Rapid Eye Movement Sleep Loss Research Articles

REM Sleep Loss-Induced Elevated Noradrenaline Plays a Significant Role in Neurodegeneration: Synthesis of Findings to Propose a Possible Mechanism of Action from Molecule to Patho-Physiological Changes.

Wear and tear are natural processes for all living and non-living bodies. All living cells and organisms are metabolically active to generate energy for their routine needs, including for survival. In the process, the cells are exposed to oxidative load, metabolic waste, and bye-products. In an organ, the living non-neuronal cells divide and replenish the lost or damaged cells; however, as neuronal cells normally do not divide, they need special feature(s) for their protection, survival, and sustenance for normal functioning of the brain. The neurons grow and branch as axons and dendrites, which contribute to the formation of synapses with near and far neurons, the basic scaffold for complex brain functions. It is necessary that one or more basic and instinct physiological process(es) (functions) is likely to contribute to the protection of the neurons and maintenance of the synapses. It is known that rapid eye movement sleep (REMS), an autonomic instinct behavior, maintains brain functioning including learning and memory and its loss causes dysfunctions. In this review we correlate the role of REMS and its loss in synaptogenesis, memory consolidation, and neuronal degeneration. Further, as a mechanism of action, we will show that REMS maintains noradrenaline (NA) at a low level, which protects neurons from oxidative damage and maintains neuronal growth and synaptogenesis. However, upon REMS loss, the level of NA increases, which withdraws protection and causes apoptosis and loss of synapses and neurons. We propose that the latter possibly causes REMS loss associated neurodegenerative diseases and associated symptoms.

A Study on REM Sleep Homeostasis in the Day-Active Tree Shrew (Tupaia belangeri): Cold-Induced Suppression of REM Sleep Is Not Followed by a Rebound.

The function and regulation of rapid-eye-movement (REM) sleep is a topic of ongoing debate. It is often assumed that REM sleep is a homeostatically regulated process and that a need for REM sleep builds up, either during prior wakefulness or during preceding slow wave sleep. In the current study, we tested this hypothesis in six diurnal tree shrews (Tupaia belangeri), small mammals closely related to primates. All animals were individually housed and kept under a 12:12 light-dark cycle with an ambient temperature of 24 °C. We recorded sleep and temperature in the tree shrews for 3 consecutive 24 h days. During the second night, we exposed the animals to a low ambient temperature of 4 °C, a procedure that is known to suppress REM sleep. Cold exposure caused a significant drop in brain temperature and body temperature and also resulted in a strong and selective suppression of REM sleep by 64.9%. However, contrary to our expectation, the loss of REM sleep was not recovered during the subsequent day and night. These findings in a diurnal mammal confirm that the expression of REM sleep is highly sensitive to environmental temperature but do not support the view that REM sleep is homeostatically regulated in this species.

Sleep and Neuroimmunomodulation for Maintenance of Optimum Brain Function: Role of Noradrenaline.

Immune function and sleep are two normal physiological processes to protect the living organism from falling sick. There is hardly any disease in which they remain unaffected, though the quantum of effect may differ. Therefore, we propose the existence of a strong correlation between sleep (quality or quantity) and immune response. This may be supported by the fact that sleep loss modulates many of the immunological molecules, which includes interferons; however, not much is known about their mechanism of action. Sleep is divided into rapid eye movement sleep (REMS) and non-REMS. For practical reasons, experimental studies have been conducted mostly by inducing loss of REMS. It has been shown that withdrawal of noradrenaline (NA) is a necessity for generation of REMS. Moreover, NA level increases in the brain upon REMS loss and the elevated NA is responsible for many of the sleep loss-associated symptoms. In this review, we describe how sleep (and its disturbance/loss) modulates the immune system by modulating the NA level in the brain or vice versa to maintain immune functions, physiological homeostasis, and normal healthy living. The increased levels of NA during REMS loss may cause neuroinflammation possibly by glial activation (as NA is a key modulator of microglia). Therefore, maintaining sleep hygiene plays a crucial role for a normal healthy living.

