Paradoxical Sleep Deprivation Research Articles

Exercise improves learning and memory impairments in sleep deprived female rats

Inadequate sleep is a common problem in modern societies. It has been previously shown that female rats are more vulnerable to the deleterious effects of sleep deprivation on cognitive functions. Physical exercise has been suggested to attenuate the cognitive impairments induced by sleep deprivation in male rats. The objective of the current study was to investigate the effects of physical exercise on cognitive functions of female rats following paradoxical sleep deprivation.Intact and ovariectomized (OVX) female Wistar rats were used in the present study. The exercise protocol was 4weeks of treadmill running. The multiple platform method was applied for the induction of 72h paradoxical sleep deprivation and the cognitive function was evaluated using Morris water maze (MWM). Plasma corticosterone level was evaluated in separate groups of study. ANOVA and repeated measures were used to analyze the data and P<0.05 was considered statistically significant.Throughout the investigation, significant learning impairment was observed in sleep-deprived OVX rats compared to the intact and the other OVX groups. Short term memory impairment was observed in both sleep-deprived OVX and intact groups. Physical exercise alleviated the PSD-induced learning and memory impairments in both intact and OVX groups. Corticosterone levels were not statistically significant among the different groups.The results of our study confirmed the negative effects of PSD on cognitive functions in female rats and regular physical exercise seems to protect rats from these effects. Further studies are suggested to be carried out in order to evaluate the possible underlying mechanisms, and also to evaluate the possible interactions between sex hormones and PSD-induced cognitive impairments.

Sleep deprivation alters energy homeostasis through non-compensatory alterations in hypothalamic insulin receptors in Wistar rats

Studies have shown a gradual reduction of sleep time in the general population, accompanied by increased food intake, representing a risk for developing obesity, type II diabetes and cardiovascular disease. Rats subjected to paradoxical sleep deprivation (PSD) exhibit feeding and metabolic alterations, both of which are regulated by the communication between peripheral signals and the hypothalamus. This study aimed to investigate the daily change of 96h of PSD-induced food intake, body weight, blood glucose, plasma insulin and leptin concentrations and the expression of their receptors in the hypothalamus of Wistar rats. Food intake was assessed during the light and dark phases and was progressively increased in sleep-deprived animals, during the light phase. PSD produced body weight loss, particularly on the first day, and decreased plasma insulin and leptin levels, without change in blood glucose levels. Reduced leptin levels were compensated by increased expression of leptin receptors in the hypothalamus, whereas no compensations occurred in insulin receptors. The present results on body weight loss and increased food intake replicate previous studies from our group. The fact that reduced insulin levels did not lead to compensatory changes in hypothalamic insulin receptors, suggests that this hormone may be, at least in part, responsible for PSD-induced dysregulation in energy metabolism.

Can Ayahuasca and sleep loss change sexual performance in male rats?

The ingestion of the beverage Ayahuasca usually occurs in religious ceremonies that are performed during the night leading to sleep deprivation. The purpose of the present study was to characterize the acute effects of Ayahuasca upon the sexual response of sleep deprived male rats. One group of sexually experienced male Wistar rats were submitted to a paradoxical sleep deprivation (PSD) protocol for 96h, while another group spent the same amount of time in the home cage (CTRL). After this period, either saline or Ayahuasca drink (250, 500 and 1000μgmL−1) was administered by gavage and sexual behavior and hormonal concentrations were measured. Ayahuasca alone significantly decreased sexual performance at all doses. However, in sleep deprived rats, the lower dose increased sexual performance while the intermediate dose produced a detrimental effect on sexual response compared to the CTRL rats at the same dose. Regarding the hormonal analyses, a lower testosterone concentration was observed in sleep-deprived saline rats in relation to the CTRL group. Progesterone was significantly lower only in PSD rats at the dose 500μgmL−1 compared with CTRL-500μgmL−1 group. Corticosterone was unchanged among the groups evaluated. Our results suggest that Ayahuasca intake markedly impaired sexual performance alone, but, when combined with sleep deprivation, had significant, but heterogeneous, effects on male sexual response.

