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PubMed2005

Drosophila melanogaster: an insect model for fundamental studies of sleep.

In 2000, Drosophila melanogaster joined the ranks of vertebrates and invertebrates with a defined behavioral sleep state. The characterization of this sleep state revealed striking similarities to sleep in humans: sleep in flies has both circadian and homeostatic components, it is influenced by sex and age, and it is affected by pharmacological agents such as caffeine and antihistamines. As in mammals, arousal thresholds in flies increase with sleep deprivation. Furthermore, changes in brain electrical activity accompany the change from wake to sleep states. Not only do flies and vertebrates share these behavioral and physiological traits of sleep, but they are likely to share at least some genetic mechanisms underlying the regulation of sleep as well. This article reviews the methods currently used to identify and characterize the Drosophila sleep state. As these methods become more refined and our understanding of Drosophila sleep more detailed, the powerful techniques afforded by this organism are likely to unveil deep insights into the function(s) and regulatory mechanisms of sleep.

Animals↗
PubMed2003

Sleepiness as a state-trait phenomenon, comprising both a sleep drive and a wake drive.

In this paper it is proposed to extend the classical models of sleepiness in two ways. Firstly, the role of a wake drive, besides a sleep drive, in determining sleepiness is emphasised. Although this has already been suggested in literature and convincing arguments can be found, it is not generally accepted. Secondly, we argue to incorporate trait aspects of sleepiness or a long-term person-specific level of sleepiness, besides short-term changes of sleepiness or 'state-sleepiness'. Shortly, a conceptualisation of sleepiness in which situational wake drive and sleep drive modify a basal level of both wake drive and sleep drive, is proposed. It implies that sleepiness can result from essentially different factors involved: a chronic condition or an acute state of either a high level of sleep drive, a low level of arousal or a combination of both. This is illustrated in a working model and potential assessment tools for the wake drive and state versus trait sleepiness are discussed.

Humans↗
PubMed1996

Quantitative trait locus analyses of sleep-times induced by sedative-hypnotics in LSXSS recombinant inbred strains of mice.

The long-sleep (LS) and short-sleep (SS) selected lines of mice show highly significant differences in sleep-time for many sedative-hypnotic drugs, and the quantitative genetic nature of these differences has been well-established. Using an interval-mapping approach, quantitative trait locus (QTL) analyses of LSXSS recombinant inbred (RI) strains have been applied to sleep-time responses for various classes of sedative-hypnotic drugs: alcohols (ethanol, n-propanol, and n-butanol), the atypical anesthetic chloral hydrate, barbiturates (pentobarbital and secobarbital), and benzodiazepines (chlordiazepoxide and flurazepam). Several provisional QTLs were mapped to similar locations within and between drug classes, suggesting that some common loci are involved in sleep-times elicited by these drugs. Consistent with correlations of strain mean sleep-times between drugs tested in the LSXSS recombinant inbred strains, the number of provisional QTLs mapping to the locations of highest significance for ethanol decreases when the lipid solubility of a particular drug becomes less similar to that of ethanol. Provisional QTLs mapped for the benzodiazepines, however, revealed considerable overlap with those mapped for ethanol, although these drugs represented the most lipid-soluble category of sedative-hypnotics tested. Provisional QTLs for pentobarbital and secobarbital differed from most of those mapped for the alcohols, which supports the hypothesis that alcohols and barbiturates exert their effects mainly through different biological mechanisms in the LS and SS lines. Blood ethanol concentrations at regaining the righting reflex also mapped to several provisional QTLs corresponding to ethanol-induced sleep-times that support the contention that sleep-time is a reasonable index of the observed differences in central nervous system sensitivities to ethanol between LS and SS mice.

1-Butanol↗
PubMed2005

Reduced sleep in Drosophila Shaker mutants.

Most of us sleep 7-8 h per night, and if we are deprived of sleep our performance suffers greatly; however, a few do well with just 3-4 h of sleep-a trait that seems to run in families. Determining which genes underlie this phenotype could shed light on the mechanisms and functions of sleep. To do so, we performed mutagenesis in Drosophila melanogaster, because flies also sleep for many hours and, when sleep deprived, show sleep rebound and performance impairments. By screening 9,000 mutant lines, we found minisleep (mns), a line that sleeps for one-third of the wild-type amount. We show that mns flies perform normally in a number of tasks, have preserved sleep homeostasis, but are not impaired by sleep deprivation. We then show that mns flies carry a point mutation in a conserved domain of the Shaker gene. Moreover, after crossing out genetic modifiers accumulated over many generations, other Shaker alleles also become short sleepers and fail to complement the mns phenotype. Finally, we show that short-sleeping Shaker flies have a reduced lifespan. Shaker, which encodes a voltage-dependent potassium channel controlling membrane repolarization and transmitter release, may thus regulate sleep need or efficiency.

