Sleep-deprived Rats Research Articles

Attenuation Effect of Recovery Sleep for Impaired Reproductive Function in Male Rats by Sleep Deprivation.

The aim of the present study was to test the hypothesis that recovery sleep could counteract the detrimental effects of sleep deprivation (SD) on male rats' fertility. Twenty-two rats were housed in groups of six per cage with unrestricted access to food and water in a room. The modified multiple platform method was used to induce SD in rats over a 96-hour period. We examined the effect of SD on semen quality, reproductive hormones, and testicular histology in adult male rats. Then, we investigated the effect of 7 days recovery sleep on impaired reproductive function induced by SD. After the acclimation period, 22 rats were randomly separated into three experimental groups (SD, recovery sleep, and the control groups). Ninety-six hours of SD resulted in a significant decrease in sperm motility (24.33±10.93 vs. 48.20±8.55, p<0.001) and the number of morphologically normal sperm (9.68±2.77 vs. 26.21±14.60, p<0.01) in rats, accompanied by a decrease in testosterone levels (1.53±0.55 vs. 4.44±0.56, p<0.001) and destruction of testicular tissue structure compared with control group. After 7 days of recovery sleep, semen quality, especially sperm motility, was improved and testosterone levels were significantly higher compared to post-SD (3.70±0.53 vs. 1.53±0.55, p<0.05), but remained low compared to the control group. In conclusion, 96 hours of SD deteriorated the parameters of sperm motility and the number of morphologically normal sperm in rats, probably due to the decrease in serum testosterone levels and the disruption of testicular tissue structure when compared to the control group. After 7 days of recovery sleep, semen parameter, especially sperm motility and testosterone levels did not return to baseline levels compared to the control group.

Modulatory effect of n-3 polyunsaturated fatty acids on depressive-like behaviors in rats with chronic sleep deprivation: potential involvement of melatonin receptor pathway and brain lipidome.

Clinical evidence suggests that a bidirectional relationship is present between sleep loss and psychiatric disorders. Both melatonin receptor agonist ramelteon (RMT) and n-3 polyunsaturated fatty acids (n-3 PUFAs) exhibit antidepressant effects, while their underlying molecular mechanisms might be different. Thus, the present study aims to investigate the add-on effects and possible mechanisms of how RMT and different n-3 PUFAs modulate the melatonin receptor pathway as well as brain lipidome to ameliorate the neuropsychiatric behaviors displayed in rats under chronic sleep deprivation. Thirty-one 6-week-old male Wistar rats were divided into five groups: control (C), sleep deprivation (S), sleep deprivation treated with RMT (SR), sleep deprivation treated with RMT and eicosapentaenoic acid (C20:5n-3, EPA) (SRE), and sleep deprivation treated with RMT and docosahexaenoic acid (C22:6n-3, DHA) (SRD) groups. The results reveal that RMT plus EPA alleviated depressive-like behavior when the rats were subjected to the forced swimming test, whereas RMT plus DHA alleviated anxiety-like behavior when the rats were subjected to the elevated plus maze test. The results of a western blot analysis further revealed that compared with the rats in the S group, those in the SRE and SRD groups exhibited a significantly increased expression of MT2 in the prefrontal cortex, with greater benefits observed in the SRE group. In addition, decreased BDNF and TrkB expression levels were upregulated only in the SRE group. Lipidomic analysis further revealed possible involvement of aberrant lipid metabolism and neuropsychiatric behaviors. RMT plus EPA demonstrated promise as having the effects of reversing the levels of the potential biomarkers of depressive-like behaviors. RMT plus EPA or DHA could ameliorate depressive- and anxiety-like behaviors in sleep-deprived rats through the alteration of the lipidome and MT2 receptor pathway in the brain, whereas EPA and DHA exerted a differential effect.

Amide Proton Transfer-Weighted Imaging Detects Hippocampal Proteostasis Disturbance Induced by Sleep Deprivation at 7.0 T MRI.

