Physiological time structure of the tibialis anterior motor activity during sleep in mice, rats and humans

The validation of rodent models for restless legs syndrome (Willis-Ekbom disease) and periodic limb movements during sleep requires knowledge of physiological limb motor activity during sleep in rodents. This study aimed to determine the physiological time structure of tibialis anterior activity during sleep in mice and rats, and compare it with that of healthy humans. Wild-type mice (n = 9) and rats (n = 8) were instrumented with electrodes for recording the electroencephalogram and electromyogram of neck muscles and both tibialis anterior muscles. Healthy human subjects (31 ± 1 years, n = 21) underwent overnight polysomnography. An algorithm for automatic scoring of tibialis anterior electromyogram events of mice and rats during non-rapid eye movement sleep was developed and validated. Visual scoring assisted by this algorithm had inter-rater sensitivity of 92-95% and false-positive rates of 13-19% in mice and rats. The distribution of the time intervals between consecutive tibialis anterior electromyogram events during non-rapid eye movement sleep had a single peak extending up to 10 s in mice, rats and human subjects. The tibialis anterior electromyogram events separated by intervals <10 s mainly occurred in series of two-three events, their occurrence rate in humans being lower than in mice and similar to that in rats. In conclusion, this study proposes reliable rules for scoring tibialis anterior electromyogram events during non-rapid eye movement sleep in mice and rats, demonstrating that their physiological time structure is similar to that of healthy young human subjects. These results strengthen the basis for translational rodent models of periodic limb movements during sleep and restless legs syndrome/Willis-Ekbom disease.

Identification of Sleep-Modulated Pathways Involved in Neuroprotection from Stroke.

STUDY OBJECTIVES Sleep deprivation (SDp) performed before stroke induces an ischemic tolerance state as observed in other forms of preconditioning. As the mechanisms underlying this effect are not well understood, we used DNA oligonucleotide microarray analysis to identify the genes and the gene-pathways underlying SDp preconditioning effects. DESIGN Gene expression was analyzed 3 days after stroke in 4 experimental groups: (i) SDp performed before focal cerebral ischemia (IS) induction; (ii) SDp performed before sham surgery; (iii) IS without SDp; and (iv) sham surgery without SDp. SDp was performed by gentle handling during the last 6 h of the light period, and ischemia was induced immediately after. SETTINGS Basic sleep research laboratory. MEASUREMENTS AND RESULTS Stroke induced a massive alteration in gene expression both in sleep deprived and non-sleep deprived animals. However, compared to animals that underwent ischemia alone, SDp induced a general reduction in transcriptional changes with a reduction in the upregulation of genes involved in cell cycle regulation and immune response. Moreover, an upregulation of a new neuroendocrine pathway which included melanin concentrating hormone, glycoprotein hormones-α-polypeptide and hypocretin was observed exclusively in rats sleep deprived before stroke. CONCLUSION Our data indicate that sleep deprivation before stroke reprogrammed the signaling response to injury. The inhibition of cell cycle regulation and inflammation are neuroprotective mechanisms reported also for other forms of preconditioning treatment, whereas the implication of the neuroendocrine function is novel and has never been described before. These results therefore provide new insights into neuroprotective mechanisms involved in ischemic tolerance mechanisms.

The spectrum of the non-rapid eye movement sleep electroencephalogram following total sleep deprivation is trait-like

The sleep electroencephalogram (EEG) spectrum is unique to an individual and stable across multiple baseline recordings. The aim of this study was to examine whether the sleep EEG spectrum exhibits the same stable characteristics after acute total sleep deprivation. Polysomnography (PSG) was recorded in 20 healthy adults across consecutive sleep periods. Three nights of baseline sleep [12 h time in bed (TIB)] following 12 h of wakefulness were interleaved with three nights of recovery sleep (12 h TIB) following 36 h of sustained wakefulness. Spectral analysis of the non-rapid eye movement (NREM) sleep EEG (C3LM derivation) was used to calculate power in 0.25 Hz frequency bins between 0.75 and 16.0 Hz. Intraclass correlation coefficients (ICCs) were calculated to assess stable individual differences for baseline and recovery night spectra separately and combined. ICCs were high across all frequencies for baseline and recovery and for baseline and recovery combined. These results show that the spectrum of the NREM sleep EEG is substantially different among individuals, highly stable within individuals and robust to an experimental challenge (i.e. sleep deprivation) known to have considerable impact on the NREM sleep EEG. These findings indicate that the NREM sleep EEG represents a trait.

Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer's Disease: From Early to Advanced Pathological Stages.

In addition to cognitive decline, individuals affected by Alzheimer's disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.

translin Is Required for Metabolic Regulation of Sleep

Dysregulation of sleep or feeding has enormous health consequences. In humans, acute sleep loss is associated with increased appetite and insulin insensitivity, while chronically sleep-deprived individuals are more likely to develop obesity, metabolic syndrome, type II diabetes, and cardiovascular disease. Conversely, metabolic state potently modulates sleep and circadian behavior; yet, the molecular basis for sleep-metabolism interactions remains poorly understood. Here, we describe the identification of translin (trsn), a highly conserved RNA/DNA binding protein, as essential for starvation-induced sleep suppression. Strikingly, trsn does not appear to regulate energy stores, free glucose levels, or feeding behavior suggesting the sleep phenotype of trsn mutant flies is not a consequence of general metabolic dysfunction or blunted response to starvation. While broadly expressed in all neurons, trsn is transcriptionally upregulated in the heads of flies in response to starvation. Spatially restricted rescue or targeted knockdown localizes trsn function to neurons that produce the tachykinin family neuropeptide Leucokinin. Manipulation of neural activity in Leucokinin neurons revealed these neurons to be required for starvation-induced sleep suppression. Taken together, these findings establish trsn as an essential integrator of sleep and metabolic state, with implications for understanding the neural mechanism underlying sleep disruption in response to environmental perturbation.

Implicit memory for the content but not the speaker of sleep-played messages

We presented 28 sentences uttered by 28 unfamiliar speakers to sleeping participants to investigate whether humans can encode new verbal messages, learn voices of unfamiliar speakers, and form associations between speakers and messages during EEG-defined deep sleep. After waking, participants performed three tests which assessed the unconscious recognition of sleep-played speakers, messages, and speaker-message associations. Recognition performance in all tests was at chance level. However, response latencies revealed implicit memory for sleep-played messages but neither for speakers nor for speaker-message combinations. Only participants with excellent implicit memory for sleep-played messages also displayed implicit memory for speakers but not speaker-message associations. Hence, deep sleep allows for the semantic encoding of novel verbal messages.

Post-H1N1 Flu Vaccination Narcolepsy in Switzerland: A Retrospective Survey in the 30 Sleep-Certified Swiss Centers

Narcolepsy-cataplexy is a sleep-wake disorder and suggested to be immune-mediated, involving genetic and environmental factors. The autoimmune process eventually leads to a loss of hypocretin neurons in the lateral hypothalamus. Epidemiological studies in several countries proved an increased incidence of narcolepsy after H1N1 flu vaccination and infection. This survey in 30 sleep centers in Switzerland led to the identification of 9 H1N1-vaccinated children and adults as newly diagnosed narcolepsy. Clinical features included the abrupt and severe onset of sleepiness, cataplexy and sleep fragmentation.

Sleep-wake disorders persist 18 months after traumatic brain injury but remain underrecognized

OBJECTIVE This study is a prospective, controlled clinical and electrophysiologic trial examining the chronic course of posttraumatic sleep-wake disturbances (SWD). METHODS We screened 140 patients with acute, first-ever traumatic brain injury of any severity and included 60 patients for prospective follow-up examinations. Patients with prior brain trauma, other neurologic or systemic disease, drug abuse, or psychiatric comorbidities were excluded. Eighteen months after trauma, we performed detailed sleep assessment in 31 participants. As a control group, we enrolled healthy individuals without prior brain trauma matched for age, sex, and sleep satiation. RESULTS In the chronic state after traumatic brain injury, sleep need per 24 hours was persistently increased in trauma patients (8.1 ± 0.5 hours) as compared to healthy controls (7.1 ± 0.7 hours). The prevalence of chronic objective excessive daytime sleepiness was 67% in patients with brain trauma compared to 19% in controls. Patients significantly underestimated excessive daytime sleepiness and sleep need, emphasizing the unreliability of self-assessments on SWD in trauma patients. CONCLUSIONS This study provides prospective, controlled, and objective evidence for chronic persistence of posttraumatic SWD, which remain underestimated by patients. These results have clinical and medicolegal implications given that SWD can exacerbate other outcomes of traumatic brain injury, impair quality of life, and are associated with public safety hazards.