Lack of rebound of non-rapid eye movement sleep after sleep deprivation in adenosine A2A receptor knockout mice

Sleep and Biological Rhythms -     

Promotion of non-rapid eye movement sleep in mice after oral administration of ornithine

We examined the effects of ornithine on the sleep-wake cycle by monitoring the electroencephalo-gram, electromyogram, and locomotor activity of freely moving mice after oral administration of it at lights-off time (18:00). Ornithine (1.0 and 3.0 g/kg of body weight) increased the amount of non-rapid eye movement (non-REM, NREM) sleep for 2 h after its administration, with a peak at 60 min post administration, to 164% and 198%, respectively, of that of the vehicle-administered mice, without changing the amount of REM sleep. The administration of ornithine at a lower dose (0.3 g/kg of body weight) did not increase the amount of NREM sleep compared with the vehicle administration. Ornithine did not affect the power spectrum density of NREM sleep but increased the number of episodes of wakefulness and NREM sleep and that of transitions between wakefulness and NREM sleep, and decreased the mean duration of wake episodes in a dose-dependent manner for 2 h after the oral administration. These results indicate that ornithine increased the amount of NREM sleep without reducing the power spectrum density of NREM sleep.

     

Inhibition of caspase-1 in rat brain reduces spontaneous nonrapid eye movement sleep and nonrapid eye movement sleep enhancement induced by lipopolysaccharide

Evidence suggests that IL-1beta is involved in promoting physiological nonrapid eye movement (NREM) sleep. IL-1beta has also been proposed to mediate NREM sleep enhancement induced by bacteria or their components. Mature and biologically active IL-1beta is cleaved from an inactive precursor by a cysteinyl aspartate-specific protease (caspase)-1. This study aimed to test the hypothesis that inhibition in brain of the cleavage of biologically active IL-1beta will reduce in rats both spontaneous NREM sleep and NREM sleep enhancement induced by the peripheral administration of components of the bacterial cell wall. To test this hypothesis, rats were intracerebroventricularly administered the caspase-1 inhibitor Ac-Tyr-Val-Ala-Asp chloromethyl ketone (YVAD; 3, 30, 300, and 1,500 ng) or were pretreated intracerebroventricularly with YVAD (300 ng) and then intraperitoneally injected with the gram-negative bacterial cell wall component LPS (250 microg/kg). Subsequent sleep-wake behavior was determined by standard polygraphic recordings. YVAD administration at the beginning of the light phase of the light-dark cycle significantly reduced time spontaneously spent in NREM sleep during the first 12 postinjection hours. YVAD pretreatment also completely prevented NREM sleep enhancement induced by peripheral LPS administration at the beginning of the dark phase. These results, in agreement with previous evidence, support the involvement of brain IL-1beta in physiological promotion of NREM sleep and in mediating NREM sleep enhancement induced by peripheral immune challenge.     

Photoperiod alters duration and intensity of non-rapid eye movement sleep following immune challenge in Siberian hamsters (Phodopus sungorus)

Sleep is regulated by circadian and homeostatic processes, but can be altered by infectious disease. During infection or exposure to inflammatory stimuli, such as bacterial lipopolysaccharide (LPS), the duration and intensity of non-rapid eye movement sleep (NREMS), as measured by electoencephalogram (EEG) delta waves (.5-4 Hz), increase. These sleep alterations are hypothesized to conserve or redirect energy for immune system activation. Many vertebrates exhibit seasonal changes in immune function and sleep-wake cycle, and photoperiod (day length) serves as a reliable environmental cue. For example, winter is energetically demanding for most animals, and Siberian hamsters (Phodopus sungorus) adapted to short winter day lengths display reduced fever after LPS administration to presumably conserve energy. We hypothesized that short days increase the duration and intensity of NREMS after LPS challenge to create additional energy savings, despite evidence to the contrary that high fever is associated with increased NREMS. Male hamsters were housed under long (16 h light (L):8 h dark (D)) or short (8L:16D) day lengths, and chronically implanted with transmitters that recorded EEG and electromyogram (EMG) biopotentials simultaneously or core body temperature. After >10 wks in photoperiod conditions, hamsters received an i.p. injection of LPS or saline (control), and vigilance states (duration and distribution of NREMS, rapid eye movement sleep (REMS), and wakefulness) and EEG delta power spectra (NREMS intensity) were assessed. As expected, LPS treatment increased the duration and intensity of NREMS compared to controls. Hamsters adapted to short photoperiods exhibited cumulatively larger increases in NREMS duration and EEG delta wave amplitude 0-8 h after LPS injection compared to long-day LPS-treated hamsters despite short-day attenuation of fever. These results suggest a seasonal decoupling of LPS-induced fever with sleep to promote energy conservation during predictable energy shortages. Ultimately, the combination of increased sleep and reduced fever could represent a suite of physiological adaptations that increase the probability of surviving winter.     

