Tumor necrosis factor (TNF) ligand and TNF receptor deficiency affects sleep and the sleep EEG

Tumor necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha) are proinflammatory cytokines involved in host defense and pathogenesis of various diseases. In addition, there is evidence that TNF is involved in sleep. TNF and LT-alpha both bind to the tumor necrosis factor receptors (TNFR). Recently, it was shown that TNF receptor 1 (TNFR1) knockout mice (R1KO) sleep less during the light period than controls. We investigated the effect of a TNF and LT-alpha double deficiency on sleep in mice (Ligand KO) and compared their sleep with that of R1KO, TNFR2 knockout (R2KO) mice, and wild-type (WT) controls. All mice were adapted to a 12:12 h light:dark cycle and their electroencephalographs (EEG) and electromyographs (EMG) were continuously recorded during a baseline day, 6-h sleep deprivation (SD), and 18-h recovery. Ligand KO and R2KO had 15% less rapid eye movement (REM) sleep during the baseline light period due to a reduction in REM sleep episode frequency. After SD, all genotypes showed an initial increase in slow-wave activity (SWA) (EEG power density between 0.75 and 4.0 Hz) in non-REM sleep, which gradually declined in the following hours. In Ligand KO the increase was mainly caused by an increase in fast SWA (2.75-4.0 Hz), which was also increased in R2KO. In contrast, in R1KO mice the increase was limited to the slow portion of SWA (0.75-2.5 Hz). R2KO and WT mice showed increases in both frequency ranges. The sub-division into fast and slow SWA frequencies corresponds to previous electrophysiological data where the two types of slow-waves were induced by either excitatory or inhibitory stimuli. Our data suggest that in Ligand KO the SWA increase is caused by an increase in excitatory input to the cortex, whereas in R1KO this input seems to be almost absent.     

Deficiency of FK506‐binding protein (FKBP) 51 alters sleep architecture and recovery sleep responses to stress in mice

FK506‐binding protein 51 (FKBP51) is a co‐chaperone of the glucocorticoid receptor, functionally linked to its activity via an ultra‐short negative feedback loop. Thus, FKBP51 plays an important regulatory role in the hypothalamic–pituitary–adrenocortical (HPA) axis necessary for stress adaptation and recovery. Previous investigations illustrated that HPA functionality is influenced by polymorphisms in the gene encoding FKBP51, which are associated with both increased protein levels and depressive episodes. Because FKBP51 is a key molecule in stress responses, we hypothesized that its deletion impacts sleep. To study FKBP51‐involved changes in sleep, polysomnograms of FKBP51 knockout (KO) mice and wild‐type (WT) littermates were compared at baseline and in the recovery phase after 6‐h sleep deprivation (SD) and 1‐h restraint stress (RS). Using another set of animals, the 24‐h profiles of hippocampal free corticosterone levels were also determined. The most dominant effect of FKBP51 deletion appeared as increased nocturnal wake, where the bout length was significantly extended while non‐rapid eye movement sleep (NREMS) and rapid eye movement sleep were rather suppressed. After both SD and RS, FKBP51KO mice exhibited less recovery or rebound sleep than WTs, although slow‐wave activity during NREMS was higher in KOs, particularly after SD. Sleep compositions of KOs were nearly opposite to sleep profiles observed in human depression. This might result from lower levels of free corticosterone in FKBP51KO mice, confirming reduced HPA reactivity. The results indicate that an FKBP51 deletion yields a pro‐resilience sleep phenotype. FKBP51 could therefore be a therapeutic target for stress‐induced mood and sleep disorders.     