NREM sleep loss increases neurofilament light chain levels in APP/PS1 and C57BL/6J mice.

Sleep disturbances exacerbate the progression of Alzheimer's disease (AD), but disturbances of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep may have different effects. Neurofilament light chain (NfL), an axon-specific protein, is an indicator of the severity of neuronal apoptosis. To investigate whether or notNREM or REM sleep is crucial to neuronal survival, we examined the effects of induced NREM or REM sleep loss on NfL levels in APP/PS1 mice, a model of AD, and their wild-type (WT) C57BL/6J littermates. At 6months of age, WT mice and AD mice were equally divided into six groups, namely, the WT-normal sleep (S), WT-total sleep deprivation (TSD), WT-REM deprivation (RD), AD-S, AD-TSD and AD-RD groups, according to the type of sleep intervention applied. All mice underwent 6days of sleep intervention. Cerebrospinal fluid (CSF) and plasma NfL levels were measured at baseline and on days 2, 4 and 6, and spatial memory was assessed in the Morris water maze (MWM) test. Among the 18 WT and 18 AD mice,CSF and plasma NfL levels were higher in AD-TSD mice than in AD-S or AD-RD mice, while no significant difference was observed between the latter two groups. In AD-TSD mice, CSF and plasma NfL levels increased with the duration of sleep deprivation. A similar pattern of results was observed for the WT groups. NREM sleep loss may increase CSF and plasma NfL levels in both WT and AD mice.

Polysomnographic Indicators of Restorative Sleep and Body Mass Trajectories in the Wisconsin Sleep Cohort Study

Previous research suggests that reductions in restorative sleep—i.e., slow-wave (N3) and rapid-eye movement (REM) sleep—are associated with weight gain and obesity in mid-to-late life. This study extends prior work by examining how within-person changes and between-person differences in restorative sleep are associated with body mass trajectories among participants in the Wisconsin Sleep Cohort Study (WSCS). We used data from 4,862 polysomnographic sleep studies and physical exams collected from 1,187 WSCS participants over an average follow-up duration of 15 years. For both men and women, we found that (1) below-average N3 and REM sleep is associated with above-average BMI, and (2) within-person loss of N3 and REM sleep is associated with larger gains in BMI, particularly between ages 30-50. Our findings highlight the importance of restorative sleep in mid-to-late life, suggesting that future clinical treatments and public health policies will benefit from heightened attention to sleep quality.

REM sleep loss-induced elevated noradrenaline could predispose an individual to psychosomatic disorders: a review focused on proposal for prediction, prevention, and personalized treatment.

Historically and traditionally, it is known that sleep helps in maintaining healthy living. Its duration varies not only among individuals but also in the same individual depending on circumstances, suggesting it is a dynamic and personalized physiological process. It has been divided into rapid eye movement sleep (REMS) and non-REMS (NREMS). The former is unique that adult humans spend the least time in this stage, when although one is physically asleep, the brain behaves as if awake, the dream state. As NREMS is a pre-requisite for appearance of REMS, the latter can be considered a predictive readout of sleep quality and health. It plays a protective role against oxidative, stressful, and psychopathological insults. Several modern lifestyle activities compromise quality and quantity of sleep (including REMS) affecting fundamental physiological and psychopathosomatic processes in a personalized manner. REMS loss-induced elevated brain noradrenaline (NA) causes many associated symptoms, which are ameliorated by preventing NA action. Therefore, we propose that awareness about personalized sleep hygiene (including REMS) and maintaining optimum brain NA level should be of paramount significance for leading physical and mental well-being as well as healthy living. As sleep is a dynamic, multifactorial, homeostatically regulated process, for healthy living, we recommend addressing and treating sleep dysfunctions in a personalized manner by the health professionals, caregivers, family, and other supporting members in the society. We also recommend that maintaining sleep profile, optimum level of NA, and/or prevention of elevation of NA or its action in the brain must be seriously considered for ameliorating lifestyle and REMS disturbance-associated dysfunctions.