Paradoxical sleep deprivation increases mortality in myocardial infarcted rats

We hypothesized that sleep deprivation affects hemodynamic parameters and, therefore, correlates with mortality after acute myocardial infarction (AMI) induced by isoproterenol. Rats were randomly assigned to one of four experimental groups: control, paradoxical sleep deprivation (PSD), AMI, and PSD + AMI. Blood pressure, heart rate and renal sympathetic nerve activity were higher in the PSD group. Mortality after isoproterenol administration was significantly higher in the PSD + AMI group compared to the AMI group. These data suggest that sleep loss is able to increase cardiovascular risk, per se, and worsens the prognosis in cases of cardiac insult.

The effects of paradoxical sleep deprivation on amphetamine-induced behavioral sensitization in adult and adolescent mice

Drug-induced behavioral sensitization (BS), paradoxical sleep deprivation (PSD) and adolescence in rodents are associated with changes in the mesolimbic dopaminergic system. We compared the effects of PSD on amphetamine-induced BS in adult and adolescent mice. Adult (90 days old) and adolescent (45 days old) Swiss mice were subjected to PSD for 48h. Immediately after PSD, mice received saline or 2.0mg/kg amphetamine intraperitoneally (i.p.), and their locomotion was quantified in activity chambers. Seven days later, all the animals were challenged with 2.0mg/kg amphetamine i.p., and their locomotion was quantified again. Acute amphetamine enhanced locomotion in both adult and adolescent mice, but BS was observed only in adolescent mice. Immediately after its termination, PSD decreased locomotion of both saline- and amphetamine-treated adolescent mice. Seven days later, previous PSD potentiated both the acute stimulatory effect of amphetamine and its sensitization in adolescent mice. In adult animals, previous PSD revealed BS. Our data suggest that adolescent mice are more vulnerable to both the immediate and long-term effects of PSD on amphetamine-induced locomotion. Because drug-induced BS in rodents shares neuroplastic changes with drug craving in humans, our findings also suggest that both adolescence and PSD could facilitate craving-related mechanisms in amphetamine abuse.

Leucine Supplementation Reverses Muscle Atrophy Type II Fibers During Paradoxical Sleep Deprivation In Sedentary Rats

Leucine Supplementation Reverses Muscle Atrophy Type II Fibers During Paradoxical Sleep Deprivation In Sedentary Rats

Resistance Training Reverses Catabolic Profile Induced By Paradoxical Sleep Deprivation

Resistance Training Reverses Catabolic Profile Induced By Paradoxical Sleep Deprivation

Sleep loss changes neuropeptidase expression and activty in rat brain (876.3)

The effect of sleep deprivation on proteolytic activity in the central nervous system has not been frequently addressed in the literature. We have started to study the changes on peptidase activities in animal models of paradoxical sleep deprivation (PSD), mainly focusing on metallopeptidases like thimet oligopeptidase (EP24.15) known to process neuropeptides. In the present study, we demonstrated that PSD in rats induces changes both in the expression and activity of EP24.15 in the male rat hypothalamus and striatum tissue extracts. In the hypothalamus, the significant decrease in activity and mRNA levels, after PSD, was only totally reversed after 96h of sleep recovery. In the striatum, albeit significative, changes in mRNA and activity do not parallel changes on protein content. Neurotensin, GnRH, dynorphins, enkephalins, orphanin/nociceptin are among the many neuropeptides whose balance can be modified by the modifications on EP24.15 activity and can be, at least partially, related with many of the physiological changes observed in PSD and during the sleep recovery periods.Grant Funding Source: Supported by FAPESP, CNPq and AFIP

Cardiovascular function alterations induced by acute paradoxical sleep deprivation in rats