Long-term vs. short-term processes regulating REM sleep

In cats, rats, and mice, the amount of rapid eye movement sleep (REMS) lost during a sleep deprivation (SD) predicts the subsequent REMS rebound during recovery sleep. This suggests that REMS is homeostatically regulated and that a need or pressure for REMS accumulates in its absence, i.e. during both wakefulness and non-rapid eye movement sleep (NREMS). Conversely, it has been proposed that REMS pressure accumulates exclusively during NREMS [Benington and Heller, Am. J. Physiol. 266 (1994) R1992; Prog. Neurobiol. 44 (1994b) 433]. This hypothesis is based on the analysis of the duration of successive NREMS and REMS episodes and of electroencephalogram (EEG) events preceding REMS. Pre-REMS events (PREs) do not always result in sustained REMS and can thus be regarded as REMS attempts that increase as NREMS progresses. It is assumed that two processes regulating REMS can resolve the apparent contradiction between these two concepts: a 'long-term' process that homeostatically regulates the daily REMS amount and a 'short-term' process that regulates the NREM--REMS cycle. These issues were addressed in two SD experiments in rats. The two SDs varied in length (12 and 24 h) and resulted in very similar compensatory changes in NREMS but evoked very different changes for all REMS parameters studied. The large REMS increase observed after 24-h SD was accompanied by a reduction in unsuccessful PREs and an increase in sustained REMS episodes, together resulting in a threefold increase in the success-rate to enter REMS. Changes in success-rate matched those of a theoretically derived long-term REMS pressure. The SD induced changes in sleep architecture could be reproduced by assuming that the increased long-term REMS pressure interacts with the short-term process by increasing the probability to enter and remain in REMS.     

Estradiol and Progesterone Modulate Spontaneous Sleep Patterns and Recovery from Sleep Deprivation in Ovariectomized Rats

Study Objectives:

Women undergo hormonal changes both naturally during their lives and as a result of sex hormone treatments. The objective of this study was to gain more knowledge about how these hormones affect sleep and responses to sleep loss.

Design:

Rats were ovariectomized and implanted subcutaneously with Silastic capsules containing oil vehicle, 17β-estradiol and/or progesterone. After 2 weeks, sleep/wake states were recorded during a 24-h baseline period, 6 h of total sleep deprivation induced by gentle handling during the light phase, and an 18-h recovery period.

Measurements and Results:

At baseline and particularly in the dark phase, ovariectomized rats treated with estradiol or estradiol plus progesterone spent more time awake at the expense of non-rapid eye movement sleep (NREMS) and/or REMS, whereas those given progesterone alone spent less time in REMS than ovariectomized rats receiving no hormones. Following sleep deprivation, all rats showed rebound increases in NREMS and REMS, but the relative increase in REMS was larger in females receiving hormones, especially high estradiol. In contrast, the normal increase in NREMS EEG delta power (an index of NREMS intensity) during recovery was attenuated by all hormone treatments.

Conclusions:

Estradiol promotes arousal in the active phase in sleep-satiated rats, but after sleep loss, both estradiol and progesterone selectively facilitate REMS rebound while reducing NREMS intensity. These results indicate that effects of ovarian hormones on recovery sleep differ from those on spontaneous sleep. The hormonal modulation of recovery sleep architecture may affect recovery of sleep related functions after sleep loss.

Citation:

Deurveilher S; Rusak B; Semba K. Estradiol and progesterone modulate spontaneous sleep patterns and recovery from sleep deprivation in ovariectomized rats. SLEEP 2009;32(7):865-877.     

Genetic Evidence for a Role for Protein Kinase A in the Maintenance of Sleep and Thalamocortical Oscillations

Study Objectives:

Genetic manipulation of cAMP-dependent protein kinase A (PKA) in Drosophila has implicated an important role for PKA in sleep/wake state regulation. Here, we characterize the role of this signaling pathway in the regulation of sleep using electroencephalographic (EEG) and electromyographic (EMG) recordings in R(AB) transgenic mice that express a dominant negative form of the regulatory subunit of PKA in neurons within cortex and hippocampus. Previous studies have revealed that these mutant mice have reduced PKA activity that results in the impairment of hippocampus-dependent long-term memory and long-lasting forms of hippocampal synaptic plasticity.

Design:

PKA assays, in situ hybridization, immunoblots, and sleep studies were performed in R(AB) transgenic mice and wild-type control mice.

Measurements and Results:

We have found that R(AB) transgenic mice have reduced PKA activity within cortex and reduced Ser845 phosphorylation of the glutamate receptor subunit GluR1. R(AB) transgenic mice exhibit non-rapid eye movement (NREM) sleep fragmentation and increased amounts of rapid eye movement (REM) sleep relative to wild-type mice. Further, R(AB) transgenic mice have more delta power but less sigma power during NREM sleep relative to wild-type mice. After sleep deprivation, the amounts of NREM and REM sleep were comparable between wild-type and R(AB) transgenic mice. However, the homeostatic rebound of sigma power in R(AB) transgenic mice was reduced.