The Brain-Derived Neurotrophic Factor: Missing Link Between Sleep Deprivation, Insomnia, and Depression.

The brain-derived neurotrophic factor (BDNF) mediates the plasticity-related changes that associate with memory processing during sleep. Sleep deprivation and chronic stress are associated with propensity to depression, anxiety, and insomnia. We propose a model by which explain alterations in the CNS and serum expression of BDNF associated with chronic sleep deprivation, depression, and insomnia. Mild sleep deprivation activates the cerebral cortex and brainstem to generate the physiologic drive for non-rapid eye movement (NREM) and rapid eye movement (REM) sleep drive respectively, associated with BDNF upregulation in these regions. This physiological response loses effectiveness with longer episodes or during chronic of total or selective REM sleep loss, which are associated with impaired hippocampal BDNF expression, impaired memory and cognition. Chronic sleep deprivation and insomnia can act as an external stressors and result in depression, characterized by hippocampal BDNF downregulation along with disrupted frontal cortical BDNF expression, as well as reduced levels and impaired diurnal alterations in serum BDNF expression. Acute REM sleep deprivation breaks the cycle by restoration of hippocampal, and possibly restoration of cortical and serum expression of BDNF. The BDNF Val66Met polymorphism alters susceptibility to depression, anxiety, and insomnia by altering availability and expression of BDNF in brain and blood. The proposed model is testable and implies that low levels and low variability in serum BDNF are associated with poor response to anti-depressive medications, electroconvulsive therapy, and REM sleep deprivation, in patients with depression. Our mode is also backed up by the existing clinical evidence but is yet to be investigated.

Obstructive Sleep Apnea and Sleep Architecture in Adolescents With Severe Obesity: Effects of a 9-Month Lifestyle Modification Program Based on Regular Exercise and a Balanced Diet.

Physical exercise and lifestyle modification are recognized as adjunct therapy for obstructive sleep apnea (OSA) in overweight adults. The objectives of this study were to investigate the effects of long-term physical exercise combined with a balanced diet on sleep architecture, sleep duration, and OSA in adolescents with severe obesity. This interventional study was conducted in a nursing institution. Participants were aged 14.6 ± 1.2 years with obesity (body mass index (BMI) = 40.2 ± 6.5 kg/m2). At admission and at 9 months, participants underwent ambulatory polysomnography and incremental maximal exercise testing to determine cardiorespiratory fitness. Twenty-four subjects completed the study. Analyses were performed on the whole population and on a subgroup of subjects with OSA (OSA-subgroup). OSA, defined as obstructive apnea-hypopnea index (OAHI) ≥ 2 events/h, was diagnosed in 58.3% of the population. OAHI was only associated with fat mass in males (r = .75, P < .05). At 9 months postintervention, weight loss (-11.1 kg, P < .0001) and improved cardiorespiratory fitness (VO2peak: +4.9 mL/min/kg, P < .001) were found in the whole population. Sleep duration was increased (+34 minutes, P < .05) and sleep architecture was changed with an increase of rapid eye movement sleep (+2.5%, P < .05) and a decrease of stage N3 sleep (-3.1%, P < .001). Similar results were found in the OSA subgroup. However, OAHI remained unchanged (P = .18). A combination of supervised aerobic exercise and a balanced diet led to weight loss, improved aerobic capacity, and modified sleep architecture without changes in OSA. A commentary on this article appears in this issue on page 907. Registry: ClinicalTrials.gov, Title: Exercise and Venous Compression on Upper Airway Resistance in Obese Teenagers With OSA (OBESOMAC), URL: https://clinicaltrials.gov/ct2/show/NCT02588469, Identifier: NCT02588469.