Amino Acid Sequence↗
PubMed2026

Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

RNA-binding proteins (RBPs) regulate gene expression, and a number of RBPs have been implicated in brain function and behavior. Here, we report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, encoding an RBP not previously linked to Mendelian disease. Thirteen individuals were identified through GeneMatcher. Their ELAVL2 variants include two structural, five nonsense, and six missense variants, supporting haploinsufficiency as the primary disease mechanism. The cohort presented with developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability, and difficulty with socialization. Three additional variants (two missense and one terminal exon truncation), each previously reported in a different large cohort study, were also included for follow-up investigations. We provide multiple lines of evidence linking variants in ELAVL2 to the observed neurodevelopmental and behavioral phenotypes. First, we show that common genetic variants in ELAVL2 are significantly associated with intelligence, motor development, sleep-related traits, and sociability in the general population. Drosophila loss-of-function models provide further independent evidence for a conserved role in the regulation of seizure-like behavior, sensory processing, and sleep. Molecular studies confirm that some of the missense variants are deleterious, leading to decreased protein levels. Together, our integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.

Humans↗
PubMed2005

Individual differences in adult human sleep and wakefulness: Leitmotif for a research agenda.

This paper reviews the literature on interindividual variability in human sleep parameters, sleepiness, responses to sleep deprivation, and manifestations of sleep disorders. Variability among individuals in sleep/wake biology and behavior is pervasive. The magnitude of such individual differences is often considerable and comparable to the effect sizes of many experimental and clinical interventions. Evidence is accumulating that certain aspects of sleep/wake-related variability--such as sleep duration, daytime sleepiness, and vulnerability to the effects of sleep loss--involve trait characteristics in healthy populations and among sleep-disordered patients. Establishing the trait-specific nature of variability in sleep/wake parameters is a prerequisite for elucidating the corresponding neurophysiologic and/or genetic mechanisms. At present, it remains largely unknown what underlies or predicts sleep/wake-related traits, what relationships these traits may have to each other, and what functional significance may be associated with specific traits. Scientific studies addressing these issues are warranted, as understanding the basis of trait variability may yield new insights into sleep/wake regulation and sleep pathology. Understanding individual differences in sleep and wakefulness may also have provocative but important implications for health economics and clinical care, as well as for safety, productivity, and general well-being. This paper gives suggestions for a research agenda focusing on individual differences in sleep research and sleep medicine.

Adolescent↗
PubMed1986

Sleep characteristics in twins.

Polysomnograms were recorded for three consecutive nights on 14 male students (mean age, 16), comprising 4 identical and 3 fraternal twin pairs. The number of body movements and the measures related to the REM cycle, which correlated among the identical twins without reference to the physical parameters, were considered to be determined by a genetic trait. The sleep spindle density was in almost complete concordance between the identical twins and was associated with some physical parameters, which suggests that sleep spindles rather reflect the individual development. %S3, %SREM and the number of SREM showed a relationship to the physical parameters, without heritability. Twitch movements during REM sleep correlated not only between the identical twins but also between the fraternal twins.

Adult↗
PubMed1994

[Sickle cell disease and depression: preliminary study using the Hamilton rating scale for depression].

Prolonged latency in the appearance of REM sleep as a marker of depression has been demonstrated in patients with the sickle-cell disease. To detect the possible existence of depressive disturbances in patients with sickle-cell disease, the Hamilton rating scale for depression (17 items) was used in 30 patients with homozygote sickle-cell disease and 31 carriers of the sickle-cell trait, treated or not with vasodilator drugs. None of the 61 subjects studied presented a score of 18 or more on the Hamilton rating scale, this being the threshold value for confirming the existence of moderate depression. However, analysis of variance showed an increase in mental dullness, agitation and somatization disorder. Dullness was related to the extent of anemia and the number of sickle-cell crises per year. Treatment had an effect on agitation in patients, with pentoxyfylline having a soothing effect unlike cinepazide maleate. Women complained of insomnia in the middle of the night and somatic anxiety and presented higher total scores than men. Men exhibited a higher degree of mental dullness. The findings of this preliminary study indicate that while not associated with frank depression, the sickle-cell gene has psychological repercussions on various depressive parameters and that these patients can benefit from treatment with pentoxyfylline.

Adolescent↗
PubMed1977

Neuroticism and dreaming sleep: a case for interactionism in personality research.