Sleep deprivation leads to hippocampal injury. Proteostasis disturbance is an important mechanism linking sleep deprivation and hippocampal injury. However, identifying noninvasive imaging biomarkers for hippocampal proteostasis disturbance remains challenging. Amide proton transfer-weighted (APTw) imaging is a chemical exchange saturation transfer technique based on the amide protons in proteins and peptides. We aimed to explore the ability of APTw imaging in detecting sleep deprivation-induced hippocampal proteostasis disturbance and its biological significance, as well as its biological basis. In vitro, the feasibility of APTw imaging in detecting changes of the protein state was evaluated, demonstrating that APTw imaging can detect alterations in the protein concentration, conformation, and aggregation state. In vivo, the hippocampal APTw signal declined with increased sleep deprivation time and was significantly lower in sleep-deprived rats than that in normal rats. This signal was positively correlated with the number of surviving neurons counted in Nissl staining and negatively correlated with the expression of glucose-regulated protein 78 evaluated in immunohistochemistry. Differentially expressed proteins in proteostasis network pathways were identified in the hippocampi of normal rats and sleep-deprived rats via mass spectrometry proteomics analysis, providing the biological basis for the change of the hippocampal APTw signal in sleep-deprived rats. These findings demonstrate that APTw imaging can detect hippocampal proteostasis disturbance induced by sleep deprivation and reflect the extent of neuronal injury and endoplasmic reticulum stress.

Image discrimination reversal learning is impaired by sleep deprivation in rats: Cognitive rigidity or fatigue?

Insufficient sleep is pervasive worldwide, and its toll on health and safety is recapitulated in many settings. It is thus important to understand how poor sleep affects the brain and decision making. A robust literature documents the adverse effects of sleep deprivation on cognitive processes including cognitive flexibility, which is the capacity to appraise new feedback and make behavioral adjustments to respond appropriately. Animal models are often used to unravel the molecules, genes and neural circuits that are altered by sleep loss. Herein we take a translational approach to model the effects of sleep deprivation on cognitive rigidity, i.e., impaired cognitive flexibility in rats. There are several approaches to assess cognitive rigidity; in the present study, we employ a pairwise discrimination reversal task. To our knowledge this is the first time this paradigm has been used to investigate sleep deprivation. In this touchscreen operant platform, we trained rats to select one of two images to claim a sucrose pellet reward. If the non-rewarded image was selected the rats proceeded to a correction trial where both images were presented in the same position as before. This image presentation continued until the rat selected the correct image. Once rats reached performance criteria, the reward contingencies were reversed. In one group of rats the initial reversal session was preceded by 10 h of sleep deprivation. We compared those rats to controls with undisturbed sleep on the number of sessions to reach performance criteria, number of trials per session, response latencies, correct responses, errors, perseverative errors and perseveration bouts in the initial training and reversal phases. We report that on reversal session one, sleep deprived rats completed a fraction of the trials completed by controls. On subsequent reversal sessions, the sleep deprived rats struggled to adapt to the reversed contingencies despite completing a similar number of trials, suggesting an effect of cognitive rigidity separate from fatigue. We discuss the delayed performance dynamics incurred by sleep loss in the context of fatigue and the implications of using pairwise discrimination reversal as a model to further examine the effects of sleep loss on adaptive decision making.

Dose-dependent manner of luteolin in the modulation of spatial memory with respect to the hippocampal level of HSP70 and HSP90 in sleep-deprived rats