Conclusions:

Alterations in cortical synaptic receptors, impairments in sleep continuity, and alterations in sleep oscillations in R(AB) mice imply that PKA is involved not only in synaptic plasticity and memory storage but also in the regulation of sleep/wake states.

Citation:

Hellman K; Hernandez P; Park A; Abel T. Genetic evidence for a role for protein kinase a in the maintenance of sleep and thalamocortical oscillations. SLEEP 2010;33(1):19-28.     

Interleukin-8 promotes non-rapid eye movement sleep in rabbits and rats

Interleukin-8 (IL-8) is a cytokine found in the brain. In this study, the ability of IL-8 to induce sleep in rabbits and rats was investigated. Twenty-seven Sprague-Dawley rats and 16 male New Zealand White rabbits were provided electroencephalographic (EEG) electrodes, a brain thermistor, and a lateral intracerebroventricular cannula. The animals were injected intracerebroventricularly (i.c.v.) with pyrogen-free saline and, one of the following doses of IL-8 on a separate day: 1.25 or 12.5 ng in rabbits and 10, 50, or 100 ng in rats. EEG, brain temperature, and motor activity were recorded for 23 h after the i.c.v. injections. IL-8 increased time spent in non-rapid eye movement sleep (NREMS) without affecting rapid eye movement sleep (REMS). In rabbits, both doses of IL-8 promoted NREMS. In rats, the 10 and 50 ng doses of IL-8 failed to affect sleep, but the 100 ng dose of IL-8 enhanced NREMS. EEG slow-wave activity during NREMS was increased after the high dose of IL-8 in rabbits. IL-8 also induced fever in rabbits but not rats. Heat inactivated IL-8 did not alter any of the parameters measured. Current results support the notion that the brain cytokine network plays a role in sleep regulation.     

CDKL5 deficiency entails sleep apneas in mice

A recently discovered neurodevelopmental disorder caused by the mutation of the cyclin‐dependent kinase‐like 5 gene (CDKL5) entails complex autistic‐like behaviours similar to Rett syndrome, but its impact upon physiological functions remains largely unexplored. Sleep‐disordered breathing is common and potentially life‐threatening in patients with Rett syndrome; however, evidence is limited in children with CDKL5 disorder, and is lacking altogether in adults. The aim of this study was to test whether the breathing pattern during sleep differs between adult Cdkl5 knockout (Cdkl5‐KO) and wild‐type (WT) mice. Using whole‐body plethysmography, sleep and breathing were recorded non‐invasively for 8 h during the light period. Sleep apneas occurred more frequently in Cdkl5‐KO than in WT mice. A receiver operating characteristic (ROC) analysis discriminated Cdkl5‐KO significantly from WT mice based on sleep apnea occurrence. These data demonstrate that sleep apneas are a core feature of CDKL5 disorder and a respiratory biomarker of CDKL5 deficiency in mice, and suggest that sleep‐disordered breathing should be evaluated routinely in CDKL5 patients.     

Cortical temperature and EEG slow-wave activity in the rat: analysis of vigilance state related changes

Vigilance states, cortical temperature (T _CRT), and electroencephalograph (EEG) slow-wave-activity (SWA, mean power density in the 0.75–4.0 Hz range) of ten rats were recorded continuously during a baseline day, and two recovery days (Recovery 1 and 2) after 24 h of sleep deprivation (SD). The short term changes of T _CRT were analysed within episodes of nonrapid eye movement sleep (NREMS), REM sleep (REMS) and waking (W), and at transitions between vigilance states. SWA was analysed within NREMS episodes and at W to NREMS (WN) transitions. T _CRT increased during episodes of W and REMS, and decreased during NREMS episodes. These changes were a function of episode duration, and, for W and NREMS, of T _CRT at episode onset. In Recovery 1 the increase in T _CRT at NREMS to REMS (NR) and NREMS to W (NW) transitions tended to be attenuated. SWA within NREMS episodes was enhanced after SD. Over all experimental days, the increase of SWA and the decrease of T _CRT in NREMS episodes were not correlated.It is concluded that during recovery from SD the changes in T _CRT at state transitions were little affected. The lack of a relationship between changes in T _CRT and SWA indicates that separate mechanisms underlie the regulation of brain temperature and sleep intensity.     

