletion to elevate acetate levels, we observed mitigated metabolic and cognitive impairments in SF mice. Mechanistically, acetate binds and activates pyruvate carboxylase, thereby restoring glycolysis and the tricarboxylic acid cycle. Among individuals most commonly affected by SF, patients with obstructive sleep apnea exhibited elevated acetate levels when coupled with type 2 diabetes. Our study uncovers the protective effect of acetate against sleep-induced metabolic and cognitive impairments.

Effectiveness of preventive parental education delivered from pregnancy to 1 month postpartum for improving infant sleep and parental sleep and depression: a systematic review protocol.

This review aims to evaluate the effectiveness of preventive parental education on infant sleep problems, delivered from pregnancy to 1 month postpartum, on infant sleep, postpartum parental sleep, and depression. Infant sleep problems are likely to persist into childhood if not treated and are associated with difficulties in later development. Parents of children with sleep problems had lower sleep quality and emotional regulation than those without sleep problems. Chronic sleep deprivation and fragmentation increases the risk of maternal depression. Therefore, preventive parental education regarding infant sleep problems can improve the long-term well-being of both children and their parents. Experimental and quasi-experimental study designs, including preventive parental education about infant sleep problems delivered from pregnancy to 1 month postpartum, will be considered. The outcomes will be infants' sleep, postpartum parental sleep, and parental depression. MEDLINE (Ovid), CINAHL (EBSCOhost), PsycINFO (Ovid), the Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi (Japan Medical Abstracts Society) will be searched without restrictions on language or date of publication. Eligible studies will be critically appraised, and data will be extracted by 2 independent reviewers using the JBI methodology. The studies will be pooled for statistical meta-analysis. Where statistical pooling is not possible, the findings will be presented in narrative format. We will use the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to assess the certainty in the quality of evidence. PROSPERO CRD42023430562.

Obstructive Sleep Apnea and Acute Lower Respiratory Tract Infections: A Narrative Literature Review.

Both obstructive sleep apnea (OSA) and acute lower respiratory tract infections (LRTIs) are important global health issues. The pathophysiological links between OSA and LRTIs include altered immune responses due to chronic intermittent hypoxia and sleep fragmentation, increased aspiration risk, and a high burden of comorbidities. In this narrative review, we evaluated the current evidence on the association between OSA and the incidence and outcomes of acute LRTIs in adults, specifically community-acquired pneumonia and viral pneumonia caused by influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Studies have demonstrated that OSA patients are more likely to develop bacterial pneumonia and exhibit a higher risk of invasive pneumococcal disease. The risk intensifies with the severity of OSA, influencing hospitalization rates and the need for intensive care. OSA is also associated with an increased risk of contracting influenza and suffering more severe disease, potentially necessitating hospitalization. Similarly, OSA contributes to increased COVID-19 disease severity, reflected by higher rates of hospitalization, longer hospital stays, and a higher incidence of acute respiratory failure. The effect of OSA on mortality rates from these infections is, however, somewhat ambiguous. Finally, we explored antibiotic therapy for OSA patients with LRTIs, addressing care settings, empirical regimens, risks, and pharmacokinetic considerations. Given the substantial burden of OSA and its significant interplay with acute LRTIs, enhanced screening, targeted vaccinations, and optimized management strategies for OSA patients should be prioritized.

Chronic sleep fragmentation impairs brain interstitial clearance in young wildtype mice

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.

Chronic sleep fragmentation reduces left ventricular contractile function and alters gene expression related to innate immune response and circadian rhythm in the mouse heart

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.