Fur Seals Suppress REM Sleep for Very Long Periods without Subsequent Rebound

Virtually all land mammals and birds have two sleep states: slow-wave sleep (SWS) and rapid eye movement (REM) sleep [1, 2]. After deprivation of REM sleep by repeated awakenings, mammals increase REM sleep time [3], supporting the idea that REM sleep is homeostatically regulated. Some evidence suggests that periods of REM sleep deprivation for a week or more cause physiological dysfunction and eventual death [4, 5]. However, separating the effects of REM sleep loss from the stress of repeated awakening is difficult [2, 6]. The northern fur seal (Callorhinus ursinus) is a semiaquatic mammal [7]. It can sleep on land and in seawater. The fur seal is unique in showing both the bilateral SWS seen in most mammals and the asymmetric sleep previously reported in cetaceans [8]. Here we show that when the fur seal stays in seawater, where it spends most of its life [7], it goes without or greatly reduces REM sleep for days or weeks. After this nearly complete elimination of REM, it displays minimal or no REM rebound upon returning to baseline conditions. Our data are consistent with the hypothesis that REM sleep may serve to reverse the reduced brain temperature and metabolism effects of bilateral nonREM sleep, a state that is greatly reduced when the fur seal is in the seawater, rather than REM sleep being directly homeostatically regulated. This can explain the absence of REM sleep in the dolphin and other cetaceans and its increasing proportion as the end of thesleep period approaches in humans and other mammals.

Clinical Features and Sleep Analysis of Chinese Patients with Fatal Familial Insomnia

This study aimed to examine clinical features, sleep, abnormal sleep-wake transition and non-sleep disturbances as well as lab tests in Chinese fatal familial insomnia (FFI) subjects. Patients with confirmed clinical and laboratory diagnosis of FFI have been retrospectively reviewed. The clinical features and the results of the complementary tests, including polysomnography (PSG), brain imaging and genetic analysis, were used. Two male and three female patients were recruited in this study. Three of the five patients had more comprehensive family medical records. The most typical clinical manifestations in all 5 patients were sleep disturbances, including insomnia, laryngeal stridor, sleep breath disturbance, and sleep-related involuntary movements. PSG of all these five cases showed reduction in total sleep time, sleep fragmentation, abnormal short non-rapid eye movement - rapid eye movement (REM) cycling, REM sleep reduction or loss, and REM sleep instruction in wakefulness. Patient 2's emission tomography scan demonstrated a reduction in glucose uptake in the left thalamus and bilateral inferior parietal lobe. In summary, Chinese FFI patients are typically characterized by organic sleep related symptoms, rapidly progressive dementia and sympathetic symptoms. We propose that structural damages in the thalamus and cortex are mostly responsible for clinical manifestations of FFI.

Transcriptome Analysis Reveals Altered Expression of Memory and Neurotransmission Associated Genes in the REM Sleep Deprived Rat Brain.

Sleep disorders are associated with cognitive impairment. Selective rapid eye movement sleep (REMS) deprivation (REMSD) alters several physiological processes and behaviors. By employing NGS platform we carried out transcriptomic analysis in brain samples of control rats and those exposed to REMSD. The expression of genes involved in chromatin assembly, methylation, learning, memory, regulation of synaptic transmission, neuronal plasticity and neurohypophysial hormone synthesis were altered. Increased transcription of BMP4, DBH and ATP1B2 genes after REMSD supports our earlier findings and hypothesis. Alteration in the transcripts encoding histone subtypes and important players in chromatin remodeling was observed. The mRNAs which transcribe neurotransmitters such as OXT, AVP, PMCH and LNPEP and two small non-coding RNAs, namely RMRP and BC1 were down regulated. At least some of these changes are likely to regulate REMS and may participate in the consequences of REMS loss. Thus, the findings of this study have identified key epigenetic regulators and neuronal plasticity genes associated to REMS and its loss. This analysis provides a background and opens up avenues for unraveling their specific roles in the complex behavioral network particularly in relation to sustained REMS-loss associated changes.