Own or dam’s genotype? Classical colony breeding may bias spontaneous and stress-challenged activity in DAT-mutant rats

There is considerable interest in understanding what makes an individual vulnerable or resilient to the deleterious effects of stressful events. From candidate genes, dopamine (DA) and dopamine transporter (DAT) have been linked to anxiety, depression, and post-traumatic stress disorder. We investigated role of DAT using the new DAT heterozygous (DAT-HET) and homozygous mutant (DAT-KO) rat models of hyperdopaminergia. We studied the impact of two breeding conditions in spontaneous locomotor behavior of female rats. The classical colony, through mating DAT-HET males × DAT-HET females (breeding HET–HET), was used. A second WT colony was derived and maintained (breeding WT–WT). Additionally, a subgroup of rats was bred through mating DAT-KO males × WT females (atypical HET, breeding KO–WT). We studied the effects of genotype and its interaction with maternal care (depending by breeding condition). HET–HET breeding led to reduced activity in HET females compared to WT rats (from WT–WT breeding). However, HET females from KO–WT breeding did not differ so much from WT rats (WT–WT breeding). The maternal-care impact was then confirmed: HET mothers (breeding HET–HET) showed reduced liking/grooming of pups and increased digging away from nest, compared to WT mothers (breeding WT–WT). In their female offspring (HET, breeding HET–HET vs. WT, breeding WT–WT), isolation plus wet bedding induced higher and more persistent impact on activity of HET rats, even when the stressor was removed. Our results highlight the importance of epigenetic factors (e.g., maternal care) in responses to stress expressed by offspring at adulthood, quite independently of genotype. DAT hypofunction could determinate vulnerability to stressful agents via altered maternal care.     

Decreased behavioral activation following caffeine, amphetamine and darkness in A3 adenosine receptor knock-out mice

We have examined behavioral consequences of genetic deletion of the adenosine A₃ receptors in mice. The open field behavior of A₃ adenosine receptor knock-out (A₃R KO) mice was investigated both under basal conditions and after stimulation with psychostimulants. Adolescent (21 day-old) and adult A₃R KO males showed an increase in overall motor activity compared to wild type (WT) males, but the type of activity differed. The motor activity, especially rearing, was also higher in A₃R KO compared to WT adult females. A₃ receptors have a low affinity for caffeine and it was therefore surprising to find a decreased response to stimulation with either caffeine or amphetamine in A₃R KO as compared to WT mice in males as well as females. Telemetry recordings also showed a significantly smaller increase in activity upon darkness in A₃R KO. There were no compensatory changes in the mRNA expression of any other adenosine receptor subtypes (A₁, A_2A and A_2B) or any changes in dopamine D₁ and D₂ receptor binding in A₃R KO brains. Challenge with the developmental toxicant methylmercury (1 µM in drinking water) during pregnancy and lactation did not cause any behavioral alterations in adolescent and adult WT female offspring. In contrast, the A₃R KO female offspring displayed changes in locomotion indicating an interaction between perinatal methylmercury and adenosine A₃ receptors. In conclusion, despite low expression of A₃ receptors in wild type mouse brain we observed several behavioral consequences of genetic elimination of the adenosine A₃ receptors. The possibility that this is due to a role of A₃ receptors in development is discussed.     

Interleukin 1 receptor contributes to methamphetamine- and sleep deprivation-induced hypersomnolence