The value of a trait approach to sleep and dreaming characteristics is evaluated by reviewing recent research on differential patterns and interactions manifest by high and low neuroticism subjects. Differential patterning of dream content and REM sleep characteristics under positive and negative presleep conditions suggest a qualitative difference in experience and behavior, and a quantitative difference in "importance" attributable to the dreaming sleep process. It is hypothesized that, under "normal" conditions, low neuroticism individuals make more exclusive use of the dreaming period, while under "artificial" conditions, they demonstrate a greater motivation to compensate for restricted REM by intensification of the REM process (shortened REM onset latencies, greater REM rebound, intensified dream experiences). Finally, it is suggested that theories of dreaming sleep should recognize the importance of traits, as well as situational factors to the psychology of dreaming sleep.

Affect↗
PubMed2002

Personality, anxiety and mood traits in patients with sleep-related breathing disorders: effect of reduced daytime alertness.

OBJECTIVE: The etiology of depression and personality disorders in patients with sleep-disordered breathing (SDB) is not well defined and it is still unclear if they are directly related to the severity of the disease. In this study we test the hypothesis as to whether daytime sleepiness largely contributes to appearance of mood disorders. METHODS: Sixty patients diagnosed as having snoring (n=16) or OSA (n=44) were examined. Daytime sleepiness was assessed by the administration of the Epworth Sleepiness Scale (ESS) and by the Maintenance Wakefulness Test (MWT). The Hospital Anxiety (HAD-A) and Depression (HAD-D) Scale and the Temperament and Character Inventory (TCI) questionnaires were used for psychopathological evaluation. RESULTS: The mean HAD-A score was 6.9+/-0.45 and the average HAD-D score was 4.6+/-0.48, with no significant difference between snorers and OSA patients. Anxiety was present in 16% of cases and depression in 7%. The HAD-D score was related to the ESS score (R=0.37, P=0.003), the mean sleep latency at the MWT (R=-0.34, P=0.04), and the mean low SaO(2), ESS score alone explaining the 17% of variance in the HAD-D score. Compared to controls, there were no differences in almost all TCI scores, with novelty-seeking temperament score higher in patients. No relationships were found between HAD or TCI scores and apnea density. CONCLUSIONS: We conclude that among patients evaluated for SDB, higher depression scores show an association with reduced daytime alertness, which therefore may have important effects on mood.

Journal Article↗
PubMed2006

Nocturnal autonomic nervous system activity impairment in sickle cell trait carriers.

Sickle cell trait (SCT) is a genetic disease affecting the synthesis of normal haemoglobin (Hb) and marked by the heterozygous presence of HbA and HbS. Some studies have suggested that SCT carriers might be prone to vascular alterations, cardiac ischaemia and arrhythmias leading, in some subjects, to sudden death. It is well known that a loss or a disequilibrium of autonomic activity are powerful predictors of sudden cardiac death. We hypothesized that SCT subjects might exhibit alterations in the activity of the autonomic nervous system that could constitute further risk factors for cardiac complications. Resting haemorheological parameters (eta(b), blood viscosity; eta(p), plasma viscosity; Hct, haematocrit; Tk, red blood cell rigidity), and sympathetic and parasympathetic indices of nocturnal autonomic activity (temporal and frequency analysis of heart rate variability) were thus compared between a group of nine SCT subjects and a group of nine control subjects. eta(b) was higher in the SCT group than in the control group while Hct, eta(p) and Tk were not different. Global variability (SDNN, SDNNIDX) and parasympathetic (PNN50, RMSSD, HF) indices were significantly lower in the SCT group compared with the control group, while the LF/HF ratio was highly increased, underlining a major sympathetic shift. The autonomic imbalance in SCT subjects was mainly related to lowered parasympathetic activity. Thus, our study suggests an additional global decrease and imbalance of autonomic nervous system activity to biological disorders of SCT carriers, that may constitute further risk factors for cardiac complications in this population.

Adult↗
PubMed1992

[Interindividual differences in tolerance to shift work and characteristics of shift workers: relation between the quality and duration of sleep and certain worker characteristics].

The investigation aimed at examining the relationship between the quality and duration of sleep on the one hand and various shift workers' characteristics on the other, as well as establishing whether sleep characteristics were congruent with some other indices of night shift tolerance. A total of 604 rotating shift workers working in a fast rotating shift system were administered a battery of questionnaires. The results showed that sleep quality was related to their many characteristics, especially to neuroticism, rigidity of sleeping habits, flexibility of habits, and relaxedness. Actually, the shift workers' characteristics accounted for a notable percentage (48%) of interindividual differences in sleep quality. However, there were fewer traits related to sleep duration than to sleep quality so that only a small percentage of interindividual differences in sleep duration could be explained (12-30%). Sleep quality proved to be a good indicator of night shift tolerance. The results concerning sleep duration indicated only sleep duration on the afternoon shift and days off, as well as average sleep duration in the complete shift cycle, to be relatively good indices of night shift tolerance.