Disrupting circadian control of autophagy induces podocyte injury and proteinuria

The circadian clock influences a wide range of biological process and controls numerous aspects of physiology to adapt to the daily environmental changes caused by Earth’s rotation. The kidney clock plays an important role in maintaining tubular function, but its effect on podocytes remains unclear. Here, we found that podocytes expressed CLOCK proteins, and that 2666 glomerular gene transcripts (13.4%), including autophagy related genes, had 24-hour circadian rhythms. Deletion of Clock in podocytes resulted in 1666 gene transcripts with the loss of circadian rhythm including autophagy genes. Therefore, there was no decrease in their expression. Podocyte-specific Clock knockout mice at age three and eight months showed deficient autophagy, loss of podocytes and increased albuminuria. Chromatin immunoprecipitation (ChIP) sequence analysis indicated autophagy related genes were targets of CLOCK in podocytes. ChIP-PCR further confirmed Clock binding to the promoter regions of Becn1 and Atg12, two autophagy related genes. Furthermore, the association of CLOCK regulated autophagy with chronic sleep fragmentation and diabetic kidney disease was analyzed. Chronic sleep fragmentation resulted in the loss of glomerular Clock rhythm, inhibition of podocyte autophagy, and proteinuria. Rhythmic oscillations of Clock also disappeared in high glucose treated podocytes and in glomeruli from diabetic mice. Finally, circadian differences in podocyte autophagy were also abolished in diabetic mice. Deletion Clock in podocytes aggravated podocyte injury and proteinuria in diabetic mice. Thus, our findings demonstrate that clock-dependent regulation of autophagy may be essential for podocyte survival. Hence. loss of circadian controlled autophagy may play an important role in podocyte injury and proteinuria.

Sleep fragmentation affects glymphatic system through the different expression of AQP4 in wild type and 5xFAD mouse models

AbstractBackgroundSleep is an important physiological process, during which extracellular metabolic wastes, such as amyloid and tau protein, are cleared via paravascular pathway. Changes in the timing and structure of sleep occur across the lifespan. Increased sleep fragmentation and reductions in slow wave sleep (SWS) represent the hallmark signs of age‐related changes in sleep. The origin of sleep disturbances in AD is thought to be multifactorial. In the aging brain, the impairment of glymphatic pathway function slows the clearance of interstitial Aβ, rendering the aging brain vulnerable to neurodegenerative disease. Several authors have independently shown that glymphatic flux depends upon the expression and perivascular localization of the astroglial water channel aquaporin‐4 (AQP4).MethodIn this study, we performed and validated a mouse model of AD and chronic sleep fragmentation, a sleep disorder that mimics more correctly a real condition of intermittent and continuous awakening. We analyzed the effect of sleep fragmentation in wild type and 5xFAD mice. All the animals underwent to behavioral studies to analyze anxiety and spatial and working memory. We had validated sleep fragmentation and its effect through EEG and biomolecular analysis, by observing all the macro‐areas implied in sleep regulation.ResultWe noticed that sleep fragmentation induces a general acceleration of AD progression in 5xFAD mice, while in wild type mice it affects cognitive behaviors in particular learning and memory. Both these events may be correlated to AQP4 modulation, a crucial player of the glymphatic system activity. In particular, sleep fragmentation differentially affects AQP4 expression according to the stage of the disease, with an up‐regulation in younger animals, while such change cannot be detected in older ones. Moreover, in wild type mice sleep fragmentation affects cognitive behaviors, in particular learning and memory, by compromising the glymphatic system through the decrease of AQP4.ConclusionNevertheless, an in‐depth study is needed to better understand the mechanism by which AQP4 is modulated and whether it could be considered a risk factor for the disease development in wild type mice. If our hypotheses are going to be confirmed, AQP4 modulation may represent the convergence point between AD and sleep disorder pathogenic mechanisms

Sex differences in baseline sleep and dark phase rebound sleep after chronic sleep fragmentation in the APPXPS1 and 5XFAD mouse models