Methamphetamine-induced wakefulness is dependent on monoamine transporter blockade. Subsequent to methamphetamine-induced wakefulness, the amount of time spent asleep and the depth of sleep are increased relative to baseline sleep. The mechanisms that drive methamphetamine-induced hypersomnolence are not fully understood. We recently observed that methamphetamine exposure elevates the expression of the sleep-promoting cytokine, interleukin-1β in CD11b-positive monocytes within the brain. Here, we sought to determine whether activation of the interleukin 1 receptor (IL1R) drives the increase in the depth and amount of sleep that occurs subsequent to methamphetamine-induced wakefulness. IL1R-deficient mice and wild type control mice were subjected to systemic methamphetamine (1 and 2mg/kg) and saline treatments. The wake-promoting effect of methamphetamine was modestly potentiated by IL1R-deficiency. Additionally, the increase in time spent in NREMS subsequent to methamphetamine-induced wakefulness in wild type mice was abolished in IL1R-deficient mice. The increase in time spent asleep after 3h of behaviorally enforced wakefulness was also abolished in IL1R-deficient mice. Increases in EEG slow wave activity triggered by methamphetamine and sleep deprivation were of equal magnitude in IL1R-deficient and wild type mice. These data demonstrate that IL1R activation contributes to hypersomnolence that occurs after sleep loss, whether that sleep loss is triggered pharmacologically by methamphetamine or through behavioral sleep deprivation.     

The effect of light on sleep and the EEG of young rats

Sleep states, the power spectra of the cortical electroencephalogram (EEG) and cortical temperature (T _crt) were determined in young rats (age 23–24 days). Recordings were made for 1 day under habitual 12 h light: 12 h dark (LD 1212) conditions and on the subsequent day under continuous darkness (DD). The amount and distribution of the vigilance states differed little between experimental conditions. Sleep occurred predominantly during the actual (LD) or habitual (DD) 12-h light period. The EEG power density in the actual light period was lower than in the habitual light period. These differences were largest in the delta range for the EEG of non-rapid eye movement of sleep (NREMS) and in the theta range for the EEG of REM sleep (REMS) and waking. EEG power density in NREMS was somewhat lower in the LD dark period than in the corresponding DD period. The typical 24-h pattern of EEG power density in NREMS, which reflects processes underlying sleep regulation, was little affected by the experimental conditions. It is concluded that the light during an LD 1212 schedule suppresses the EEG but has little effect on the vigilance states.     

The effect of subcutaneous administration of delta sleep-inducing peptide (DSIP) on some parameters of sleep in the cat

Delta sleep inducing peptide (DSIP) significantly increases deep-slow-wave sleep (DSWS) of cats after subcutaneous (SC) injection. Cats (n = 8) were SC injected with DSIP (120 nmol.kg-1) prior to polygraphic recording of EEG combined with electro-oculography, EOG) and electromyography (EMG) for 8 hours. DSIP was found to significantly increase slow-waves (delta sleep) in the sleep EEG. There was a tendency to reduced waking time and a prolongation of slow wave sleep time, and a shortening of sleep onset and REM sleep latencies but the differences from control (Ringer injection) were not statistically significant. There was no change in the amount of REM sleep. These findings support the belief that DSIP can increase sleep wave activity when administered by peripheral route.     

The role of active zone protein Rab3 interacting molecule 1 alpha in the regulation of norepinephrine release, response to novelty, and sleep

Sleep mechanisms and synaptic plasticity are thought to interact to regulate homeostasis and memory formation. However, the influences of molecules that mediate synaptic plasticity on sleep are not well understood. In this study we demonstrate that mice lacking Rab3 interacting molecule 1 alpha (RIM1 alpha) (Rim1 alpha KO), a protein of the synaptic active zone required for certain types of synaptic plasticity and learning, had 53+/-5% less baseline rapid eye movement (REM) sleep compared with their wild type littermates. Also, compared with wild type littermates, exposure of the mice to an open field or to a novel object induced more robust and longer lasting locomotion suggesting altered habituation. This difference in exploratory behavior correlated with genotype specific changes in REM and deregulated release of norepinephrine in the cortex and basal amygdala of the Rim1 alpha KO mice. Also, moderate sleep deprivation (4 h), a test of the homeostatic sleep response, induced REM sleep rebound with different time course in Rim1 alpha KO and their wild type littermates. As norepinephrine plays an important role in regulating arousal and REM sleep, our data suggest that noradrenergic deficiency in Rim1 alpha KO animals impacts exploratory behavior and sleep regulation and contributes to impairments in learning.     

Dysregulation of Heart Rhythm During Sleep in Leptin-Deficient Obese Mice

Study Objectives:

Sleep deeply affects cardiac autonomic control, the impairment of which is associated with cardiovascular mortality. Obesity entails increased cardiovascular risk and derangements in sleep and cardiac autonomic control. We investigated whether cardiac autonomic control is impaired during sleep in ob/ob mice with morbid obesity caused by congenital leptin deficiency.