Sleep loss has been implicated in triggering the hypertension. The goal of the present study was investigated the possible mechanisms underlying cardiovascular alterations after acute paradoxical sleep deprivation (PSD). Male Wistar rats were assigned in two experimental groups: (1) control and (2) PSD for 24 h using the modified single platform method. Paradoxical sleep deprived rats exhibited higher blood pressure, heart rate (HR) and impaired baroreceptor sensitivity. After pharmacological autonomic double blockade (propranolol and methylatropine administration), intrinsic heart rate was decreased after PSD. The PSD rats showed a reduction in the vagal tone without affecting sympathetic tone. Isoproterenol administration (0.001, 0.01 and 1 µg/kg) induced an increase in ΔHR responses in PSD group. Electrocardiographic analysis in response to β-adrenergic stimulation indicated that PSD contributed to ventricular cardiac arrhythmias. Our findings suggest that acute paradoxical sleep loss induce cardiovascular alterations, autonomic imbalance accompanied by impaired baroreflex sensitivity and increased arrhythmia susceptibility.

The effects of sleep deprivation on microRNA expression in rats submitted to pilocarpine-induced status epilepticus

Epilepsy is a neurological disorder with significant prevalence and the individuals affected by this disease have a great probability of occurrence of a lethal phenomenon known as Sudden Unexpected Death in Epilepsy (SUDEP). SUDEP occurs mainly during the night and probably during sleep. The pathophysiological mechanisms involved in this lethal phenomenon are still obscure and new evidences that could corroborate in this area are warranted. Thus, the aim of the present study was to evaluate the effect of sleep deprivation in the expression of microRNA (miRNA) in the frontal cortex and heart tissues of adult male rats after 50days of saline (SAL) or pilocarpine-induced status epilepticus (PILO). Initially 389 miRNA expressions were evaluated between SAL and PILO groups by microarray. Subsequently, 3 differentially expressed miRNAs of each tissue were investigated after total sleep deprivation (TSD 6h) and paradoxical sleep deprivation (PSD 24h). Still, it was analyzed that the effects of sleep rebound with equivalent duration of PSD and TSD. There was a significant increase of miR-146a expression, an important inflammatory modulator in the frontal cortex of PILO rats when compared to SAL animals. Animals treated with pilocarpine were affected by TSD (through overexpression of miRNAs related to inflammatory process) and these changes were maintained even after a sleep window of 6h. In contrast, miRNAs associated with heart diseases were down-regulated in PSD rebound, suggesting a possible restoration of homeostasis in cardiovascular system of SAL and PILO groups.

Differential effects of paradoxical sleep deprivation on memory and oxidative stress

Sleep has important functions for every organ in the body and sleep deprivation (SD) leads to disorders that cause irreparable damage. The aim of this study was to investigate behavioral and brain structural alterations in mice deprived of paradoxical sleep for 48 and 72 h. Working memory, aversive memory as well as levels of nitric oxide (NO) and thiobarbituric acid reactive substances (TBARS) in the hippocampus, body striatum, and prefrontal cortex were evaluated. Working memory was affected in the 48- and 72-h SD groups while aversive memory was altered only in the 48-h SD group (p ≤ 0.05). Our findings showed that SD reduces NO levels in most brain areas (p < 0.05): NO levels were unaltered in the striatum of animals sleep-deprived for 48 h. Higher levels of TBARS were observed in all areas of the SD groups (p ≤ 0.05). Thus, we confirmed that SD has duration-dependent effects on behavior as well as on NO and TBARS levels in the brain. Preserved striatum NO levels suggest that this structure is less vulnerable to oxidative stress and is only affected by SD of longer duration. Increased TBARS and reduced NO levels in the hippocampus and prefrontal cortex confirm a central role for both these structures in working memory and aversive memory. Contextual fear conditioning was not affected by longer periods of SD. Thus, our findings suggest that shorter SD time may be more beneficial to avoid aversive memory where this may have implications for the management of posttraumatic stress.

Is Lack of Sleep Capable of Inducing DNA Damage in Aged Skin?