Sleep deprivation (SD) induces a variety of deleterious effects on different cognitive functions such as memory. Elevated neuroinflammation, oxidative stress, and apoptosis, and decreased synaptic plasticity and antioxidant capacity are involved in the deleterious effects of SD on memory. On the other hand, luteolin (a flavonoid compound) has antioxidant, neuroprotective, and anti-inflammatory properties. Also, Heat shock protein 70 (HSP70) and Heat shock protein 90 (HSP90) can be involved in modulating memory. In this study, we aimed to assess the effects of SD and luteolin on spatial learning and memory using Morris Water Maze apparatus in rats, with respect to the level of HSP70 and HSP90 in the hippocampus. Luteolin was injected intracerebroventricular (i.c.v.) at the doses of 0.5, 1, and 2 µg/rat. The results showed that SD impaired spatial memory, while luteolin dose-dependently restored SD-induced spatial memory impairment. SD increased the expression level of HSP90 in the hippocampus, whereas luteolin dose-dependently reversed the effect of SD. Furthermore, SD decreased the expression level of HSP70 protein in the hippocampus, while luteolin dose-dependently reversed the effect of SD. In conclusion, HSP70 and HSP90 may be involved in the deleterious effect of SD on memory, and in the improvement effect of luteolin on memory. This is a novel study reporting novel data and we suggest further detailed studies to better understand the interactions between SD, luteolin, and Heat shock proteins.

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.

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.

Intervention Effects of Okra Extract on Brain-Gut Peptides and Intestinal Microorganisms in Sleep Deprivation Rats.

Objective Okra, possessing various bioactive components, is used to treat different diseases. This study sought to estimate the intervention effects of okra extract (OE) on brain-gut peptides (BGPs) and intestinal microorganisms in sleep deprivation (SD) rats. Methods SD rat models were established using the modified multiple platform method and then treated with normal saline, diazepam tablets, or different doses of OE. Body weight and average daily water consumption of rats were recorded. Depressive behaviors of rats were assessed by the open field test and sucrose preference test. Serum levels of noradrenaline, melatonin, inflammatory factors (IL-1β/IL-6/TNF-α/IL-4/IL-10), and BGP indexes, including gastrin (GAS), motilin (MTL), 5-hydroxytryptamine (5-HT), cholecystokinin (CCK), and vasoactive intestinal peptide (VIP) were measured by ELISA. Additionally, the DNA relative contents of representative intestinal microorganisms in the collected rat feces were determined using RT-qPCR. Results SD decreased body weight and average daily water consumption and induced depressive behaviors as well as stress and inflammatory responses in rats. SD rats exhibited lowered GAS, MTL, 5-HT, and VIP but elevated CCK and showed diminished DNA relative contents of Bacteroidetes and probiotics (Bifidobacteria and Lactobacilli) but increased Clostridium perfringens. OE at different doses ameliorated the depressive behaviors and mitigated the stress and inflammatory responses in SD rats, raised the serum contents of GAS, MTL, 5-HT, and VIP, reduced CCK level, elevated the DNA relative contents of Bacteroidetes and probiotics, but diminished Clostridium perfringens. OE exhibited similar intervention effects to diazepam tablets (positive control). Conclusion OE exerts intervention effects on BGPs and intestinal microorganisms in SD rats.

Lithium Treatment Improves Cardiac Dysfunction in Rats Deprived of Rapid Eye Movement Sleep.

Rapid eye movement (REM) sleep deprivation triggers mania and induces cardiac fibrosis. Beyond neuroprotection, lithium has cardioprotective potential and antifibrotic activity. This study investigated whether lithium improved REM sleep deprivation-induced cardiac dysfunction and evaluated the potential mechanisms. Transthoracic echocardiography, histopathological analysis, and Western blot analysis were performed in control and REM sleep-deprived rats with or without lithium treatment (LiCl of 1 mmol/kg/day administered by oral gavage for 4 weeks) in vivo and in isolated ventricular preparations. The results revealed that REM sleep-deprived rats exhibited impaired contractility and greater fibrosis than control and lithium-treated REM sleep-deprived rats. Western blot analysis showed that REM sleep-deprived hearts had higher expression levels of transforming growth factor beta (TGF-β), phosphorylated Smad 2/3, and alpha-smooth muscle actin than lithium-treated REM sleep-deprived and control hearts. Moreover, lithium-treated REM sleep-deprived hearts had lower expression of angiotensin II type 1 receptor, phosphorylated nuclear factor kappa B p65, calcium release-activated calcium channel protein 1, transient receptor potential canonical (TRPC) 1, and TRPC3 than REM sleep-deprived hearts. The findings suggest that lithium attenuates REM sleep deprivation-induced cardiac fibrogenesis and dysfunction possibly through the downregulation of TGF-β, angiotensin II, and Ca2+ signaling.