AbstractBackgroundFragmentation of the daily sleep‐wake rhythm is a risk factor for Alzheimer’s disease (AD) (Li et al, Lancet Healthy Longev 1:e96‐e105 [2020]). While women have a higher AD incidence than men, whether women are more sensitive to sleep fragmentation (SF) is not known. Studies in female 3xTg‐AD mice (8‐11 months old) show that chronic SF for four weeks alters the daily sleep‐wake rhythm and stimulates AD‐like neuropathology (Duncan et al, Neuroscience 481:111‐122 [2022]).MethodTo investigate possible sex differences in the effects of sleep fragmentation, we studied two AD mouse models and matching wild‐type controls, APPxPS1‐knock‐in mice (6.2‐11 months old; N = 127) and 5XFAD mice (2.3‐3.3 months old; N = 52). All mice were exposed to 3‐4 weeks of SF or undisturbed sleep while individually housed in cages interfaced for piezo electric sleep recording for monitoring of daily sleep‐wake rhythms. SF consisted of four daily sessions (1 hour each) of enforced wakefulness (induced with toys and paintbrush stimulation) that were evenly distributed during the light phase, for 5 days/week. Immediately after the last SF session, mice in both groups were euthanized and cortical and hippocampal tissue was dissected and frozen. Amyloid‐beta levels were determined in soluble fractions using ELISA.ResultsSF redistributed sleep from the light phase (loss) to the dark phase (gain) in APPxPS1‐ki (p<0.0001) and 5XFAD (p<0.05) mice and WT controls. Overall, females slept less than males (p<0.001) and were more affected by SF. Dark phase “rebound” sleep after SF was greater in APPxPS1‐ki females (∼70% of undisturbed controls) than in APPxPS1 males or WT mice of either sex (∼20% of undisturbed controls) (p<0.001). Cortical amyloid‐beta levels were higher in female than male AD mice, but surprisingly, neither cortical nor hippocampal amyloid‐beta levels were affected by SF in either strain.ConclusionThese findings suggest an interaction between sex, AD mutations, and neuropathology on dark phase rebound sleep after chronic SF. To elucidate this interaction, on‐going studies are investigating the role of amyloid‐beta in sex‐differences in SF‐induced rebound sleep and potential sex differences in SF effects on gene expression in brain regions regulating sleep or circadian rhythms.

Shedding light on neurofilament involvement in cognitive decline in obstructive sleep apnea and its possible role as a biomarker.

Obstructive sleep apnea is one of the most common sleep disorders with a high estimated global prevalence and a large number of associated comorbidities in general as well as specific neuropsychiatric complications such as cognitive impairment. The complex pathogenesis and effects of the disorder including chronic intermittent hypoxia and sleep fragmentation may lead to enhanced neuronal damage, thereby contributing to neuropsychiatric pathologies. Obstructive sleep apnea has been described as an independent risk factor for several neurodegenerative diseases, including Alzheimer's disease and all-cause dementia. The influence of obstructive sleep apnea on cognitive deficits is still a topic of recent debate, and several mechanisms, including neurodegeneration and depression-related cognitive dysfunction, underlying this correlation are taken into consideration. The differentiation between both pathomechanisms of cognitive impairment in obstructive sleep apnea is a complex clinical issue, requiring the use of multiple and costly diagnostic methods. The studies conducted on neuroprotection biomarkers, such as brain-derived neurotrophic factors and neurofilaments, are recently gaining ground in the topic of cognition assessment in obstructive sleep apnea patients. Neurofilaments as neuron-specific cytoskeletal proteins could be useful non-invasive indicators of brain conditions and neurodegeneration, which already are observed in many neurological diseases leading to cognitive deficits. Additionally, neurofilaments play an important role as a biomarker in other sleep disorders such as insomnia. Thus, this review summarizes the current knowledge on the involvement of neurofilaments in cognitive decline and neurodegeneration in obstructive sleep apnea patients as well as discusses its possible role as a biomarker of these changes.