Skin naturally changes with age, becoming more fragile. Various stimuli can alter skin integrity. The aim of this study was to evaluate whether sleep deprivation affects the integrity of DNA in skin and exacerbates the effects of aging. Fifteen-month old female Hairless mice underwent 72 h of paradoxical sleep deprivation or 15 days of chronic sleep restriction. Punch biopsies of the skin were taken to evaluate DNA damage by single cell gel (comet) assay. Neither paradoxical sleep deprivation nor sleep restriction increased genetic damage, measured by tail movement and tail intensity values. Taken together, the findings are consistent with the notion that aging overrides the effect of sleep loss on the genetic damage in elderly mice.

Acute total sleep deprivation potentiates amphetamine-induced locomotor-stimulant effects and behavioral sensitization in mice

It has been demonstrated that a prolonged period (48h) of paradoxical sleep deprivation (PSD) potentiates amphetamine (AMP)-induced behavioral sensitization, an animal model of addiction-related neuroadaptations. In the present study, we examined the effects of an acute short-term deprivation of total sleep (TSD) (6h) on AMP-induced behavioral sensitization in mice and compared them to the effects of short-term PSD (6h). Three-month-old male C57BL/6J mice underwent TSD (experiment 1—gentle handling method) or PSD (experiment 2—multiple platforms method) for 6h. Immediately after the sleep deprivation period, mice were tested in the open field for 10min under the effects of saline or 2.0mg/kg AMP. Seven days later, to assess behavioral sensitization, all of the mice received a challenge injection of 2.0mg/kg AMP and were tested in the open field for 10min. Total, peripheral, and central locomotion, and grooming duration were measured. TSD, but not PSD, potentiated the hyperlocomotion induced by an acute injection of AMP and this effect was due to an increased locomotion in the central squares of the apparatus. Similarly, TSD facilitated the development of AMP-induced sensitization, but only in the central locomotion parameter. The data indicate that an acute period of TSD may exacerbate the behavioral effects of AMP in mice. Because sleep architecture is composed of paradoxical and slow wave sleep, and 6-h PSD had no effects on AMP-induced hyperlocomotion or sensitization, our data suggest that the deprivation of slow wave sleep plays a critical role in the mechanisms that underlie the potentiating effects of TSD on both the acute and sensitized addiction-related responses to AMP.

Interconnectivity of sympathetic and sleep networks is mediated through reduction of gamma aminobutyric acidergic inhibition in the paraventricular nucleus

Chronic short sleep duration has been linked to sympathoexcitation and increased risk of cardiovascular disease. The central nervous system plays an important role in the regulation of sympathetic activity. Thus, the present study evaluates the pre-autonomic neurones in the paraventricular nucleus of the hypothalamus and rostral ventrolateral medulla after sleep restriction using various protein expression measurements and electrophysiological approaches. Wistar male rats were assigned randomly to two experimental groups: control or sleep restriction for 14days. Sleep restriction was defined as 20h of paradoxical sleep deprivation followed by a 4h sleep permission period using the modified multiple platform method. Micropunches of the paraventricular nucleus of the hypothalamus and rostral ventrolateral medulla were dissected to evaluate the protein expression of angiotensin II receptor, type 1 (AT1), AT2, gamma aminobutyric acidA ) (N-methyl-d-aspartate receptor1) and neuronal nitric oxide synthase neuronal nitric oxide synthase isoform through immunoblotting. Sleep restriction induced a down-regulation of the gamma aminobutyric acidA receptor in the paraventricular nucleus of the hypothalamus. Microinjection of bicuculline, a gamma aminobutyric acid receptor blocker, into the paraventricular nucleus of the hypothalamus increased renal sympathetic activity renal sympathetic nerve activity, mean arterial pressure and heart rate in anaesthetized control rats. However, the amplitude and frequency of renal sympathetic nerve activity was higher in the sleep restriction group. These findings suggest that gamma aminobutyric acidergic inhibition within the paraventricular nucleus of the hypothalamus is involved in sympathoexcitation induced by sleep restriction.

