Sleep Deprivation Model Research Articles

Effects of the Radix Ginseng and Semen Ziziphi Spinosae drug pair on the GLU/GABA-GLN metabolic cycle and the intestinal microflora of insomniac rats based on the brain-gut axis.

Introduction: To explore the mechanism of action of appling Radix Ginseng and Semen Ziziphi Spinosae Drug pair (R-S) in the treatment of insomnia by investigating the effect of R-S on GLU/GABA-GLN metabolic cycle and intestinal microflora of rats with insomnia. Methods: Rats were intraperitoneally injected with 4-chloro-DL-phenylalanine (PCPA) to make sleep deprivation (SD) models. The rats were divided into 6 groups, with 8 rats in each group. The general status of the rats was observed and the pentobarbital sodium sleep synergy experiment was performed. The contents of GABA, GLU, GLN, GAD65, and GS in hippocampus of rats were determined by ELISA. The expressions of GABAARα1mRNA, mGluR5mRNA, NR1mRNA and GluR1mRNA in rats' hippocampal tissue were determined by Realtime PCR. 16SrRNA gene sequencing was used to analyze the intestinal microflora of insomnia rats. Results: In PCPA-induced insomnia rats, the state of insomnia was relieved, the sleep rate was improved, the duration of sleep latency was shortened and the sleep duration was prolonged in each dose group of R-S (p < 0.05, p < 0.01) compared with the model group. The contents of GABA, GLN, GAD65 and GS were increased (p < 0.05, p < 0.01) while GLU content was decreased (p < 0.01) in both medium and high dose groups, especially in the high dose group. The expression of GABAARα1mRNA was increased (p < 0.01), and the expressions of mGluR5mRNA, NR1mRNA and GluR1mRNA were decreased (p < 0.01) in hippocampal tissue of rats in R-S groups, especially in the high dose group. At the same time, the various dose groups of R-S could improve the species diversity, microflora abundance of insomnia rats and regulate the KEGG metabolic pathway related to sleep. Discussion: R-S can improve the sleep of PCPA-induced insomnia rats by regulating GLU/GABA-GLN metabolic cycle and intestinal microflora, which provides experimental basis for appling R-S in the treatment of insomnia.

Sleep Deprivation and Central Appetite Regulation.

Research shows that reduced sleep duration is related to an increased risk of obesity. The relationship between sleep deprivation and obesity, type 2 diabetes, and other chronic diseases may be related to the imbalance of appetite regulation. To comprehensively illustrate the specific relationship between sleep deprivation and appetite regulation, this review introduces the pathophysiology of sleep deprivation, the research cutting edge of animal models, and the central regulatory mechanism of appetite under sleep deprivation. This paper summarizes the changes in appetite-related hormones orexin, ghrelin, leptin, and insulin secretion caused by long-term sleep deprivation based on the epidemiology data and animal studies that have established sleep deprivation models. Moreover, this review analyzes the potential mechanism of associations between appetite regulation and sleep deprivation, providing more clues on further studies and new strategies to access obesity and metabolic disease.

Effects of Sleep Deprivation on Functional Connectivity of Brain Regions after High-Intensity Exercise in Adolescents