Durative sleep fragmentation with or without hypertension suppress rapid eye movement sleep and generate cerebrovascular dysfunction

Either hypertension or chronic insomnia is the risk factor of developing vascular dementia. Durative hypertension can induce vascular remodeling and is used for modeling small vessel disease in rodents. It remains undetermined if the combination of hypertension and sleep disturbance exacerbates vascular dysfunction or pathologies. Previously, we found chronic sleep fragmentation (SF) dampened cognition in young mice without disease predispositions. In the current study, we superimposed SF with hypertension modeling in young mice. Angiotensin II (AngII)-releasing osmotic mini pumps were subcutaneously implanted to generate persistent hypertension, while sham surgeries were performed as controls. Sleep fragmentation with repetitive arousals (10 s every 2 min) during light-on 12 h for consecutive 30 days, while mice undergoing normal sleep (NS) processes were set as controls. Sleep architectures, whisker-stimulated cerebral blood flow (CBF) changes, vascular responsiveness as well as vascular pathologies were compared among normal sleep plus sham (NS + sham), SF plus sham (SF + sham), normal sleep plus AngII (NS + AngII), and SF plus AngII (SF + AngII) groups. SF and hypertension both alter sleep structures, particularly suppressing REM sleep. SF no matter if combined with hypertension strongly suppressed whisker-stimulated CBF increase, suggesting the tight association with cognitive decline. Hypertension modeling sensitizes vascular responsiveness toward a vasoactive agent, Acetylcholine (ACh, 5 mg/ml, 10 μl) delivered via cisterna magna infusion, while SF exhibits a similar but much milder effect. None of the modeling above was sufficient to induce arterial or arteriole vascular remodeling, but SF or SF plus hypertension increased vascular network density constructed by all categories of cerebral vessels. The current study would potentially help understand the pathogenesis of vascular dementia, and the interconnection between sleep and vascular health.

Cognitive Impairments, Neuroinflammation and Blood-Brain Barrier Permeability in Mice Exposed to Chronic Sleep Fragmentation during the Daylight Period.

Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). In murine models, chronic SF can impair endothelial function and induce cognitive declines. These deficits are likely mediated, at least in part, by alterations in Blood-brain barrier (BBB) integrity. Male C57Bl/6J mice were randomly assigned to SF or sleep control (SC) conditions for 4 or 9 weeks and in a subset 2 or 6 weeks of normal sleep recovery. The presence of inflammation and microglia activation were evaluated. Explicit memory function was assessed with the novel object recognition (NOR) test, while BBB permeability was determined by systemic dextran-4kDA-FITC injection and Claudin 5 expression. SF exposures resulted in decreased NOR performance and in increased inflammatory markers and microglial activation, as well as enhanced BBB permeability. Explicit memory and BBB permeability were significantly associated. BBB permeability remained elevated after 2 weeks of sleep recovery (p < 0.01) and returned to baseline values only after 6 weeks. Chronic SF exposures mimicking the fragmentation of sleep that characterizes patients with OSA elicits evidence of inflammation in brain regions and explicit memory impairments in mice. Similarly, SF is also associated with increased BBB permeability, the magnitude of which is closely associated with cognitive functional losses. Despite the normalization of sleep patterns, BBB functional recovery is a protracted process that merits further investigation.