Electroacupuncture Enhances Cognitive Deficits in a Rat Model of Rapid Eye Movement Sleep Deprivation via Targeting MiR-132.

Deprivation of rapid eye movement sleep (REMSD) reduces the potential for learning and memory. The neuronal foundation of cognitive performance is synapse plasticity. MicroRNA-132 (MiR-132) is an important microRNA related to cognitive and synapse plasticity. Acupuncture is effective at improving cognitive impairment caused by sleep deprivation. Furthermore, its underlying principle is still unclear. Herein, whether electroacupuncture (EA) helps alleviate cognitive impairment in REMSD by targeting miR-132 was assessed. A rat model of REMSD was constructed using the developing multiplatform water environment technique, as well as EA therapy in Baihui (GV20) and Dazhui (GV14) was performed for 15 minutes, once daily for 7 days. Agomir or antagomir of MiR-132 was injected into the hippocampal CA1 areas to assess the EA mechanism in rats with REMSD. Then, the learning and memory abilities were detected by behavioral tests; synapse structure was assessed by transmission electron microscope (TCM); and dendrites branches and length were examined by Golgi staining. MiR-132-3p was assessed by real-time quantitative polymerase chain reaction (qRT-PCR). P250GAP, ras-related C3 botulinum toxin substrate 1 (Rac1), and cell division cycle 42 (Cdc42) expression levels in hippocampal tissues were evaluated by immunohistochemistry and Western blot. According to the research, EA therapy enhanced cognitive in REMSD rats, as evidenced by reduced escape latency; upregulated the performance of platform crossings and prolonged duration in the goal region; and improved spontaneous alternation. EA administration restored synaptic and dendritic structural damage in hippocampal neurons, enhanced miR-132 expression, and reduced p250GAP mRNA and protein levels. Additionally, EA boosted the protein level of Rac1 and Cdc42 associated with synaptic plasticity. MiR-132 agomir enhanced this effect, whereas miR-13 antagomir reversed this action. The current data demonstrate that EA at GV20 and GV14 attenuates cognitive impairment and modulates synaptic plasticity in hippocampal neurons via miR-132 in a sleep-deprived rat model.

Microglial Responses and Pain Behaviors Are Exacerbated by Chronic Sleep Deprivation in Rats with Chronic Pain Via Neuroinflammatory Pathways

The inflammatory response of central nervous system (CNS) and microglial activation is important in the development of pain behaviors induced by sleep deprivation. We found that chronic sleep deprivation (CSD) aggravated pain behaviors in rats with chronic pain by upregulating expression of Toll-like receptor 4 (TLR4), NOD-like receptor pyrin domain containing 3 (NLRP3), and interleukin 1β (IL-1β), which promoted microglial activation in the brain. We also found that CSD increased numbers of Iba1+ and TLR4+ cells, as well as neuronal apoptosis. Inhibitors of TLR4 and NLRP3 (TAK-242 and MCC950, respectively) reduced expression levels of inflammatory factor proteins and M1-related factor mRNA, decreased microglial activation, and relieved the hyperalgesia caused by CSD. These results suggest that CSD aggravated pain behavior in rats with chronic pain through the TLR4/NLRP3/IL-1β signaling pathway, which mediates microglial activation and promotes CNS inflammation and neuronal apoptosis.