Lack of sleep causes central fatigue in the body, which in turn affects brain function, and similarly, intense exercise causes both central and peripheral fatigue. This study aims to characterize the brain state, and in particular the functional changes in the relevant brain regions, after intense exercise in sleep-deprived conditions by detecting EEG signals. Thirty healthy adolescents were screened to participate in the trial, a sleep-deprivation model was developed, and a running exercise was performed the following morning. Meanwhile, pre-exercise and post-exercise Electroencephalogram (EEG) data were collected from the subjects using a 32-conductor electroencephalogram acquisition system (Neuroscan), and the data were analyzed using MATLAB (2013b) to process the data and analyzed Phase Lag Index (PLI) and graph theory metrics for different brain connections. Compared with the control group, the pre-exercise sleep-deprivation group showed significantly lower functional brain connectivity in the central and right temporal lobes in the Delta band (p &lt; 0.05), significantly lower functional brain connectivity in the parietal and occipital regions in the Theta band (p &lt; 0.05), and significantly higher functional brain connectivity in the left temporal and right parietal regions in the Beta2 band (p &lt; 0.05). In the post-exercise sleep-deprivation group, functional brain connectivity was significantly lower in the central to right occipital and central regions in the Delta band (p &lt; 0.05), significantly higher in the whole brain regions in the Theta, Alpha2, and Beta1 bands (p &lt; 0.05 and 0.001), significantly higher in the right central, right parietal, and right temporal regions in the Alpha1 band (p &lt; 0.05), and in the Beta2 band, the functional brain connections from the left frontal region to the right parietal region were significantly lower (p &lt; 0.05). The results of the brain functional network properties showed that the clustering coefficients in the Delta band were significantly lower in the pre-exercise sleep-deprivation group compared to the control group (p &lt; 0.05); the characteristic path length and global efficiency in the Theta band were significantly lower (p &lt; 0.05 and 0.001). The post-exercise sleep-deprivation group showed significantly higher clustering coefficients, input lengths, and local efficiencies (p &lt; 0.001), and significantly lower global efficiencies in the Delta and Theta bands (p &lt; 0.001), and significantly higher clustering coefficients and local efficiencies (p &lt; 0.001) and significantly lower input lengths and global efficiencies in the Alpha1 band compared with the control group (p &lt; 0.001). After sleep deprivation, the pre-exercise resting state reduces the rate of information transfer in the functional networks of the adolescent brain, slowing the transfer of information between brain regions. After performing strenuous exercise, sleep deprivation leads to decreased athletic performance in adolescents. After a prolonged period of intense exercise, brain activity is gradually suppressed, resulting in even slower work efficiency and, eventually, increased information transfer in adolescents.

Therapeutic effects of growth hormone in a rat model of total sleep deprivation: Evaluating behavioral, hormonal, biochemical and electrophysiological parameters

ObjectiveTotal sleep deprivation (TSD) causes several harmful changes in the brain, including memory impairment, increased stress and depression levels, as well as reduced antioxidant activity. Growth hormone (GH) has been shown to boost antioxidant levels while improving memory and depression. The present study was conducted to explain the possible effects of exogenous GH against behavioral and biochemical disorders caused by TSD and the possible mechanisms involved. Main methodsTo induce TSD, rats were housed in homemade special cages equipped with stainless steel wire conductors to induce general and inconsistent TSD. They received a mild repetitive electric shock to their paws every 10 min for 21 days. GH (1 ml/kg, sc) was administered to rats during induction of TSD for 21 days. Memory retrieval, anxiety, depression-like behaviors, pain behaviors, antioxidant activity, hippocampal level of BDNF, and simultaneously brain electrical activity were measured at scheduled times after TSD. Key findingsThe results showed that GH treatment improved memory (p < 0.001) in the PAT test of rats exposed to TSD. These beneficial effects were associated with lowering the level of anxiety and depression-like behavior (p < 0.001), rising the pain threshold (p < 0.01), increasing the activity of antioxidants (p < 0.01), hippocampal BDNF (p < 0.001), and regular brain electrical activity. SignificanceOur findings show that GH plays a key role in modulating memory, anxiety and depression behaviors, as well as reducing oxidative stress and improve hippocampal single-unit activity in the brain during TSD.

Myricetin prevents sleep deprivation-induced cognitive impairment and neuroinflammation in rat brain via regulation of brain-derived neurotropic factor.

Memory formation in the hippocampus is formed and maintained by circadian clock genes during sleep. Sleep deprivation (SD) can lead to memory impairment and neuroinflammation, and there remains no effective pharmacological treatment for these effects. Myricetin (MYR) is a common natural flavonoid that has various pharmacological activities. In this study, we investigated the effects of MYR on memory impairment, neuroinflammation, and neurotrophic factors in sleep-deprived rats. We analyzed SD-induced cognitive and spatial memory, as well as pro-inflammatory cytokine levels during SD. SD model rats were intraperitoneally injected with 10 and 20 mg/kg/day MYR for 14 days. MYR administration significantly ameliorated SD-induced cognitive and spatial memory deficits; it also attenuated the SD-induced inflammatory response associated with nuclear factor kappa B activation in the hippocampus. In addition, MYR enhanced the mRNA expression of brain-derived neurotropic factor (BDNF) in the hippocampus. Our results showed that MYR improved memory impairment by means of anti-inflammatory activity and appropriate regulation of BDNF expression. Our findings suggest that MYR is a potential functional ingredient that protects cognitive function from SD.