Pontogeniculooccipital waves: spontaneous visual system activity during rapid eye movement sleep

1. Pontogeniculooccipital (PGO) waves are recorded during rapid eye movement (REM) sleep from the pontine reticular formation, lateral geniculate bodies, and occipital cortex of many species. 2. PGO waves are associated with increased visual system excitability but arise spontaneously and not via stimulation of the primary visual afferents. Both auditory and somatosensory stimuli influence PGO wave activity. 3. Studies using a variety of techniques suggest that the pontine brain stem is the site of PGO wave generation. Immediately prior to the appearance of PGO waves, neurons located in the region of the brachium conjunctivum exhibit bursts of increased firing, while neurons in the dorsal raphe nuclei show a cessation of firing. 4. The administration of pharmacological agents antagonizing noradrenergic or serotonergic neurotransmission increases the occurrence of PGO waves independent of REM sleep. Cholinomimetic administration increases the occurrence of both PGO waves and other components of REM sleep. 5. Regarding function, the PGO wave-generating network has been postulated to inform the visual system about eye movements, to promote brain development, and to facilitate the response to novel environmental stimuli.     

Interleukin 1beta enhances non-rapid eye movement sleep and increases c-Fos protein expression in the median preoptic nucleus of the hypothalamus

Both temporary access to a running wheel and temporary exposure to light systematically influence the phase producing entrainment of the circadian activity rhythm in the golden hamster (Mesocricetus auratus). However, precise determination of entrainment limits remains methodologically difficult, because such calculations may be influenced by varying experimental paradigms. In this study, effects on the entrainment of the activity pattern during successive light-dark (LD) cycles of stepwise decreasing periods, as well as wheel running activity, were investigated. In particular, the hamster activity rhythm under LD cycles with a period (T) shorter than 22 h was studied, i.e., when the LD cycle itself had been shown to be an insufficiently strong zeitgeber to synchronize activity rhythms. Indeed, it was confirmed that animals without a wheel do not entrain under 11:11-h LD cycles (T = 22 h). Subsequently providing hamsters continuous access to a running wheel established entrainment to T = 22 h. Moreover, this paradigm underwent further reductions of the T period to T = 19.6 h without loss of entrainment. Furthermore, restricting access to the wheel did not result in loss of entrainment, while even entrainment to T = 19 h was observed. To explain this observed shift in the lower entrainment limit, our speculation centers on changes in pacemaker response facilitated by stepwise changes of T spaced very far apart, thus allowing time for adaptation.     

Cerebral white matter blood flow is constant during human non-rapid eye movement sleep: a positron emission tomographic study.

This study aimed to identify brain regions with the least decreased cerebral blood flow (CBF) and their relationship to physiological parameters during human non-rapid eye movement (NREM) sleep. Using [(15)O]H(2)O positron emission tomography, CBF was measured for nine normal young adults during nighttime. As NREM sleep progressed, mean arterial blood pressure and whole brain mean CBF decreased significantly; arterial partial pressure of CO(2) and, selectively, relative CBF of the cerebral white matter increased significantly. Absolute CBF remained constant in the cerebral white matter, registering 25.9 +/- 3.8 during wakefulness, 25.8 +/- 3.3 during light NREM sleep, and 26.9 +/- 3.0 (ml.100 g(-1).min(-1)) during deep NREM sleep (P = 0.592), and in the occipital cortex (P = 0.611). The regression slope of the absolute CBF significantly differed with respect to arterial partial pressure of CO(2) between the cerebral white matter (slope 0.054, R = - 0.04) and frontoparietal association cortex (slope - 0.776, R = - 0.31) (P = 0.005) or thalamus (slope - 1.933, R = - 0.47) (P = 0.004) and between the occipital cortex (slope 0.084, R = 0.06) and frontoparietal association cortex (P = 0.021) or thalamus (P < 0.001), and, with respect to mean arterial blood pressure, between the cerebral white matter (slope - 0.067, R = - 0.10) and thalamus (slope 0.637, R = 0.31) (P = 0.044). The cerebral white matter CBF keeps constant during NREM sleep as well as the occipital cortical CBF, and may be specifically regulated by both CO(2) vasoreactivity and pressure autoregulation.     