Wake-sleep and cardiovascular regulatory changes in rats made obese by a high-fat diet

Obesity is known to be associated with alterations in wake-sleep (WS) architecture and cardiovascular parameters. This study was aimed at assessing the possible influence of diet-induced obesity (DIO) on sleep homeostasis and on the WS state‐dependent levels of arterial pressure (AP) and heart rate in the rat. Two groups of age-matched Sprague-Dawley rats were fed either a high-fat hypercaloric diet, leading to DIO, or a normocaloric standard diet (lean controls) for 8 weeks. While under general anesthesia, animals were implanted with instrumentation for the recording of electroencephalogram, electromyogram, arterial pressure, and deep brain temperature. The experimental protocol consisted of 48h of baseline, 12h of gentle handling, enhancing wake and depressing sleep, and 36-h post-handling recovery. Compared to lean controls, DIO rats showed: i) the same amount of rapid-eye movement (REM) and non-REM (NREM) sleep in the rest period, although the latter was characterized by more fragmented episodes; ii) an increase in both REM sleep and NREM sleep in the activity period; iii) a comparable post-handling sleep homeostatic response, in terms of either the degree of Delta power increase during NREM sleep or the quantitative compensation of the REM sleep loss at the end of the 36-h recovery period; iv) significantly higher levels of AP, irrespectively of the different WS states and of the changes in their intensity throughout the experimental protocol. Overall, these changes may be the reflection of a modification in the activity of the hypothalamic areas where WS, autonomic, and metabolic regulations are known to interact.

Chemogenetic inhibition of the medial prefrontal cortex reverses the effects of REM sleep loss on sucrose consumption.

Rapid eye movement (REM) sleep loss is associated with increased consumption of weight-promoting foods. The prefrontal cortex (PFC) is thought to mediate reward anticipation. However, the precise role of the PFC in mediating reward responses to highly palatable foods (HPF) after REM sleep deprivation is unclear. We selectively reduced REM sleep in mice over a 25-48 hr period and chemogenetically inhibited the medial PFC (mPFC) by using an altered glutamate-gated and ivermectin-gated chloride channel that facilitated neuronal inhibition through hyperpolarizing infected neurons. HPF consumption was measured while the mPFC was inactivated and REM sleep loss was induced. We found that REM sleep loss increased HPF consumption compared to control animals. However, mPFC inactivation reversed the effect of REM sleep loss on sucrose consumption without affecting fat consumption. Our findings provide, for the first time, a causal link between REM sleep, mPFC function and HPF consumption.

Rapid Eye Movement Sleep Deprivation Induces Neuronal Apoptosis by Noradrenaline Acting on Alpha1 Adrenoceptor and by Triggering Mitochondrial Intrinsic Pathway.

Many neurodegenerative disorders are associated with rapid eye movement sleep (REMS) loss; however, the mechanism was unknown. As REMS loss elevates noradrenaline (NA) level in the brain as well as induces neuronal apoptosis and degeneration, in this study, we have delineated the intracellular molecular pathway involved in REMS deprivation (REMSD)-associated NA-induced neuronal apoptosis. Rats were REMS deprived for 6 days by the classical flower pot method; suitable controls were conducted and the effects on apoptosis markers evaluated. Further, the role of NA was studied by one, intraperitoneal (i.p.) injection of NA-ergic alpha1 adrenoceptor antagonist prazosin (PRZ) and two, by downregulation of NA synthesis in locus coeruleus (LC) neurons by local microinjection of tyrosine hydroxylase siRNA (TH-siRNA). Immunoblot estimates showed that the expressions of proapoptotic proteins viz. Bcl2-associated death promoter protein, apoptotic protease activating factor-1 (Apaf-1), cytochrome c, caspase9, caspase3 were elevated in the REMS-deprived rat brains, while caspase8 level remained unaffected; PRZ treatment did not allow elevation of these proapoptotic factors. Further, REMSD increased cytochrome c expression, which was prevented if the NA synthesis from the LC neurons was blocked by microinjection of TH-siRNA in vivo into the LC during REMSD in freely moving normal rats. Mitochondrial damage was re-confirmed by transmission electron microscopy, which showed distinctly swollen mitochondria with disintegrated cristae, chromosomal condensation, and clumping along the nuclear membrane, and all these changes were prevented in PRZ-treated rats. Combining findings of this study along with earlier reports, we propose that upon REMSD NA level increases in the brain as the LC, NA-ergic REM-OFF neurons do not cease firing and TH is upregulated in those neurons. This elevated NA acting on alpha1 adrenoceptors damages mitochondria causing release of cytochrome c to activate intrinsic pathway for inducing neuronal apoptosis in REMS-deprived rat brain.