Network pharmacology and pharmacological evaluation for deciphering novel indication of Sishen Wan in insomnia treatment

BackgroundInsomnia is the most frequent sleep disorder worldwide and is a prominent risk factor for mental and physical health deterioration. The clinical application of common pharmacological treatments for insomnia is far from satisfactory due to their various adverse effects. In recent years, drugs developed from natural herbs have become potential alternative therapies for insomnia. Sishen Wan (SSW), a traditional Chinese medicine (TCM) used for centuries to treat diarrheal disease, consists of multiple neurologically active herbs with sleep-regulating potential that may have therapeutic effects on insomnia. However, its hypnotic and sleep-regulating effects have not been evaluated in clinical practice or laboratory experiments. PurposeTo investigate the anti-insomnia effects of SSW and explore its possible mechanisms using preclinical models. Study design and methodsThe sedative effect of the SSW formula was investigated using network pharmacology analysis that was validated using various pharmacological approaches, including the evaluation of locomotor activity (LMA), pentobarbital-induced sleep time, and electroencephalography/electromyogram (EEG/EMG)-based sleep profiling in normal rats. Several animal models of insomnia, including sleep deprivation, serotonin depletion, and cage-changing models, have been used to further assess the anti-insomnia effects of SSW. Furthermore, the potential underlying mechanisms of action of SSW were predicted using bioinformatics methods and verified using in vivo and in silico experiments. ResultsThe results showed that SSW reduced LMA and prolonged pentobarbital-induced sleep time in a dose-dependent manner, which was consistent with the increase in non-rapid eye movement (NREM) sleep in normal rats, indicating a solid sedative effect. In animal models of insomnia, SSW alleviated sleep disturbance by increasing NREM sleep time, shortening NREM sleep latency, and inhibiting sleep fragmentation, suggesting a possible curative effect of SSW on insomnia. Finally, through functional enrichment analysis and in vivo and in silico experiments, 5-HT1A was identified as the key target of the anti-insomnia effect of SSW. Moreover, (S)-propranolol, nuciferine, zizyphusine, and N,N-dimethyl-5-methoxytryptamine may be the active compounds of SSW responsible for its anti-insomnia effect. ConclusionThis study extended the possible indication scope for SSW, which provides a potential therapeutic TCM that may be used for insomnia treatment, as well as a reference scheme for the discovery of novel indications of TCM.

Oxidative Stress Induces Endothelial Dysfunction and Endothelial Cell Damage in Rapid Eye Movement (REM) Sleep Deprivation Animal Model

INTRODUCTION: Rapid eye movement (REM) sleep deprivation causes oxidative stress, leading to endothelial dysfunction, a predictor of cardiovascular disease. It is still unclear what causes endothelial dysfunction in patients with sleep disorder. This study evaluates the effects of REM sleep deprivation on the endothelium in the rat model of REM sleep deprivation. MATERIALS AND METHODS: Sprague-Dawley male rats (N=28) were divided into four groups (n=7); (1) free-moving control (FMC), (2) REM sleep deprivation (REMsd), (3) tank control (TC), and (4) sleep recovery (SR). The inverted flowerpot technique was utilised to develop REM sleep deprivation. Bodyweight gain (BWg), food consumption (Fc), and systolic blood pressure (SBP) were evaluated. The descending thoracic aorta was isolated to assess oxidative stress markers, in vitro functional study, and histomorphological examination. RESULTS: REM sleep deprivation showed a decrease in BWg significantly despite a significant increase in Fc, increased SBP, increased oxidative stress markers, caused endothelial dysfunction and endothelial cell damage. In REM sleep-deprived rats, there was a significant reduction in antioxidant markers, including total antioxidant capacity (TAC), superoxide dismutase (SOD) activity, catalase (CAT), and glutathione (GSH), while the levels of malondialdehyde (MDA) were significantly increased. The REM sleep-deprived rats displayed altered vascular function, including impaired vasorelaxation and hypercontractility. Histomorphology of the endothelium in REM sleep-deprived rats revealed features of endothelial damage. CONCLUSION: REM sleep deprivation is suggested to be linked to endothelial dysfunction due to endothelial damage. These changes are proposed to result from increased oxidative stress. Sleep recovery reduced the harmful effects following REM sleep deprivation.