Anxiety-like effects of meta-chlorophenylpiperazine in paradoxically sleep-deprived mice

Chlorophenylpiperazines (CPP) are psychotropic drugs used in nightclub parties and are frequently used in a state of sleep deprivation, a condition which can potentiate the effects of psychoactive drugs. This study aimed to investigate the effects of sleep deprivation and sleep rebound (RB) on anxiety-like measures in mCPP-treated mice using the open field test. We first optimized our procedure by performing dose-effect curves and examining different pretreatment times in naïve male Swiss mice. Subsequently, a separate cohort of mice underwent paradoxical sleep deprivation (PSD) for 24 or 48h. In the last experiment, immediately after the 24h-PSD period, mice received an injection of saline or mCPP, but their general activity was quantified in the open field only after the RB period (24 or 48h). The dose of 5mgmL(-1) of mCPP was the most effective at decreasing rearing behavior, with peak effects 15min after injection. PSD decreased locomotion and rearing behaviors, thereby inhibiting a further impairment induced by mCPP. Plasma concentrations of mCPP were significantly higher in PSD 48h animals compared to the non-PSD control group. Twenty-four hours of RB combined with mCPP administration produced a slight reduction in locomotion. Our results show that mCPP was able to significantly change the behavior of naïve, PSD, and RB mice. When combined with sleep deprivation, there was a higher availability of drug in plasma levels. Taken together, our results suggest that sleep loss can enhance the behavioral effects of the potent psychoactive drug, mCPP, even after a period of rebound sleep.

Effects of sleep deprivation during pregnancy on the reproductive capability of the offspring

To investigate the effects of sleep deprivation during pregnancy on the reproductive capability of the offspring. Using a sleep loss model or control home-cage group (male and females rats) to evaluate sexual behavior and hormonal profile in males and females F1 offspring. Laboratory. First experiment: Pregnant females were exposed to sleep restriction (SR) protocol and the F1 generation was evaluated. Second experiment: male rats were submitted to SR or paradoxical sleep deprivation (PSD) protocol and the F1 generation was evaluated. Male and female rats were subjected to sleep restriction (SR) for 21 days or paradoxal sleep-deprived (PSD) for 96 hours. Sexual behavior and hormonal levels during the adult phase were analyzed in F1 offspring of female and male rats submitted to sleep loss. F1 male offspring of SR females had lower motivation for sex and reduced progesterone concentrations. In contrast, F1 female offspring displayed significantly enhanced proceptivity compared with control offspring. F1 female offspring also demonstrated hypersexuality by mounting the males in the absence of any significant hormonal alterations. F1 male offspring of SR or paradoxically sleep-deprived (PSD) males presented a decline in the sexual response, accompanied by a reduction in testosterone concentrations. Proceptivity was significantly increased among F1 female offspring of PSD and SR males compared with control offspring. SR in progenitors may alter sexual behavior of the F1 offspring in adulthood. These findings reveal far-reaching consequences of sleep deprivation, and suggest that parental sleep influences the reproductive capability of subsequent generations.

Susceptibility to life-threatening ventricular arrhythmias in an animal model of paradoxical sleep deprivation

BackgroundAccording to some reports regarding the increase of cardiac events following sleep deprivation, our study was conducted to clarify the effects of rapid eye movement (REM) sleep deprivation on susceptibility to lethal ventricular arrhythmias in rat. MethodsThe animal groups included the control group; the sham 48 and sham 72 groups (without sleep deprivation); and the test 48 and test 72 groups, who experienced REM sleep deprivation for 48h and 72h, respectively. For induction of cardiac arrhythmia, aconitine was infused via the tail vein of the animals. ResultsAfter 72h of REM sleep deprivation, the blood pressure (BP) levels and the QTc interval of the electrocardiogram (ECG) were significantly increased (P<.05 and P<.01, respectively). However, the sleep deprivation had no significant effect on the heart rate (HR), myocardial oxygen consumption index, and plasma corticosterone level. Furthermore, sleep deprivation increased the latency times of premature ventricular contraction (PVC), ventricular tachycardia (VT), and also the PVC number; however, it did not increase the number, duration, and severity of VT and ventricular fibrillation (VF). ConclusionOur findings suggest that 72h of REM sleep deprivation is associated with increased risk for hypertension and QT interval prolongation under nonstressful conditions; however, it does not increase the susceptibility to lethal ventricular arrhythmia in rat.