REM sleep and its Loss-Associated Epigenetic Regulation with Reference to Noradrenaline in Particular.

Sleep is an essential physiological process, which has been divided into rapid eye movement sleep (REMS) and non-REMS (NREMS) in higher animals. REMS is a unique phenomenon that unlike other sleep-waking states is not under voluntary control. Directly or indirectly it influences or gets influenced by most of the physiological processes controlled by the brain. It has been proposed that REMS serves housekeeping function of the brain. Extensive research has shown that during REMS at least noradrenaline (NA) -ergic neurons must cease activity and upon REMS loss, there are increased levels of NA in the brain, which then induces many of the REMS loss associated acute and chronic effects. The NA level is controlled by many bio-molecules that are regulated at the molecular and transcriptional levels. Similarly, NA can also directly or indirectly modulate the synthesis and levels of many molecules, which in turn may affect physiological processes. The burgeoning field of behavioral neuroepigenetics has gained importance in recent years and explains the regulatory mechanisms underlying several behavioral phenomena. As REMS and its loss associated changes in NA modulate several pathophysiological processes, in this review we have attempted to explain on one hand how the epigenetic mechanisms regulating the gene expression of factors like tyrosine hydroxylase (TH), monoamine oxidase (MAO), noradrenaline transporter (NAT) control NA levels and on the other hand, how NA per se can affect other molecules in neural circuitry at the epigenetic level resulting in behavioral changes in health and diseases. An understanding of these events will expose the molecular basis of REMS and its loss-associated pathophysiological changes; which are presented as a testable hypothesis for confirmation.

REM Sleep Loss and Recovery Regulates Blood-Brain Barrier Function

The functions of rapid eye movement (REM) sleep have remained elusive since more than 50 years. Previous reports have identified several independent processes affected by the loss and subsequent recovery of REM sleep (hippocampal neurogenesis, brain stem neuronal cell death, and neurotransmitter content in several brain regions); however, a common underlying mechanism has not been found. We propose that altered brain homeostasis secondary to blood-brain barrier breakdown may explain all those changes induced by REM sleep loss. Therefore, the present report aimed to study the consequences of REM sleep restriction upon blood-brain barrier permeability to Evans blue. REM sleep restriction was induced by the multiple platform technique; male rats were REM sleep restricted 20h daily (with 4h sleep opportunity) during 10 days; control groups included large platform and intact rats. To study blood-brain barrier permeability Evans blue was intracardially administered; stained brains were sliced and photographed for optical density quantification. An independent experiment was carried out to elucidate the mechanism of blood-brain breakdown by transmission electron microscopy. REM sleep restriction increased blood-brain barrier permeability to Evans blue in the whole brain as compared to both control groups. Brief periods of sleep recovery rapidly and effectively restored the severe alteration of blood-brain barrier function by reducing blood-to-brain transfer of Evans blue. The mechanism of blood-brain barrier breakdown involved increased caveolae formation at brain endothelial cells. In conclusion, our data suggest that REM sleep regulates the physical barrier properties of the blood-brain barrier.

REM sleep loss increases brain excitability: Role of noradrenalin and its mechanism of action

Ever since the discovery of rapid eye movement sleep (REMS), studies have been undertaken to understand its necessity, function and mechanism of action on normal physiological processes as well as in pathological conditions. In this review, first, we briefly surveyed the literature which led us to hypothesise REMS maintains brain excitability. Thereafter, we present evidence from in vivo and in vitro studies tracing behavioural to cellular to molecular pathways showing REMS deprivation (REMSD) increases noradrenaline level in the brain, which stimulates neuronal Na-K ATPase, the key factor for maintaining neuronal excitability, the fundamental property of a neuron for executing brain functions; we also show for the first time the role of glia in maintaining ionic homeostasis in the brain. As REMSD exerts a global effect on most of the physiological processes regulated by the brain, we propose that REMS possibly serves a housekeeping function in the brain. Finally, subject to confirmation from clinical studies, based on the results reviewed here, it is being proposed that the subjects suffering from REMS loss may be effectively treated by reducing either noradrenaline level or Na-K ATPase activity in the brain.