Quercetin ameliorates memory impairment by inhibiting abnormal microglial activation in a mouse model of paradoxical sleep deprivation

Paradoxical sleep deprivation (PSD) is prevalent in modern society, and impaired memory is one of its serious consequences. The pathogenic mechanism is still unclear, and the therapeutic strategies for PSD are limited. Here, we found that quercetin treatment ameliorated memory impairments caused by PSD in a dose-dependent manner in an animal model. Quercetin could restore the dynamic changes of the gamma band while the animals performed novel object recognition (NOR) tasks as determined by electroencephalogram analysis. Morphological analysis showed that quercetin, by targeting the hippocampal CA1 region, strikingly ameliorated the overactivation of microglia induced by PSD. Mechanistically, quercetin inhibited the toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa-b (NF-κB) cascade, which is critical for abnormal microglial activation following PSD stress. Our results provided experimental evidence for the therapeutic effects of quercetin on PSD-related memory impairments by suppressing TLR4/MyD88/NF-κB signaling that mediated abnormal microglia activation in the hippocampus.

Sleep deprivation and recovery sleep affect healthy male resident’s pain sensitivity and oxidative stress markers: The medial prefrontal cortex may play a role in sleep deprivation model

Sleep is essential for the body’s repair and recovery, including supplementation with antioxidants to maintain the balance of the body’s redox state. Changes in sleep patterns have been reported to alter this repair function, leading to changes in disease susceptibility or behavior. Here, we recruited healthy male physicians and measured the extent of the effect of overnight sleep deprivation (SD) and recovery sleep (RS) on nociceptive thresholds and systemic (plasma-derived) redox metabolism, namely, the major antioxidants glutathione (GSH), catalase (CAT), malondialdehyde (MDA), and superoxide dismutase (SOD). Twenty subjects underwent morning measurements before and after overnight total SD and RS. We found that one night of SD can lead to increased nociceptive hypersensitivity and the pain scores of the Numerical Rating Scale (NRS) and that one night of RS can reverse this change. Pre- and post-SD biochemical assays showed an increase in MDA levels and CAT activity and a decrease in GSH levels and SOD activity after overnight SD. Biochemical assays before and after RS showed a partial recovery of MDA levels and a basic recovery of CAT activity to baseline levels. An animal study showed that SD can cause a significant decrease in the paw withdrawal threshold and paw withdrawal latency in rats, and after 4 days of unrestricted sleep, pain thresholds can be restored to normal. We performed proteomics in the rat medial prefrontal cortex (mPFC) and showed that 37 proteins were significantly altered after 6 days of SD. Current findings showed that SD causes nociceptive hyperalgesia and oxidative stress, and RS can restore pain thresholds and repair oxidative stress damage in the body. However, one night of RS is not enough for repairing oxidative stress damage in the human body.

Synergistic antidepressant effects of citalopram and SB-334867 in the REM sleep-deprived mice: Possible role of BDNF