Nitric oxide modulates the hyperalgesic response to mechanical noxious stimuli in sleep-deprived rats.

BackgroundSleep restriction alters pain perception in animals and humans, and many studies have indicated that paradoxical sleep deprivation (PSD) promotes hyperalgesia. The hyperalgesia observed after mechanical nociceptive stimulus is reversed through nitric oxide synthase (NOS) inhibition. Both nitric oxide (NO) and the dorsolateral periaqueductal gray matter (dlPAG) area of the brainstem are involved in hyperalgesia. Thus, in this work, we investigated the pain-related behavior response after mechanical noxious stimuli (electronic von Frey test), and the activity of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), an indicator of NOS activity, within the dlPAG of paradoxical sleep-deprived rats. We also evaluated the effects of pre-treatment with L-NAME on these parameters.ResultsThese data revealed that PSD reduced the hindpaw withdrawal threshold (−47%, p < 0.0001) confirming the hyperalgesic effect of this condition. In addition, there were more NADPH-d positive cells in dlPAG after PSD than in control rats (+ 59%, p < 0.0001). L-NAME treatment prevented the reduction in the hindpaw withdrawal threshold (+ 93%, p < 0.0001) and the increase in the NADPH-d positive cells number in the dlPAG of PSD-treated rats (−36%, p < 0.0001).ConclusionThese data suggest that the hyperalgesic response to mechanical noxious stimuli in paradoxical sleep-deprived rats is associated with increased NOS activity in the dlPAG, which presumably influences the descending antinociceptive pathway.

Modafinil ameliorates cognitive deficits induced by maternal separation and sleep deprivation

Animals exposed to an early adverse event may be more susceptible to a second source of stress later in life, and these stressors may have additive deleterious effects. Sleep deprivation is known to be a stressor, affecting multiple body functions such as the cognition. Modafinil enhances working memory and attention in healthy non-sleep deprived subjects and in animal models of sleep deprivation. The first aim of the present study was to investigate the effects of maternal separation (MS) combined with paradoxical sleep deprivation (PSD) in adulthood on recognition memory in rats. Second, we aimed to evaluate whether the administration of modafinil would be able to ameliorate memory deficits induced by MS and PSD. Wistar rat pups were initially distributed into MS and handling (H) groups, with their litters standardized in 4 females and 4 males. In adulthood, the male rats were submitted to PSD or control condition, being redistributed afterwards in modafinil- or vehicle-treatment immediately after the training session of object recognition task. PSD did not potentiate the cognitive deficit due to MS. However, modafinil was able to recover memory impairments associated to PSD and also to MS in the neonatal period. This study demonstrates for the first time that modafinil ameliorates cognitive deficits associated to MS and to PSD in adulthood, independent from MS in the neonatal period.

Aerobic exercise attenuates inhibitory avoidance memory deficit induced by paradoxical sleep deprivation in rats

The deleterious effects of paradoxical sleep deprivation (SD) on memory processes are well documented. Physical exercise improves many aspects of brain functions and induces neuroprotection. In the present study, we investigated the influence of 4 weeks of treadmill aerobic exercise on both long-term memory and the expression of synaptic proteins (GAP-43, synapsin I, synaptophysin, and PSD-95) in normal and sleep-deprived rats. Adult Wistar rats were subjected to 4 weeks of treadmill exercise training for 35min, five times per week. Twenty-four hours after the last exercise session, the rats were sleep-deprived for 96h using the modified multiple platform method. To assess memory after SD, all animals underwent training for the inhibitory avoidance task and were tested 24h later. The aerobic exercise attenuated the long-term memory deficit induced by 96h of paradoxical SD. Western blot analysis of the hippocampus revealed increased levels of GAP-43 in exercised rats. However, the expression of synapsin I, synaptophysin, and PSD-95 was not modified by either exercise or SD. Our results suggest that an aerobic exercise program can attenuate the deleterious effects of SD on long-term memory and that this effect is not directly related to changes in the expression of the pre- and post-synaptic proteins analyzed in the study.