Adult↗
PubMed1996

[Evaluation of the character of morphologic traits in persons with obstructive sleep apnea].

The aim of the study was carried out to show the anthropometric analysis of patients with obstructive sleep apnoea syndrome and to answer the question about the relations between the degree of SAS and obesity. The research has begun since May 1993 in an interdisciplinary team. The study was carried out in a group of 40 men diagnosed as SAS in Sleep Apnoea Unit of Department of Pulmonary Diseases. The anthropometric analysis consists of basic somatometric measurements. The relations between obesity and the degree of apnoeas was determined by analysis of variance and the model of single and multiple regression. The obtained results demonstrate the dependence between the grade of apnoeas pathology during sleep and the measurements of upper body parts. The slope of the line B not equal to 0 indicates that the intensity of SAS increases in patients "commonly considered as obese". Obesity is an important factor leading to disturbances in respiratory ventilation. An important development of fatty tissue of the neck can cause pressure changes and can induce adipose degeneration. An increased fatty thickness of the thorax is a factor which can lead to the aggravation of symptoms.

Adult↗
PubMed1989

The cholinergic rapid eye movement sleep induction test with RS-86. State or trait marker of depression?

Rapid eye movement (REM) sleep disinhibition at the beginning of the night is one of the most frequently described biologic abnormalities in depression. As REM sleep in animals and humans seems to be facilitated by cholinergic neuronal activity, it has been postulated that REM sleep disinhibition in depression is a consequence of cholinergic neuronal overactivity. The current study with the newly available cholinergic agonist RS-86, which is orally active, has a half-life of six to eight hours, and exhibits only minor peripheral side effects, supports this assumption. The application of this compound before sleep led to a significantly faster induction of REM sleep at the beginning of the night in patients with major depressive disorders compared with healthy subjects and patients with other nondepressive psychiatric diseases, such as eating disorders. Whereas 14 of 16 depressed patients displayed sleep-onset REM periods after the administration of RS-86, this happened only in three of the 16 healthy controls and in one of the 20 patients with other diagnoses. The increased susceptibility of REM sleep to cholinergic stimulation was limited to the state of depression and was not observed in a group of remitted depressed patients.

Adolescent↗
PubMed2004

Differential effects of ethanol on gamma-aminobutyric acid-A receptor-mediated synaptic currents in congenic strains of inbred long and short-sleep mice.

BACKGROUND: Ethanol enhances gamma-aminobutyric acid (GABA)A receptor-mediated responses in the brain, and this enhancement is greater in a mouse line behaviorally more sensitive to ethanol (long sleep) than in a line (short sleep) behaviorally less ethanol sensitive (assayed by loss of righting; sleep time). Quantitative trait locus (QTL) analysis of inbred long sleep (ILS) and inbred short sleep (ISS) phenotypes revealed four chromosomal regions (Lore1, Lore2, Lore4, and Lore5) that together account for approximately 50% of ethanol-induced sleep-time variance. Congenic strains were generated, each of which is homozygous for one of four ISS Lore QTLs on the ILS background. These congenic mouse strains are ideally suited for asking which QTL regions might correlate with other phenotypes that differ between ILS and ISS mice. Here we used the congenics to investigate altered GABAA responses to ethanol. METHODS: Evoked GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) were measured by whole-cell voltage-clamp recording procedures in CA1 pyramidal neurons in hippocampal brain slices. RESULTS: GABAA IPSC responses in hippocampal brain slices from ILS mice were significantly enhanced by 80 mM ethanol, whereas those from ISS mice were not affected. ILS.Lore2 and ILS.Lore5 congenic strains were significantly enhanced by 80 mM ethanol, similar to the background (control) ILS mice. However, ethanol had no significant effect on GABAA responses in ILS.Lore1 and ILS.Lore4 congenic mice, similar to the ISS mice, thus reflecting the influence of ISS alleles on the ILS phenotype. CONCLUSIONS: Our results suggest that alleles located in the Lore1 and Lore4 QTL regions confer ethanol sensitivity of GABAA receptor-mediated IPSCs. Thus, for these QTLs, GABAA IPSCs may represent an endophenotype of sedative/hypnotic sensitivity to ethanol. Although the Lore2 and Lore5 QTL regions have a significant effect on sleep time, they do not play a significant role in the differential ethanol enhancement of GABAA IPSCs between ILS and ISS mice.

Animals↗