Effects of dopamine transporter in the ventral tegmental area on sleep recovery after propofol anesthesia in sleep-deprived rats

ObjectivePrevious studies indicate that propofol can help with recovery from sleep deprivation and has anti-anxiety effects. However, the underlying neurochemical mechanism remains unclear. This study aimed to investigate the effects of dopamine transporter (DAT) in the ventral tegmental area (VTA) on sleep and anxiety recovery after propofol anesthesia in rats with 24 h total sleep deprivation (TSD). MethodsAdult male Sprague-Dawley rats were in natural sleep or sleep deprived for 24 h in a sleep deprivation rat system. The rats received propofol anesthesia (75 mg/kg, i.p.) or natural sleep. Dopamine transporter knockdown was performed by microinjection of AAV-DAT-RNAi vector. EEG was measured in each group to evaluate the subsequent sleep. The elevated plus maze test (EPMT) and open field test (OFT) were used to evaluate locomotion and anxiety level in rats. Immunofluorescence was used to verify virus location and transfection efficiency. ResultsCompared with NC group, the anxiety level of Propofol group showed no significant difference, but REM sleep decreased. Compared with the TSD group, the anxiety level of the TSD + Propofol group was reduced and the sleep recovery was closer to baseline. Compared with TSD + AAV-NC group, anxiety level and sleep time increased in TSD + AAVi group, REM increased within 24 h after sleep deprivation. The sleep time of TSD + AAVi + Propofol group was between those of TSD + AAV-NC group and TSD + AAVi group. TSD + AAV-NC + Propofol group had the least sleep time and the lowest anxiety level. Conclusion1. Propofol did not change anxiety level in normal rats, but reduced REM sleep, while it could accelerate sleep recovery and reduce anxiety level in sleep-deprived rats. 2. In sleep deprived rats with DAT knockdown, propofol improved sleep and anxiety levels more slowly, especially producing more REM rebound, suggesting that the improvement of sleep and anxiety levels in sleep-deprived rats with propofol may be related to DAT in VTA region.

Effects of beta adrenergic receptor in hippocampal dentate gyrus on spatial learning and memory in sleep deprived rats and its mechanisms

目的: 探究海马齿状回(DG)内beta肾上腺素能受体(beta-AR)对睡眠剥夺(SD)大鼠空间学习记忆的作用及其机制。方法: 本研究应用剥夺杆式睡眠剥夺仪建立21 d(18 h/d)慢性SD模型。动物分为4组(n=6):对照组,ISO组(异丙肾上腺素组),SD组和SD+ISO组。每天训练前30 min,以0.5 ml/min速度向DG区微量注入ISO (2 mg/μl) 或盐水1 ml。Morris水迷宫检测大鼠空间学习记忆能力。免疫组织化学和免疫印迹法检测海马DG区c-Fos和脑源性神经营养因子(BDNF)表达。结果: 与对照组相比, SD组大鼠前4 d逃逸时间显著增加(P＜0.01),且第5日目标象限时间比和穿台次数明显减少(P＜0.05),与SD组相比SD+ISO组上述行为学指标显著改善(P均＜0.05)。与对照组比较,SD组大鼠海马DG区c-Fos和BDNF蛋白表达水平均显著降低(P均＜0.05),然而与SD组比较,SD+ISO组两蛋白表达水平明显增加(P均＜0.05)。结论: 海马DG区beta-AR激活可改善SD诱发的空间学习和记忆障碍,其机制可能与上调DG区c-Fos和BDNF蛋白表达有关。.

Effects of uridine administration on hippocampal matrix metalloproteinases and their endogenous inhibitors in REM sleep-deprived rats

Rapid eye movement (REM) sleep is associated with synaptic plasticity which is considered essential for long-term potentiation (LTP). The composition of extracellular matrix (ECM), in part, plays a role in REM sleep-associated synaptic functioning. The objective of this study was to investigate the effects of uridine administration on levels of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) in rats subjected to REM sleep deprivation (REMSD). REMSD was induced by modified multiple platform method for 96-hour. Rats were randomized to receive either saline or uridine (1 mmol/kg) intraperitoneally twice a day for four days. Rats were then decapitated and their hippocampi were dissected for analyzing the levels of MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2 and TIMP-3 by Western-blotting and the activities of MMP-2 and MMP-9 by Gelatin zymography. REMSD resulted in reduced levels of MMP-3, MMP-9, TIMP-3 and activity of MMP-9 in saline-treated rats, while uridine treatment significantly enhanced their impairment. TIMP-1 was enhanced following REMSD but uridine treatment had no significant effect on TIMP-1 levels. MMP-2, TIMP-2 levels and MMP-2 activity were not affected by either REMSD or uridine administration. These data show that REMSD significantly affects ECM composition which is ameliorated by uridine administration suggesting a possible use of uridine in sleep disorders.