Design:

Indexes of cardiac autonomic control based on spontaneous cardiovascular fluctuations were compared between ob/ob and lean wild-type (+/+) mice during wakefulness, non-rapid eye movement sleep (NREMS), and rapid eye movement sleep (REMS).

Setting:

N/A

Patients or Participants:

7 ob/ob and 11 +/+ male mice.

Interventions:

Instrumentation with electrodes for sleep recordings and a telemetric transducer for measuring blood pressure and heart period.

Measurements and Results:

In ob/ob mice, the variability of heart period and cardiac baroreflex sensitivity (sequence technique) were significantly lower than in +/+ mice during each wake-sleep state. The vagal modulation of heart period was significantly weaker in ob/ob than in +/+ mice during NREMS and REMS. In ob/ob mice, the cross-correlation function between heart period and blood pressure suggested that the baroreflex contribution to cardiac control was lower than in +/+ mice during wakefulness and NREMS, whereas the contribution of central autonomic commands was lower than in +/+ mice during NREMS and REMS.

Conclusions:

These data indicate a dysregulation of cardiac autonomic control during sleep in ob/ob mice. Ob/ob mice may represent a useful tool to understand the molecular pathways that lead to cardiac autonomic dysregulation during sleep in obesity.

Citation:

Silvani A; Bastianini S; Berteotti C; Franzini C; Lenzi P; Lo Martire V; Zoccoli G. Dysregulation of heart rhythm during sleep in leptin-deficient obese mice. SLEEP 2010;33(3):355-361.     

Selective increase in brain dopamine metabolism during REM sleep rebound in the rat

Rats implanted with electrodes for EEG and EMG recording were placed on small or large platforms for either 24 or 96 hr and the effects on the subsequent REM sleep rebound were observed. Only the 96 hr protocol produced a selective REM sleep rebound in rats placed on small platforms. Brain MOPEG-SO₄, a final metabolite of norepinephrine, was determined fluorometrically and dopamine metabolites HVA and DOPAC, as well as the serotonin metabolite 5-HIAA, were measured by using an HPLC method with electrochemical detection. The results show that selective increases in brain HVA and DOPAC were obtained only during the REM sleep rebound in rats from small platforms. Non-specific increases were observed in MOPEG-SO₄ and 5-HIAA during the recovery period in rats from both small and large platforms which could be related to the effects of immobilization stress.     

IL-1 and TNF independent pathways mediate ICAM-1/VCAM-1 up-regulation in ischemia reperfusion injury

In vitro studies have suggested that targeting interleukin (IL)-1 and tumor necrosis factor (TNF) can be used to regulate intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and potentially treat kidney inflammation. We therefore evaluated ICAM-1 and VCAM-1 regulation in knockout (KO) mice deficient in both IL-1 receptor 1 (R1) and TNF-R1 during renal ischemia reperfusion injury. ICAM-1 and VCAM-1 mRNA expression was measured with specific murine probes and Northern blotting (n =4/group). Protein expression was measured using immunohistochemistry. Serum creatinine (SCr), tubular histology, and neutrophil infiltration into postischemic kidneys were also quantified. ICAM-1 and VCAM-1 mRNA expression increased in both wild-type (WT) and KO mice at 2, 6, and 24 h. Protein expression of ICAM-1 and VCAM-1 was also increased at 24 h postischemia. SCr levels and tubular necrosis scores were comparable in WT and KO mice at 24 and 48 h. Neutrophil migration in KO mice was decreased at 24 h but comparable to WT at 48 h. These data demonstrate that IL-1 and TNF are not essential for postischemic increases in ICAM-1 and VCAM-1.     