Mechanism of noradrenaline-induced stimulation of Na–K ATPase activity in the rat brain: implications on REM sleep deprivation-induced increase in brain excitability

Rapid eye movement (REM) sleep is a unique phenomenon expressed in all higher forms of animals. Its quantity varies in different species and with ageing; it is also affected in several psycho-somatic disorders. Several lines of studies showed that after REM sleep loss, the levels of noradrenaline (NA) increase in the brain. The NA in the brain modulates neuronal Na-K ATPase activity, which helps maintaining the brain excitability status. The detailed mechanism of increase in NA level after REM sleep loss and the effect of NA on stimulation of Na-K ATPase in the neurons have been discussed. The findings have been reviewed and discussed with an aim to understand the role of REM sleep in maintaining brain excitability status.

Spontaneous sleep and homeostatic sleep regulation in ghrelin knockout mice

Ghrelin is well known for its feeding and growth hormone-releasing actions. It may also be involved in sleep regulation; intracerebroventricular administration and hypothalamic microinjections of ghrelin stimulate wakefulness in rats. Hypothalamic ghrelin, together with neuropeptide Y and orexin form a food intake-regulatory circuit. We hypothesized that this circuit also promotes arousal. To further investigate the role of ghrelin in the regulation of sleep-wakefulness, we characterized spontaneous and homeostatic sleep regulation in ghrelin knockout (KO) and wild-type (WT) mice. Both groups of mice exhibited similar diurnal rhythms with more sleep and less wakefulness during the light period. In ghrelin KO mice, spontaneous wakefulness and rapid-eye-movement sleep (REMS) were slightly elevated, and non-rapid-eye-movement sleep (NREMS) was reduced. KO mice had more fragmented NREMS than WT mice, as indicated by the shorter and greater number of NREMS episodes. Six hours of sleep deprivation induced rebound increases in NREMS and REMS and biphasic changes in electroencephalographic slow-wave activity (EEG SWA) in both genotypes. Ghrelin KO mice recovered from NREMS and REMS loss faster, and the delayed reduction in EEG SWA, occurring after sleep loss-enhanced increases in EEG SWA, was shorter-lasting compared with WT mice. These findings suggest that the basic sleep-wake regulatory mechanisms in ghrelin KO mice are not impaired and they are able to mount adequate rebound sleep in response to a homeostatic challenge. It is possible that redundancy in the arousal systems of the brain or activation of compensatory mechanisms during development allow for normal sleep-wake regulation in ghrelin KO mice.

Increased apoptosis in rat brain after rapid eye movement sleep loss

Rapid eye movement (REM) sleep loss impairs several physiological, behavioral and cellular processes; however, the mechanism of action was unknown. To understand the effects of REM sleep deprivation on neuronal damage and apoptosis, studies were conducted using multiple apoptosis markers in control and experimental rat brain neurons located in areas either related to or unrelated to REM sleep regulation. Furthermore, the effects of REM sleep deprivation were also studied on neuronal cytoskeletal proteins, actin and tubulin. It was observed that after REM sleep deprivation a significantly increased number of neurons in the rat brain were positive to apoptotic markers, which however, tended to recover after the rats were allowed to undergo REM sleep; the control rats were not affected. Further, it was also observed that REM sleep deprivation decreased amounts of actin and tubulin in neurons confirming our previous reports of changes in neuronal size and shape after such deprivation. These findings suggest that one of the possible functions of REM sleep is to protect neurons from damage and apoptosis.