Cardiovascular and autonomic consequences of sleep fragmentation

Introduction: Sleep disruption is commonly found in normal individuals and those with sleep disorders. Risk factors for sleep fragmentation involve a combination of lifestyle, environmental, psychosocial factors and/or medical conditions. The main objective of this study was to analyse the impact of acute, induced sleep fragmentation upon autonomic cardiovascular regulation, measured by a non-invasive haemodynamic measurement technique. Material and methods: The authors analysed beat-to-beat measurements of haemodynamic and autonomic parameters at 5-time points during sleep fragmentation: 9:00 a.m. (baseline), 9:00 p.m., 00:30 a.m., 4:00 a.m., and 7:30 a.m. Differences in the mean values for chronotropic parameters, cardiac contractility, parameters related to blood pressure regulation and workload of the left ventricle, and autonomic parameters were examined in seventeen healthy male volunteers. Direct results obtained from every time point were analysed using analysis of variance with repeated measures or the Friedman rank sum test. Results: Sleep fragmentation had a significant negative impact on haemodynamic parameters related to cardiac contractility (SV p &lt; 0.001, IC p &lt; 0.001, HI p &lt; 0.001); parameters related to workload of the left ventricle (CO p &lt; 0.001, LVWI p &lt; 0.001, ACI p &lt; 0.001); parameters related to blood pressure regulation (sBP p = 0.001, TPR p &lt; 0.001); on chronotropic parameters (HR p &lt; 0.001, PEP p &lt; 0.001, LVET p &lt; 0.001) and an indicator of cardiac autonomic regulation: LF-RRI (p = 0.001). Conclusions: Acute sleep fragmentation can modify haemodynamic control and autonomic cardiovascular regulation in healthy men; the most important changes were seen in the morning hours (4:00 a.m.). Therefore, conditions of chronic sleep fragmentation (e.g. shift work, uniformed services, clinicians), might lead to disturbance in the autonomic nervous system and therefore to problems with homeostasis in the cardiovascular system. Future research is needed in standardized conditions with large-scale studies to clarify the effects of chronic sleep fragmentation.

Solriamfetol improves chronic sleep fragmentation-induced increases in sleep propensity and ameliorates explicit memory in male mice.

Obstructive sleep apnea (OSA) is a highly prevalent condition characterized by episodes of partial or complete breath cessation during sleep that induces sleep fragmentation (SF). One of the frequent manifestations of OSA is the presence of excessive daytime sleepiness (EDS) associated with cognitive deficits. Solriamfetol (SOL) and modafinil (MOD) are wake-promoting agents commonly prescribed to improve wakefulness in OSA patients with EDS. This study aimed to assess the effects of SOL and MOD in a murine model of OSA characterized by periodic SF. Male C57Bl/6J mice were exposed to either control sleep (SC) or SF (mimicking OSA) during the light period (06:00 h to 18:00 h) for 4 weeks, which consistently induces sustained excessive sleepiness during the dark phase. Both groups were then randomly assigned to receive once-daily intraperitoneal injections of SOL (200 mg/kg), MOD (200 mg/kg), or vehicle for 1 week while continuing exposures to SF or SC. Sleep/wake activity and sleep propensity were assessed during the dark phase. Novel Object Recognition test, Elevated-Plus Maze Test, and Forced Swim Test were performed before and after treatment. SOL or MOD decreased sleep propensity in SF, but only SOL induced improvements in explicit memory, while MOD exhibited increased anxiety behaviors. Chronic SF, a major hallmark of OSA, induces EDS in young adult mice that is mitigated by both SOL and MOD. SOL, but not MOD, significantly improves SF-induced cognitive deficits. Increased anxiety behaviors are apparent in MOD-treated mice. Further studies aiming to elucidate the beneficial cognitive effects of SOL are warranted.

The protective role of Nrf2 on cognitive impairment in chronic intermittent hypoxia and sleep fragmentation mice