This study was done to evaluate the effect of co-treatment of orexin agents along with citalopram on the modulation of depression-like behavior and the expression of BDNF in the prefrontal cortex (PFC) of sleep-deprived male mice. A sleep deprivation model was performed in which rapid eye movement (REM) sleep was completely prohibited, and non-REM sleep was intensely reduced for 24 h. For drug microinjection, the guide cannula was surgically fixed in the left lateral ventricle of mice. Furthermore, we used the open-field test (OFT), forced swim test (FST), tail suspension test (TST), and splash test for recording depression-like behavior as well as Real-Time PCR amplification for assessing the expression of BDNF in the PFC of REM sleep-deprived mice. Our results revealed that REM sleep deprivation did not change locomotor activity while increased depressive-like behavior in FST, TST, and splash tests. However, the expression of BDNF was decreased in the PFC. Intraperitoneally (i.p.) administration of citalopram induced antidepressant effect in the normal and REM sleep-deprived mice. Moreover, intracerebroventricular (i.c.v.) microinjection of a non-effective dose of SB-334867, an orexin antagonist, potentiated the antidepressant-like effect of citalopram.On the other hand, a non-significant dosage of orexin-1 reversed the antidepressant effect of citalopram in the normal and REM sleep-deprived animals. Furthermore, our results showed that injection of citalopram alone or with SB-334867 increased the mRNA expression level of BDNF in the PFC of REM sleep-deprived mice. These data suggest that REM sleep deprivation interferes with the neural systems underlying the depression-like process and supports a likely interaction of the orexin system with citalopram on the modulation of depression-like behavior in REM sleep-deprived mice.

Luteolin-7-O-Glucuronide Improves Depression-like and Stress Coping Behaviors in Sleep Deprivation Stress Model by Activation of the BDNF Signaling.

Stress exposure is a major risk factor for mental disorders such as depression. Because of the limitations of classical antidepressants such as side effects, low efficacy, and difficulty in long-term use, new natural medicines and bioactive molecules from plants with greater safety and efficacy have recently attracted attention. Luteolin-7-O-glucuronide (L7Gn), a bioactive molecule present in Perilla frutescens, is known to alleviate severe inflammatory responses and oxidative stress in macrophages. However, its antistress and antidepressant effects have not been elucidated. The present study aims to explore the antidepressant the effect of L7Gn on stress-induced behaviors and the underlying mechanism in a mouse sleep deprivation (SD) model. L7Gn treatment improved depression-like and stress coping behaviors induced by SD stress, as confirmed by the tail suspension test and forced swimming test. Furthermore, L7Gn treatment reduced the blood corticosterone and hippocampal proinflammatory cytokine levels which were increased by SD stress, and L7Gn also increased the mRNA and protein levels of hippocampal brain-derived neurotrophic factor (BDNF) which were reduced by SD stress. Additionally, treatment with L7Gn resulted in increases in the phosphorylation of tropomyosin-related kinase B (TrkB), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB), which are downstream molecules of BDNF signaling. These findings suggest that L7Gn have therapeutic potential for SD-induced stress, via activating the BDNF signaling.

Brain-wide mapping of c-Fos expression with fluorescence micro-optical sectioning tomography in a chronic sleep deprivation mouse model

Chronic sleep deprivation (SD) is a common problem for humans and can lead to many deleterious effects, including depression, anxiety, stroke, permanent cognitive deficits, stress, and other physiological diseases. It is vital to acquire information about the relevant neural activities at the whole-brain level to systematically explore the mechanisms of brain dysfunction related to SD. Expression of the immediate-early gene (IEG) Fos in the mouse brain has been widely used as a functional marker of brain activity in the field of neuroscience. However, most previous studies only analyzed the change of c-Fos in several specific brain regions using traditional research methods or in short-term SD model. Here, we applied c-Fos mapping through the fluorescence micro-optical sectioning tomography (fMOST) technique and AAV-PHP.eB to comprehensive analysis the state of cumulative activation across the whole brain in a mouse model of chronic SD. The chronic rapid eyes movement (REM) SD model was induced by moving mice to a separate holding area filled with water. The experimental period lasted for 6 h per day. The results showed that after 14 days of SD, the mice displayed anxiety-like behaviors in open field test and elevated plus maze test, and displayed depression-like behaviors in tail suspension test and the sucrose preference test. The c-Fos + cells were detected in a maximum of 230 brain regions. SD-induced stress model evoked c-Fos expression in several brain regions compared to the control group. In particular, the isocortex-cerebral cortex plate area, including the retrosplenial, anterior cingulate, agranular insular, gustatory, and parasubiculum, appear to be the most sensitive regions after chronic REM SD.