Reversal of the circadian expression of tyrosine-hydroxylase but not nitric oxide synthase levels in the spinal cord of dopamine D3 receptor knockout mice

Circadian rhythms have been described for numerous transmitter synthesizing enzymes in the brain but rarely in spinal cord. We measured spinal tyrosine-hydroxylase (TH) and nitric oxide synthase (NOS) levels in the thoracic intermediolateral nucleus, the location of sympathetic preganglionic neurons, in male wild type (WT) and dopamine D(3) receptor knockout mice (D(3)KO). TH and NOS levels both displayed circadian patterns in WT and D(3)KO animals with overall reduced TH and increased NOS expression in the D(3)KO mice. The circadian pattern of NOS expression was similar in WT and D(3)KO mice. In contrast, TH expression was inverted in D(3)KO mice, with TH levels consistently lower than in WT throughout the day, but strongly increased temporarily 1 h prior to daylight. TH is the rate-limiting enzyme for the production of dopamine. Spinal dopamine dysfunction is implicated in a sleep disorder called restless legs syndrome (RLS). RLS follows a circadian rhythm and is relieved clinically by dopamine D(3) receptor agonists. Our observations of an altered circadian pattern in spinal dopamine synthesis in D(3)KO animals may provide insight into putative dopaminergic mechanisms contributing to RLS.     

Regional differences in NREM sleep slow-wave activity in mice with congenital callosal dysgenesis

Topographic differences in the sleep EEG have been repeatedly found in humans and rodents. A frontal predominance of EEG slow-wave activity (0.75-4 Hz; delta band) during non-rapid eye movement (NREM) sleep is particularly evident under conditions of increased sleep propensity. Local aspects of neuronal connectivity in the neocortex that are modified by specific neuronal stimulation may underlie these differences. To investigate the role of altered neuronal connectivity on anterior-posterior EEG topography, sleep was recorded in mice with congenital dysgenesis of the corpus callosum (B1 strain) during baseline and after 6 h sleep deprivation (SD). In these mice neuronal connections within a hemisphere are increased due to the longitudinal Probst bundle, a structure of re-routed callosal fibers. After SD the frequencies above 1.5 Hz within the delta band in NREM sleep were reduced in B1 mice compared with control C57BL/6 mice, a strain that has a normal corpus callosum, while power in the lowest frequency band (0.75-1.0 Hz) was enhanced in B1 mice. The differences between the strains subsided in the course of recovery. The redistribution of EEG power within the delta band in the frontal region in mice with a well developed Probst bundle, suggests a role of intracortical connectivity in local sleep regulation.     

Challenging sleep homeostasis in narcolepsy-cataplexy: implications for non-REM and REM sleep regulation

STUDY OBJECTIVES: We recently proposed insufficient non-rapid eye movement sleep (NREMS) intensity to contribute to disturbed nocturnal sleep in patients with narcolepsy-cataplexy (NC). To test this hypothesis, we investigated the effect of physiologically intensified NREMS in recovery sleep following sleep deprivation. DESIGN: Nocturnal baseline and recovery sleep architecture, and the sleep electroencephalogram (EEG) before and after 40 hours of sustained wakefulness were compared between 6 drug-free patients with NC (age range: 19-37 years) and 6 individually matched, healthy control subjects (18-43 years). MEASUREMENTS: Sleep and sleep EEG power spectra (C3A2 derivation). The dynamics of the homeostatic Process S were estimated from the time course of slow-wave activity (SWA, spectral power within 0.75-4.5 Hz) across consecutive NREMS episodes. SETTINGS: Sleep research laboratory. RESULTS: In baseline, SWA decreased across consecutive NREMS episodes in patients with NC and control subjects. The build-up of SWA, however, was attenuated in NC in the second episode (P = 0.01) due to a higher number of short wake periods (P = 0.02). Prolonged wakefulness increased initial SWA in both groups (P = 0.003) and normalized the baseline differences between patients and control subjects in the time course of SWA in NREMS. The changed dynamics of SWA in the patients in recovery sleep when compared with baseline were associated with reduced numbers of intermittent wake periods in the first (P = 0.01) and second (P = 0.04) NREMS episodes. All patients, but no control subjects, showed a sleep-onset rapid eye movement period (SOREMP) in both baseline and recovery sleep. Sleep deprivation increased SOREMP duration (P = 0.03). CONCLUSIONS: Increased SWA after sleep deprivation indicates that sleep homeostasis is functional in NC. Increased NREMS intensity in recovery sleep postpones sleep fragmentation, supporting our concept that sleep fragmentation is directly related to insufficient NREMS intensity in NC. The persistence of SOREMP despite enhanced NREMS pressure suggests an abnormal interaction between NREMS and REMS regulatory processes.