Sleep deprivation leads to further impairment of hippocampal synaptic plasticity by suppressing melatonin secretion in the pineal gland of chronically unpredictable stress rats

There has been ample research showing that insomnia is a potential trigger of depression as well as a symptom of depression. These two factors contribute to behavioural problems and are closely related to the plasticity of hippocampal synapses. Although depression and insomnia impair hippocampal synaptic plasticity, the mechanism by which this happens remains a mystery. This study aimed to investigate the pathogenesis of insomnia comorbidity in depression and the regulatory effect of venlafaxine combined with melatonin on hippocampal synaptic plasticity in chronic unpredictable mild stress (CUMS) with sleep deprivation (SD) rats. Thus, rats were subjected to 14 days of chronic mild unpredictable stress, gradually acclimated to sleep deprivation on days 12–14. Followed by 21 consecutive days of sleep deprivation, 18 h per day, with daily gavage of venlafaxine (13.5 mg/kg) + melatonin (72 mg/kg) on days 15–36. Venlafaxine + melatonin treatment improves depression-like behaviour, pentobarbital sodium experimental sleep latency, and sleep duration in CUMS +SD rats. In addition to improving depressive-like behaviors, sleep deprivation also upregulates the expression of caspase-specific cysteine protein 3 (Caspase 3) in the pineal glial cells of chronic mild rats, as well as in hippocampal microglia. Expression of ionic calcium-binding adaptor 1 (iba-1), downregulates the secretion of several synaptic plasticity-related proteins, notably cAMP response element binding protein (CREB), glial cell line-derived neurotrophic factor (GDNF), and the synaptic scaffolding protein Spinophiline (Spinophiline). Hematoxylin-eosin staining showed that the structure of the pineal gland and hippocampus was damaged, and Golgi staining showed that the dendrites and spines in the DG area of the hippocampus were destroyed, vaguely aggregated or even disappeared, and the connection network could not be established. Western blot analysis further revealed a positive correlation between low melatonin levels and reduced Spinophiline protein. Interestingly, venlafaxine + melatonin reversed these events by promoting hippocampal synaptic plasticity by regulating melatonin secretion from the pineal gland. Therefore, it exerted an antidepressant effect in sleep deprivation combined with CUMS model rats. Overall, the results of this study suggest that the pathophysiology of depressive insomnia comorbidity is mediated by impaired pineal melatonin secretion and impaired hippocampal synaptic plasticity. In addition, these responses are associated with melatonin secretion from the pineal gland.

Chronic caffeine consumption improves the acute sleep deprivation-induced spatial memory impairment while altering N-methyl-D-aspartate receptor subunit expression in male rats.

Caffeine is a psychostimulant substance that is mostly used to prevent fatigue, increase alertness, and ameliorate sleep loss situations. In this study, we aimed to investigate the effect of chronic caffeine consumption on learning and memory functions and related genes in rapid eye movement (REM) sleep-deprived rats. During the neonatal period (postnatal day [PND] 28) Wistar albino male rats (n = 32) were randomly assigned into four groups: Control (C), caffeine application (Cf), acute REM sleep-deprivation (RD), and caffeine application + acute RD (Cf + RD). The 48 h of RD was executed when caffeine administration was completed. The learning and memory performance was evaluated by the Morris water maze test (MWMT). Following this, the rats were decapitated to isolate hippocampus tissues. In MWMT, time spent in the targeted quadrant decreased significantly in the RD group compared with the C and Cf + RD group. NR2A expression level increased in the RD group compared with C, Cf, and Cf + RD groups (p < 0.05). NR2B expression level increased in RD and Cf + RD groups compared with C and Cf groups (p < 0.05). BDNF and c-Fos expression levels did not differ significantly between the groups. RD impaired hippocampal spatial memory performance in the MWMT test. Our results indicated that chronic caffeine consumption has a therapeutic effect on spatial memory deterioration impairment caused by RD. Furthermore, it seems that the effect of caffeine RD on the hippocampus may be mediated by NR2A.