Lactobacillus Ameliorates SD-Induced Stress Responses and Gut Dysbiosis by Increasing the Absorption of Gut-Derived GABA in Rhesus Monkeys

Sleep deprivation (SD) has become a health problem in the modern society. Although probiotics supplementation has been proven to improve SD-induced gut dysbiosis, the potential neuroendocrine mechanisms remain elusive. In this study, thirty rhesus monkeys (RMs) were recruited. Paradoxical sleep, bright light, and noise were used to build an RM SD model. We examined the plasma γ-aminobutyric acid (GABA), stress hormones, and inflammatory cytokines using ELISAs. 16S ribosomal DNA sequencing and untargeted metabolomics sequencing were employed to detect gut microbial community and metabolites, respectively. The results of our study showed that RMs subjected to SD had elevated plasma stress hormones (such as cortisol and norepinephrine) and proinflammatory cytokines (such as TNF-α, IL-6, and IL-8), and a decreased anti‐inflammatory cytokine IL-10 level. Additionally, SD could give rise to a significant change in gut microbiota and metabolites. The differential gut microbiota and metabolites caused by SD were enriched in the signaling pathways related to GABA metabolism. Pearson correlation analysis revealed that there is a significant correlation between plasma GABA and SD-induced stress responses and gut dysbiosis. The supplementation of GABA-producing probiotics could significantly increase the relative abundance of Lactobacillus and plasma GABA levels, and reverse SD‐induced stress responses and gut dysbiosis. Therefore, we speculated that SD-induced stress response and gut dysbiosis might be an outcome of reduced gut-derived GABA absorption. The supplementation of GABA-producing Lactobacillus might be beneficial for the treatment of SD-induced intestinal dysfunction.

Xiaoyao Pill Improves the Affective Dysregulation of Sleep-deprived Female Mice by Inhibiting Brain Injury and Regulating the Content of Monoamine Neurotransmitter.

Sleep curtailment is a serious problem in many societies. Clinical evidence has shown that sleep deprivation is associated with mood dysregulation, formation of false memory, cardio-metabolic risk factors and outcomes, inflammatory disease risk, and all-cause mortality. The affective disorder dysregulation caused by insufficient sleep has become an increasingly serious health problem. However, to date, not much attention has been paid to the mild affective dysregulation caused by insufficient sleep, and there is no clear and standard therapeutic method to treat it. The Xiaoyao Pill is a classic Chinese medicinal formula, with the effect of dispersing stagnated hepatoqi, invigorating the spleen, and nourishing the blood. Therefore, it is most commonly used to treat gynecological diseases in China. In the present study, the effects of the Xiaoyao Pill on affective dysregulation of sleep-deprived mice and its underlying molecular mechanisms were investigated. Forty adult female mice were used in the present study. The sleep deprivation model was established by improving the multi-platform water environment method. After 7 consecutive days of sleep deprivation, the mice were administrated low (LXYP, 0.32mg/kg) and high (HXYP, 0.64 mg/kg) doses of the Xiaoyao Pill for two weeks. Then, the body weight, behavioral deficits, and histopathology were evaluated. Meanwhile, the expression of c-fos protein and the concentrations of monoamine neurotransmitters in the hippocampus and prefrontal cortex were determined after two weeks of treatment. Xiaoyao Pill treatment significantly increased body weight and sucrose consumption and decreased the irritability scores of the sleep-deprived mice. Meanwhile, Xiaoyao Pill treatment prevented brain injury and inhibited the expression of c-fos protein in the hippocampus and prefrontal cortex. In addition, HXYP treatment significantly upregulated the levels of NE in the hippocampus and prefrontal cortex (p < 0.01). LXYP treatment significantly up-regulated the levels of 5-HT in the prefrontal cortex. Meanwhile, both HXYP and LXYP treatment significantly upregulated the levels of DA in the prefrontal cortex (p < 0.05 or p < 0.01) of sleep-deprived mice. The present study demonstrates that Xiaoyao Pill treatment prevented the behavioral deficits of mice induced by sleep deprivation by promoting the recovery of brain tissue injury and up-regulating the levels of NE, 5-HT, and DA in the brain tissue.

Propofol-induced sleep ameliorates cognition impairment in sleep-deprived rats.