Spectrum of rapid eye movement sleep behavior disorder (overlap between rapid eye movement sleep behavior disorder and other parasomnias)

Parasomnia Overlap Disorder (POD) was described and named in 1997 with a series of 33 cases of rapid eye movement (REM) sleep behavior disorder (RBD) combined with a disorder of arousal from non-rapid eye movement (NREM) sleep (sleepwalking, sleep terrors) that emerged idiopathically or symptomatically with neurological and other disorders. POD is a subtype of RBD in the International Classification of Sleep Disorders Diagnostic and Coding Manual, second edition (ICSD-2). An updated classification of POD also includes subclinical RBD-NREM parasomnia, RBD-sleep-related eating disorder, RBD-sexsomnia, RBD-rhythmic movement disorder, and status dissociatus (SD), which is another subtype of RBD in the ICSD-2. Similar to POD, a core feature of SD is sleep motor-behavioral dyscontrol, with release of dream-related behaviors suggestive of RBD, but with nearly continuous ambiguous polygraphic sleep precluding the identification of NREM/REM sleep states. SD exemplifies extreme state dissociation. SD is always a symptomatic disorder, and is causally associated with a broad range of neurologic disorders, often with thalamic, limbic, striatal, and pontine involvement. The parasomnia behaviors associated with POD and SD — typical RBD behaviors — can often be controlled with bedtime clonazepam therapy, including the abnormal dreaming.

     

Cognitive dysfunction in rapid eye movement sleep behavior disorder

Cognitive impairment is a frequent feature of rapid eye movement sleep behavior disorder (RBD). The cognitive profile of RBD patients is heterogeneous, with impairments in attention, executive functions, episodic memory, and visuospatial abilities. Moreover, over 50% of RBD patients meet the diagnostic criteria for mild cognitive impairment (MCI). Although a comprehensive neuropsychological assessment remains the most sensitive way to detect MCI, three cognitive screening tests have been validated in RBD. The Montreal Cognitive Assessment was found to be the most appropriate screening test for detecting MCI in RBD. In addition RBD in Parkinson’s disease may be a risk factor for MCI and dementia.

     

The time course of adenosine, nitric oxide (NO) and inducible NO synthase changes in the brain with sleep loss and their role in the non-rapid eye movement sleep homeostatic cascade

Both adenosine and nitric oxide (NO) are known for their role in sleep homeostasis, with the basal forebrain (BF) wakefulness center as an important site of action. Previously, we reported a cascade of homeostatic events, wherein sleep deprivation (SD) induces the production of inducible nitric oxide synthase (iNOS)-dependent NO in BF, leading to enhanced release of extracellular adenosine. In turn, increased BF adenosine leads to enhanced sleep intensity, as measured by increased non-rapid eye movement sleep EEG delta activity. However, the presence and time course of similar events in cortex has not been studied, although a frontal cortical role for the increase in non-rapid eye movement recovery sleep EEG delta power is known. Accordingly, we performed simultaneous hourly microdialysis sample collection from BF and frontal cortex (FC) during 11 h SD. We observed that both areas showed sequential increases in iNOS and NO, followed by increases in adenosine. BF increases began at 1 h SD, whereas FC increases began at 5 h SD. iNOS and Fos-double labeling indicated that iNOS induction occurred in BF and FC wake-active neurons. These data support the role of BF adenosine and NO in sleep homeostasis and indicate the temporal and spatial sequence of sleep homeostatic cascade for NO and adenosine.     

Brainstem structures involved in rapid eye movement sleep behavior disorder

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during paradoxical (REM) sleep (PS). The neuronal dysfunctions responsible for RBD are not known. In the present review, we propose an updated integrated model of the mechanisms responsible for PS and explore different hypotheses explaining RBD. We propose that RBD appears based on a specific degeneration of PS-on glutamatergic neurons localized in the caudal pontine sublaterodorsal tegmental nucleus or the glycinergic/GABAergic premotoneurons localized in the medullary ventral gigantocellular reticular nucleus.