ObjectiveObstructive Sleep Apnea Hypopnea Syndrome (OSAHS) is a sleep respiratory disease associated with cognitive impairment, The nuclear factor erythroid 2 related factor 2 (Nrf2) plays a neuroprotective role. This study was designed to investigate the mechanism of Nrf2 protecting neural cells from endoplasmic reticulum stress (ERS), induced by chronic intermittent hypoxia (CIH) and sleep fragmentation (SF) which caused cognitive impairment in mice. MethodsEstablishment of CIH and SF mice to simulate OSAHS mouse model. An eight-arm maze behavior test measured the cognitive function of mice, and Nissl staining and TUNEL staining were used to detect pathological changes in hippocampal neurons. The expression of ERS and Nrf2 and its downstream related mRNAs and proteins were detected by qRT-PCR and Western blotting. ResultsCIH and SF lead to cognitive impairment in mice, and Sulforaphane (SFN, Nrf2 agonist) plays a protective role, while Nrf2-KO aggravates the cognitive impairment. CIH and SF reduced the number of Nissl bodies in neurons and induced apoptosis. The mRNA levels of BiP, CHOP, Nrf2, GCLC and Prdx1 in CIH, SF and CIH + SF groups were increased (p = 0.001), whereas the mRNA levels of BiP and CHOP in the CIH + SF + SFN group were decreased (p = 0.02) while those of Nrf2 and Prdx1 were increased (p = 0.005). The CIH + SF + Nrf2-KO group, the mRNA levels of CHOP were increased (p = 0.001) while Nrf2, GCLC and Prdx1 were decreased (p = 0.001). The protein levels of CHOP and active Caspase-12 in CIH, SF, CIH + SF and CIH + SF + Nrf2-KO groups were increased (p = 0.03), while those of Prdx1 and Nrf2 were increased (p = 0.03) in the CIH + SF + SFN group, while decreased (p = 0.02) in the Nrf2-KO group. ConclusionsChronic intermittent hypoxia(CIH) and sleep fragmentation(SF) could aggravate the inflammatory response of nerve cells through endoplasmic reticulum stress, leading to apoptosis of nerve cells, and causing cognitive impairment in mice.Nrf2 alleviates cognitive impairment induced by chronic intermittent hypoxia and sleep fragmentation by modulating endoplasmic reticulum stress. Activation of Nrf2 protects cognitive impairment through the Nrf2-Prdx1 signaling pathway.

Neurotrophins in the Neuropathophysiology, Course, and Complications of Obstructive Sleep Apnea-A Narrative Review.

Obstructive sleep apnea (OSA) is a disorder characterized by chronic intermittent hypoxia and sleep fragmentation due to recurring airway collapse during sleep. It is highly prevalent in modern societies, and due to its pleiotropic influence on the organism and numerous sequelae, it burdens patients and physicians. Neurotrophins (NTs), proteins that modulate the functioning and development of the central nervous system, such as brain-derived neurotrophic factor (BDNF), have been associated with OSA, primarily due to their probable involvement in offsetting the decline in cognitive functions which accompanies OSA. However, NTs influence multiple aspects of biological functioning, such as immunity. Thus, extensive evaluation of their role in OSA might enlighten the mechanism behind some of its elusive features, such as the increased risk of developing an immune-mediated disease or the association of OSA with cardiovascular diseases. In this review, we examine the interactions between NTs and OSA and discuss their contribution to OSA pathophysiology, complications, as well as comorbidities.

Peripheral Sympathectomy Alters Neuroinflammatory and Microglial Responses to Sleep Fragmentation in Female Mice

Sleep loss, either induced by obstructive sleep apnea or other forms of sleep dysfunction, induces an inflammatory response, as commonly measured by increased circulating levels of pro-inflammatory cytokines. Increased catecholamines from sympathetic nervous system (SNS) activation regulates this peripheral inflammation. However, the role that catecholamines play in mediating neuroinflammation from sleep perturbations is undescribed. The aims of this study were to determine (i) the effect of peripheral SNS inhibition upon neuroinflammatory responses to sleep fragmentation (SF) and (ii) whether homeostasis can be restored after 1 week of recovery sleep. We measured gene expression levels of pro- and anti-inflammatory cytokines and microglial activity in brain (prefrontal cortex, hippocampus and hypothalamus) of female mice that were subjected to acute SF for 24 hours, chronic SF for 8 weeks, or 7 days of recovery after chronic SF. In each experiment, SF and control mice were peripherally sympathectomized with 6-hydroxydopamine (6-OHDA) or injected with vehicle. SF elevated cytokine mRNA expression in brain and increased microglial density and cell area in some regions. In addition, chronic SF promoted hyper-ramification in resting microglia upon exposure to chronic, but not acute, SF. Effects of chronic SF were more pronounced than acute SF, and 1 week of recovery was not sufficient to alleviate neuroinflammation. Importantly, 6-OHDA treatment significantly alleviated SF-induced inflammation and microglial responses. This study provides evidence of SNS regulation of neural inflammation from SF, suggesting a potential role for therapeutics that could mitigate neuroinflammatory responses to sleep dysfunction.