Propofol has been shown to clear sleep debt in rats after sleep deprivation (SD). We examined whether or not propofol-assisted sleep can restore cognitive function in SD rats and explored the possible mechanisms. A sleep deprivation model was established by housing 9 to 12 week-old rats to a multiplatform water tank for 96h. Model rats were then intraperitoneally injected with different concentrations of propofol or 10% fat emulsion (vehicle control). All treatment groups were examined for spatial learning and memory ability in the Morris water maze (MWM). After euthanasia, morphological changes in the hippocampus, hippocampal neurons, and mitochondria were examined by hematoxylin-eosin staining and transmission electron microscopy. Serum and hippocampal levels of IL-1β, TNF-α, and hippocampal concentrations of ATP and Cyt-c were measured by ELISA (enzyme-linked immunosorbent assay). Immunohistochemistry and Western blotting were performed to assess hippocampal expression of Bcl-2, Bax, and cleaved caspase-3. Results showed that escape latencies in MWM training trials were significantly shorter and target crossings in the memory probe trial significantly greater in propofol-treated SD model rats compared to vehicle-treated SD rats. Propofol also reduced the number of apoptotic bodies in the hippocampal CA1 region. Sleep deprivation reduced IL-1β and ATP in hippocampus while increasing TNF-α and Cyt-c, and propofol treatment reversed all these changes. There was no significant difference in Bcl-2 expression between propofol- and vehicle-treated SD rats, but pro-apoptotic Bax and cleaved caspase-3 expression levels were significantly reduced by propofol in SD rats. Propofol-assisted sleep restored cognitive function in SD rats possibly by attenuating mitochondria-mediated neuronal apoptosis in the hippocampus.

Modafinil Reduces Neuronal Pyroptosis and Cognitive Decline After Sleep Deprivation.

Sleep deprivation (SD) induces systemic inflammation that promotes neuronal pyroptosis. The purpose of this study was to investigate the effect of an antioxidant modafinil on neuronal pyroptosis and cognitive decline following SD. Using a mouse model of SD, we found that modafinil improved learning and memory, reduced proinflammatory factor (IL-1β, TNF-α, and IL-6) production, and increased the expression of anti-inflammatory factors (IL-10). Modafinil treatment attenuated inflammasome activity and reduced neuronal pyroptosis involving the NLRP3/NLRP1/NLRC4-caspase-1-IL-1β pathway. In addition, modafinil induced an upregulation of brain-derived neurotrophic factor (BDNF) and synaptic activity. These results suggest that modafinil reduces neuronal pyroptosis and cognitive decline following SD. These effects should be further investigated in future studies to benefit patients with sleep disorders.

Rapamycin ameliorates chronic intermittent hypoxia and sleep deprivation-induced renal damage via the mammalian target of rapamycin (mTOR)/NOD-like receptor protein 3 (NLRP3) signaling pathway

ABSTRACT Rapamycin inhibits the activation of NOD-like receptor protein 3 (NLRP3) by regulating the mammalian target of rapamycin (mTOR) to treat obstructive sleep apnea-related renal injury. Sleep deprivation (SD) and chronic intermittent hypoxia (CIH) mouse models were used to assess the effects of autophagy in vivo. Compared with the control, SD, and CIH groups, the SD+CIH group had lower body weight and higher levels of blood urea nitrogen (BUN), creatinine, and urinary albumin (U-Alb) (P < 0.05); renal injury and oxidative damage occurred in the SD+CIH group, the kidney cell nucleus ruptured, and morphological structure of the cells was unclear in the SD+CIH group. The SD+CIH group demonstrated increased apoptosis compared with the control, SD, and CIH groups using Western blot analysis. Compared to the control, SD, and CIH groups, the SD+CIH group showed a higher degree of microtubule-associated protein light chain 3\\ staining. Compared to the SD+CIH group, BUN, creatinine, and U-Alb levels decreased, and apoptosis increased in the SD+CIH+rapamycin group, and the structure of the kidney after rapamycin treatment was well preserved. The mTOR expression was increased in the kidneys of the SD+CIH group. The NLRP3, Gasdermin D (GMDSD), interleukin (IL)-18, IL-1β, and cleaved-caspase-1 protein levels were higher in the SD+CIH group than the SD+CIH+rapamycin group, and the NLRP3, GMDSD, IL-18, IL-1β, and cleaved-caspase-1 mRNA levels were higher in the SD+CIH group than the SD+CIH+rapamycin group. Following rapamycin treatment, pyroptosis was suppressed. Rapamycin ameliorates renal damage by inhibiting the mTOR/NLRP3 signaling pathway.