Integrated 16S rDNA, metabolomics, and TNF-α/NF-κB signaling pathway analyses to explain the modulatory effect of Poria cocos aqueous extract on anxiety-like behavior

BackgroundPoria cocos is an ancient medicine and modern functional food, which exerts excellent effects on anxiety, although its mechanism is unknown. PurposeTo explore the mechanisms of the aqueous extract of P. cocos (PCD) in ameliorating anxiety-like behavior caused by chronic sleep deprivation (CSD). MethodsPCD chemical composition was analyzed by UPLC-QTOF-MS/MS. A CSD rat model was established over 21 days. We examined the effects and mechanisms after 10 days of CSD using open-field tests (OFTs), enzyme-linked immunosorbent assays, 16S rDNA, non-targeted metabolomics, and Western blot analyses. ResultsSixty-two triterpenoids were identified in PCD. CSD-induced anxiety-like behavior was significantly attenuated by PCD treatment. PCD improved hypothalamic neurotransmitters, decreased proinflammatory cytokines, and depressed the proteins expression of tumor necrosis factor (TNF)-α/nuclear factor (NF)-κB signaling pathway. The full-length 16S rDNA sequence of bacterial cells was also sequenced by high-throughput analysis. CSD caused significant changes in the intestinal flora. PCD improved the species diversity and bacterial abundance in the intestines of rats with anxiety. Metabolomics analysis indicated that 12 PCD-related metabolites in serum and 32 PCD-related metabolites in feces were identified, respectively. Metabolite analysis in serum, PCD treatment affected taurine, hypotaurine, cysteine, methionine, glycine, serine, and threonine metabolism, among others. Metabolite analysis in feces showed significant effects of PCD treatment on the metabolism of vitamin B6, tyrosine, drugs, and glycerophospholipid. Additionally, the correlation analysis of heatmaps showed a tight relationship between inflammatory factors, metabolic parameters, and gut microbial phylotypes. ConclusionsPCD relieved anxiety by regulating intestinal flora, regulating metabolic disorders, and inhibiting inflammatory pathways in chronic sleep-deprived rats.

0294 Voluntary Alcohol Consumption and Sleep Deprivation in Rats

Abstract Introduction Alcohol is one of the most common psychoactive drugs that has depressant effects on the central nervous system. The vast majority of research on alcohol and sleep indicates chronic alcohol consumption has a detrimental impact on sleep architecture and homeostasis. However, less research has explored the effects of sleep deprivation on alcohol consumption; that is, the relationship in the opposite direction. Previous animal studies have explored a potential bi-directional relationship between sleep and alcohol with promising results. However, there was concern that the potential relationship may be a result of stress as a by-product of the sleep deprivation method. The present study examines the effect of sleep deprivation on voluntary alcohol consumption using two sleep deprivation methods in the rat, forced exercise wheels and the automated sleep deprivation system. Methods Twelve male Sprague-Dawley rats had ad libitum access to a 7% alcohol solution and water. Alcohol and water consumption was measured daily at 0900. Baseline consumption levels were recorded in the home cage prior to introduction to the sleep deprivation equipment. Following baseline, rats were placed in the stationary equipment for the first sleep deprivation environment control. Rats were then subjected to 6hr/day of sleep deprivation for five consecutive days in either the forced exercise wheel (n=6) or the automated sleep deprivation system (n=6). After sleep deprivation, rats were placed back in the stationary equipment as a second control measure. In total, there were four conditions, home cage baseline, first sleep deprivation environment control, sleep deprivation, second environment control. Results Data indicates that rats consumed significantly more alcohol in the sleep deprivation condition and the second sleep deprivation control. There was no difference between the two sleep deprivation methods. The mean alcohol consumption (g/kg) significantly increased from the sleep deprivation condition to the second environment control indicating a cumulative effect. Conclusion The increase in alcohol consumption in the final condition rejects the hypothesis of a bi-directional relationship. Instead, the data suggests potential receptor downregulation due to alcohol exposure over time and a conditioned compensatory effect of the sleep deprivation environment. Research methodology issues also may have confounded results. Support (If Any)