Explicit memory, anxiety and depressive like behavior in mice exposed to chronic intermittent hypoxia, sleep fragmentation, or both during the daylight period

Obstructive sleep apnea (OSA) is a chronic and highly prevalent condition characterized by chronic intermittent hypoxia (IH) and sleep fragmentation (SF), and can lead to a vast array of end-organ morbidities, particularly affecting cardiovascular, metabolic and neurobehavioral functioning. OSA can induce cognitive and behavioral and mood deficits.Male C57Bl/6J 8-week-old mice were housed in custom-designed cages with a silent motorized mechanical sweeper traversing the cage floor at 2-min intervals (SF) during daylight for four weeks. Sleep control (SC) consisted of keeping sweeper immobile. IH consisted of cycling FiO2 21% 90 seconds-6.3% 90s or room air (RA; FiO2 21%) for sixteen weeks and combined SF-IH was conducted for nine weeks. Open field novel object recognition (NOR) testing, elevated-plus maze test (EPMT), and forced swimming test (FST) were performed.SF induced cognitive NOR performance impairments in mice along with reduced anxiety behaviors while IH induced deficits in NOR performance, but increased anxiety behaviors. SF-IH induced impaired performance in NOR test of similar magnitude to IH or SF alone. Combined SF-IH exposures did not affect anxiety behaviors.Thus, both SF an IH altered cognitive function while imposing opposite effects on anxiety behaviors. SF-IH did not magnify the detrimental effects of isolated SF or IH and canceled out the effects on anxiety. Based on these findings, the underlying pathophysiologic processes underlying IH and SF adverse effects on cognitive function appear to differ, while those affecting anxiety counteract each other.

0288 Role of cofilin and calcium signaling in sleep-loss neural injury

Abstract Introduction Chronic sleep disruption (CSD) in young adult mice leads to phenotypes consistent with early (pre-plaque) Alzheimer’s Disease (AD), including increased Aβ and hippocampal neuron loss. Mechanisms underlying this injury are not known. Both acute sleep loss and AD activate cofilin, a regulator of actin dynamics. Activated cofilin (AC) in AD mouse models can impart neural injury, increase Aβ, and cofilin translocation to the mitochondria delays cytosolic Ca2+ clearance. We are critically testing the role of AC in chronic short sleep (CSS) and sleep fragmentation (SF) neural injury. Methods Synapse loss was studied using STED confocal microscopy and Imaris in CSS (n=9) and rested (n=10) mice. Synapses were identified as overlaps of pre- and postsynaptic densities. Percent area of cofilin was measured with FIJI. To further understand if and how wake-induced cofilin activation induces sleep-loss synapse and neural injury, we implanted AAV9CAMKII-GCaMP6f and then GRIN lenses, and later studied CAMKII calcium transients in CA1 of WT controls (n=4) and SF mice (n=4) by measuring GCaMP6f calcium transients. We developed a Shiny R application to analyze the frequency of Ca2+ spikes, ΔF/F0, and the rising and clearance patterns of spikes. To directly test cofilin’s role in delayed calcium clearance, we studied the calcium transients in hAPP mice (n=2) after injection of AAV-CAMKII-CofilinS3A to express AC and GCaMP6f. All data were analyzed with two-way ANOVA or unpaired t-tests. Results Results reveal significant synapse loss in CA1 of CSS mice (CSS=48.8±10.3; Rested=83.4±8.4), t(16)=2.63, p&amp;lt;0.02, and increased cofilin activation (AC=19.8±3.41; Rested=8.76±1.95), t(16)=8.43, p&amp;lt;0.0001. SF mice reveal an increase in NREM sleep firing rates, F(1,1)=22.0, p&amp;lt;0.001. In contrast, hAPP-AC mice show significantly increased ΔF/F0, F(1,1)=356, p&amp;lt;0.0001, prolonged calcium influx, F(1,1)=18.6, p&amp;lt;0.02, and prolonged calcium clearance duration, F(1,1)=23.9, p&amp;lt;0.01, but not increased firing frequencies. Conclusion CSS induces CA1 synapse loss and cofilin activation in WT mice. Increased CAMKII calcium ΔF/F0 occurs through different pathways in SF and AC, suggesting additional factors in CSD neural injury. Support (If Any) NIH AG054104; AG064231