     

Characteristics of rapid eye movement sleep behavior disorder in narcolepsy

The basal forebrain (BF) plays an important role in regulating cortical activity and sleep/wake states. Both cholinergic and non-cholinergic neurons of the BF project to the cerebral cortex and hippocampus, whereas the hypothalamus and brainstem nuclei are mostly innervated by non-cholinergic BF neurons. Neurons in the BF show various discharge profiles in relation to cortical activity and behavioral states and are differentially modulated by neurotransmitters of other sleep/wake regulatory neurons. Recent technical advances have made it possible to correlate discharge profiles of single BF neurons during sleep/wake states with their neurochemical phenotypes, and to make selective lesions of certain cell types. The goal of this review is to summarize the current knowledge of the anatomy and sleep/wake regulatory functions of cholinergic and non-cholinergic BF neurons. We will first review the anatomical heterogeneity of BF neurons, and then discuss recent evidence for the firing patterns of BF cholinergic and non-cholinergic neurons during natural sleep–wake patterns, and finally, discuss their roles in sleep homeostasis. It is proposed that through different neurotransmitters, projections, and state-regulated activity, the cholinergic and non-cholinergic BF neurons collectively and differently regulate cortical activity and sleep-wake states.

     

Preclinical dopaminergic dysfunction in rapid eye movement sleep behavior disorder

Patients with idiopathic rapid eye movement sleep behavior disorder have been reported to be at increased risk for developing Parkinson’s disease (PD), dementia with Lewy bodies, or multiple system atrophy. 6-[18F]fluoro-L-m-tyrosine/Positron emission topography (PET) is useful for evaluating PD patients from the early stage of the disease. Substantia nigra hyperechogenicity is a marker of vulnerability to PD. Decrease in 6-[18F]fluoro-L-m-tyrosine uptake in the striatum or hyperechogenic alterations in the substantia nigra may suggest the existence of an underlying neurode-generative disorder such as PD or dementia with Lewy bodies associated with preclinical dopaminergic dysfunction in patients with idiopathic rapid eye movement sleep behavior disorder.

     

Interleukin-13 and transforming growth factor-beta1 inhibit spontaneous sleep in rabbits

Proinflammatory cytokines, including interleukin-1beta and tumor necrosis factor-alpha are involved in physiological sleep regulation. Interleukin (IL)-13 and transforming growth factor (TGF)-beta1 are anti-inflammatory cytokines that inhibit proinflammatory cytokines by several mechanisms. Therefore, we hypothesized that IL-13 and TGF-beta1 could attenuate sleep in rabbits. Three doses of IL-13 (8, 40, and 200 ng) and TGF-beta1 (40, 100, and 200 ng) were injected intracerebroventricularly 3 h after the beginning of the light period. In addition, one dose of IL-13 (200 ng) and one dose of TGF-beta1 (200 ng) were injected at dark onset. The two higher doses of IL-13 and the highest dose of TGF-beta1 significantly inhibited spontanenous non-rapid eye movement sleep (NREMS) when they were given in the light period. IL-13 also inhibited NREMS after dark onset administration; however, the inhibitory effect was less potent than that observed after light period administration. The 40-ng dose of IL-13 inhibited REMS duration during the dark period. TGF-beta1 administered at dark onset had no effect on sleep. These data provide additional evidence for the hypothesis that a brain cytokine network is involved in regulation of physiological sleep.     

Differences in rapid eye movement sleep behavior disorder manifestation between synucleinopathies and tauopathies

Rapid eye movement sleep behavior disorder (RBD) frequently occurs in synucleinopathies including multiple system atrophy, Parkinson’s disease, and dementia with Lewy bodies despite the clinical course of RBD being different between these disorders. Comparatively, the existence of RBD symptoms is relatively rare in patients with progressive supranuclear palsy, a tauopathy showing atypical parkinsonism compared with Parkinson’s disease. Moreover, in patients with Alzheimer’s disease, which is another tauopathy, RBD symptoms are less frequent than dementia with Lewy bodies, although both disorders share commonalities in terms of the existence of cortical dementia. Thus, RBD is thought to be relatively specific to synucleinopathies.

     

Dream imagery,rapid eye movement sleep behavior disorder,and hallucinations

Rapid eye movement (REM) sleep behavior disorder (RBD) and hypnagogic hallucinations are salient symptoms of abnormal and dissociated REM sleep that are frequently associated in serious neurological diseases. RBD is a strong, independent risk factor for hallucinations in narcolepsy (odds ratio: 4.3) and in Parkinson’s disease (odds ratio: 2.7). In Parkinson’s disease, RBD also predicts incident hallucinations and psychosis in prospective cohorts. Status dissociatus (a mixture of hallucinations, RBD, and dissociated sleep-wake states) is observed in patients with Guillain-Barré when hallucinating, but also in Lewy bodies dementia, delirium tremens, fatal familial insomnia, and Morvan’s chorea. This co-occurrence of RBD and visual hallucinations suggests a common, extensive lesion within REM sleep executive systems.