Assessing the Influence of Salvia triloba on Memory Deficit Caused by Sleep Deprivation in the Context of Oxidative Stress.

Learning and memory deficit has been reported to be correlated to oxidative mutilation in the hippocampus. Moreover, sleep deprivation (SD) mitigates memory via distressing oxidative stress balance. In the current report, the prospective neuroprotective role of oral sage (Salvia triloba) extract on cognitive impairment induced by chronic SD was investigated. The SD was induced in adult male Wistar rats employing a modified multiple platform (8 h/day; for six weeks). Simultaneously, S. triloba extract (375 mg/kg, orally) was administered for six weeks. Thereafter, the Radial Arm Water Maze test was utilized to evaluate spatial learning and memory. Moreover, activities of different hippocampal antioxidant parameters: glutathione peroxidase (GPx), oxidized glutathione (GSSG), reduced glutathione (GSH), catalase, superoxide dismutase (SOD), and the thiobarbituric acid reactive substance (TBARS) were measured in rats' hippocampus. Moreover, the level of brain derived neurotrophic factor (BDNF) was assessed. Current results illustrate that chronic SD significantly compromised both memories, shortand long-term, while sage extract inhibited these consequences. Moreover, sage extract remarkably stabilized the antioxidant enzyme levels, which were decreased by SD, such as: SOD, catalase, and GPx (P < 0.05), and remarkably augmented the GSH/GSSG ratio in SD rats (P < 0.05). However, no substantial alterations of GSH, TBARS or BDNF levels (P > 0.05) were seen with sage extract administration. Chronic treatment with sage extract (S. Triloba) precluded SD-induced memory impairment by regularizing antioxidant parameters levels in rats' hippocampus.

Effects of citicoline administration on synaptic proteins in rapid eye movement sleep-deprived rats.

Objective(s):Sleep has a pivotal role in learning-memory and sleep deprivation (SD) negatively affects synaptic functioning. Cytidine-5-diphosphocholine (Citicoline) has been known to improve learning and memory functions. Our objective was to explore the effects of Citicoline on hippocampal and cortical synaptic proteins in rapid eye movement (REM) sleep-deprived rats.Materials and Methods:Rats (n=36) were randomly divided into 6 groups. Environmental control or sleep deprivation was done by placing the rat on a 13 cm diameter platform (Large Platform [LP] group) or on a 6.5 cm diameter platform (REMSD group), respectively, for 96 hours. Rats randomized for controls (Home Cage [HC] group) were followed up in home cages. Rats in each of the REMSD, LP or HC group were randomized to receive either saline (0,9%NaCl) or Citicoline (600 μmol/kg) intraperitoneally twice a day for four days. After the experiments, rats were sacrificed; their cerebral cortices and hippocampi were dissected for analyzing the levels of pre-synaptic proteins synaptophysin and synapsin I, and the post-synaptic density protein-95 (PSD-95) by Western-blotting. Results: Hippocampal levels of PSD-95, but not the pre-synaptic proteins, were reduced by REM sleep deprivation. Citicoline treatment ameliorated the reduction in PSD-95 levels in REM sleep-deprived rats. On the other hand, REM sleep deprivation was not found to be significantly effective on pre- or post-synaptic proteins in cerebral cortex.Conclusion:REM sleep deprivation reduces hippocampal PSD-95 levels which are enhanced by Citicoline treatment. These data propose that Citicoline may ameliorate the adverse effects of SD on hippocampal synaptic functioning.