The effects of fragmented sleep on monocyte and neutrophil distribution within the tissues during atherosclerosis

Abstract Atherosclerosis is a chronic inflammatory disease of large and medium size vessels that progresses across a lifespan and has been extensively linked to insufficient sleep. Poor fragmented sleep quality is strongly associated with all-cause mortality. Accumulating evidence demonstrates the independent effects of atherosclerosis and fragmented sleep on chronic inflammation within multiple tissues. However, there is limited data on the combined effects of sleep fragmentation (SF) and atherosclerosis on the inflammatory environments of multiples tissue. To address this question, we used flow cytometry and qPCR to investigate immune alterations within the peripheral blood, bone marrow, spleen, aorta, small intestine, and brains of female Apoe −/− mice following 12 weeks of high fat diet (HFD) feeding and SF. SF was induced by waking up mice at the day time using a moving bar. Importantly, we used an activity control (AC) group of mice that had a moving bar during nighttime. We found that chronic SF accelerated atherogenesis and induced increased myelopoiesis. Particularly, we detected increases in pro-inflammatory monocytes and neutrophils in the bone marrow, blood, spleen, aortas and small intestines of SF vs AC groups of HFD-fed female Apoe−/− mice. Additionally, we detected increase inflammatory markers in the brains of SF vs the control AC mice. Our data suggests that SF accelerates atherosclerosis and alters the immune composition of multiple tissues including the blood, bone marrow, spleen, small intestine, and aorta of atherosclerosis-prone mice. Furthermore, the increased peripheral monocytosis and neutrophilia may serve as a link to the elevated inflammatory markers in the brains of HFD-fed, female SF Apoe−/− mice. Supported by the American Heart Association Pre-Doctoral Fellowship (20PRE35180156)

Identification of sleep fragmentation-induced gut microbiota alteration and prediction of functional impact in Sprague Dawley rats harboring microbiome derived from multiple human donors.

ObjectivesPoor quality sleep, including sleep fragmentation (SF), can result in severe health consequences. Gut microbiota symbiotically coexist with the host, making essential contributions to overall well-being. In this study, the effects of both acute (6-day) and chronic (6-week) SF in a humanized rat model were examined to evaluate the impact of SF on this symbiotic relationship.Material and MethodsHuman fecal material was transplanted into antibiotic-treated, microbially depleted, Sprague Dawley rats. Animals were subjected to either acute or chronic SF and shifts to gut microbiota were investigated using 16S rRNA sequencing and predictive functional profiles were constructed with PICRUSt. We also investigated SF-induced intestinal microbial adhesion and penetration or increased microbial invasion of selected tissues and organs; as well as changes in crypt/villi architecture.ResultsMicrobiota profiling indicated that chronic, but not acute, SF significantly decreased the richness of alpha-diversity of distal ileum microbiota, and altered cecum and distal ileum beta-diversity; although both acute and chronic SF significantly changed select populations of microbiota in all three regions. Neither acute nor chronic SF induced changes to microbial adhesion, penetration, or invasion into intestinal tissues or nearby organs. Additionally, we found that chronic SF caused a reduction in villus height in the proximal colon.DiscussionOur study suggests that acute SF alters the gut microbiota in this humanized rat model, while chronic SF produces more pronounced changes to microbiota populations. This study identified potential microbiota targets for the prevention and/or intervention of the adverse effects of S F.