Archetypal physiological responses to prolonged wakefulness

Acute sleep deprivation is a common workplace and lifestyle hazard known to affect physiological and cognitive performance. Previous research emphasizes the effect that sleep deprivation has on cognitive performance and often correlates changes in physiological parameters to measured performance. One potential problem with this approach is that there is some ambiguity about the true physiological response to sleep deprivation as the cognitive task employed to elicit some performance measurements may introduce confounds. This work aims to supplement previous works by analyzing physiological metrics from the domains of heart rate variability, electrodermal activity, and eye tracking across 25 h of continual wakefulness collected during a baseline measurement period that did not include a concurrent cognitive task to identify metrics sensitive, but not necessarily specific to, time awake. Of the 78 physiological metrics computed, 31 were shown to be significantly affected by time awake according to a Friedman test (α = 0.05). The patterns of the 31 significant metrics were input into an unsupervised clustering algorithm, yielding five archetypal patterns of behavior over 25 h of wakefulness. Of the five archetypal patterns observed, two were well explained by the Sleep, Activity, Fatigue, and Task Effectiveness model of sleep deprivation and effectiveness.

Cytomorphological Analysis and Interpretation of Nitric Oxide-Mediated Neurotoxicity in Sleep-Deprived Mice Model.

Background:Sleep deprivation (SD) is a biological stress condition for the brain, and the pathogenesis of SD is closely related to elevated oxidative stress, mitochondrial dysfunction, a major cause of neurodegeneration. This oxidative stress-mediated cell death is attributed to rise in calcium ion influx which further excites or alters the neurotransmitters level by activating neuronal nitric oxide (NO) synthase (nNOS) release of NO in mouse SD model. This study indicates that the nitrergic neurons are possible therapeutic targets for the amelioration of SD-induced cognitive dysfunction and behavioral alterations.Purpose:SD is considered as a risk factor for various neurodegenerative diseases. SD leads to biochemical, behavioral, and neurochemical alterations in animals. This study was designed to explore the possible involvement of a nitrergic neuron system in six days SD-induced morphological and neurodegenerative changes in mice.Methods:Using nNOS immunohistochemistry, we have investigated the effects of SD on nNOS positive neurons. Immunohistochemical study for the distribution of nNOS positive neuronal cell bodies was carried out in the hippocampus, prefrontal cortex (PFC), and amygdaloid nuclei of mice brain.Results:Sleep-deprived animals showed a significantly increased number of nNOS positive neurons and altered neuronal cytomorphology as compared with the control group.Conclusion:These results indicate that total SD may induce morphological changes in nNOS positive neurons in the brain, thus increasing NO synthesis, which is implicated in SD-induced neuronal cell death.

Sleep Deprivation Models in Rodents

Sleep deprivation has been identified as a risk factor for various diseases. Number of patients suffering from sleep deprivation is increasing daily, subsequently, increasing the risk to develop various diseases including cardiovascular disease. However, there is a limitation to elucidate the pathophysiological changes following sleep deprivation in human. Thus, the need arises for sleep deprivation models using animal, which will serve the purpose of understanding the disease in a better way. Several techniques have been developed to model sleep deprivation in animals, including the inverted flower pot and multiple platforms techniques. Genetic and environmental factors, cost, infrastructure, and animal life spans are some of the factors need to be considered when choosing a particular model. Besides, when studying sleep deprivation, tissue samples like peripheral blood, brain samples and aorta are used to elucidate the underlying mechanisms of a particular disease. Currently, more than ninety percent of all laboratory animal experiments are conducted in rats and mice. This review article focuses on sleep deprivation models in Rodents, which are generally used in research labs. The article also tries to evaluate the advantages and disadvantages of each of the technique discussed, also gives guidance toward the sleep deprivation model and helps researchers in deciding a particular model for their own purpose. DOI : http://dx.doi.org/10.17576/JSKM-2021-1902-04