Genetics and Cognitive Vulnerability to Sleep Deprivation in Healthy Subjects: Interaction of ADORA2A, TNF-α and COMT Polymorphisms

Several genetic polymorphisms differentiate between healthy individuals who are more cognitively vulnerable or resistant during total sleep deprivation (TSD). Common metrics of cognitive functioning for classifying vulnerable and resilient individuals include the Psychomotor Vigilance Test (PVT), Go/noGo executive inhibition task, and subjective daytime sleepiness. We evaluated the influence of 14 single-nucleotide polymorphisms (SNPs) on cognitive responses during total sleep deprivation (continuous wakefulness for 38 h) in 47 healthy subjects (age 37.0 ± 1.1 years). SNPs selected after a literature review included SNPs of the adenosine-A2A receptor gene (including the most studied rs5751876), pro-inflammatory cytokines (TNF-α, IL1-β, IL-6), catechol-O-methyl-transferase (COMT), and PER3. Subjects performed a psychomotor vigilance test (PVT) and a Go/noGo-inhibition task, and completed the Karolinska Sleepiness Scale (KSS) every 6 h during TSD. For PVT lapses (reaction time >500 ms), an interaction between SNP and SDT (p < 0.05) was observed for ADORA2A (rs5751862 and rs2236624) and TNF-α (rs1800629). During TSD, carriers of the A allele for ADORA2A (rs5751862) and TNF-α were significantly more impaired for cognitive responses than their respective ancestral G/G genotypes. Carriers of the ancestral G/G genotype of ADORA2A rs5751862 were found to be very similar to the most resilient subjects for PVT lapses and Go/noGo commission errors. Carriers of the ancestral G/G genotype of COMT were close to the most vulnerable subjects. ADORA2A (rs5751862) was significantly associated with COMT (rs4680) (p = 0.001). In conclusion, we show that genetic polymorphisms in ADORA2A (rs5751862), TNF-α (rs1800629), and COMT (rs4680) are involved in creating profiles of high vulnerability or high resilience to sleep deprivation. (NCT03859882)

Sleep Extension before Sleep Loss

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Effects of acute caffeine intake on Insulin-like Growth Factor-1 responses to total sleep deprivation: interactions with COMT polymorphism, a randomized, cross over study

Abstract Introduction: Genes encoding catechol-O-methyl-transferase (COMT) and adenosine A2A receptor (ADORA2A) have been shown to influence cognitive performances and responses to caffeine intake during prolonged wakefulness. The rs4680 single nucleotide polymorphism (SNP) of COMT differentiates on memory score and circulating levels of the neurotrophic factor IGF-1. This study aimed to determine the kinetics of IGF-1, testosterone and cortisol concentrations during prolonged wakefulness under caffeine or placebo intake in 37 healthy participants, and to analyze whether the responses are dependent on COMT rs4680 or ADORA2A rs5751876 SNPs. Methods: In caffeine (2.5 mg/kg, twice over 24 hours) or placebo-controlled condition, blood sampling was performed at 1h (08:00, baseline), 11h, 13h, 25h (08:00 next day), 35h, and 37h of prolonged wakefulness, and at 08:00 after one night of recovery sleep, to assess hormonal concentrations. Genotyping was performed on blood cells. Results: Results indicated a significant increase in IGF-1 levels after 25, 35, and 37 hours of prolonged wakefulness in the placebo condition, in subjects carrying the homozygous COMT A/A genotype only (expressed in absolute values (± SEM): 118 ± 8, 121 ± 10 and 121 ± 10 versus 105 ± 7 ng/ml for A/A, 127 ± 11, 128 ± 12 and 129 ± 13 versus 120 ± 11 ng/ml for G/G, and 106 ± 9, 110 ± 10 and 106 ± 10 versus 101 ± 8 ng/ml for G/A, after 25, 35 and 37 h of wakefulness versus 1h; p<0.05, condition X time X SNP). Acute caffeine intake exerted a COMT genotype-dependent reducing effect on IGF-1 kinetic response (104 ± 26, 107 ± 27 and 106 ± 26 versus 100 ± 25 ng/ml for A/A genotype, at 25, 35 and 37 h of wakefulness versus 1h; p<0.05 condition X time X SNP), plus on resting levels after overnight recovery (102 ± 5 versus 113 ± 6 ng/ml) (p<0.05, condition X SNP). Testosterone and cortisol concentrations decreased during wakefulness, and caffeine alleviated the testosterone reduction, unrelated to the COMT polymorphism. No significant main effect of the ADORA2A SNP was shown regardless of hormonal responses. Discussion/Conclusion: Our results indicated that the COMT polymorphism interaction is important in determining the IGF-1 neurotrophic response to sleep deprivation with caffeine intake. (NCT03859882)

Exercise-specific effects on the motor performance, glycemia regulation and muscle histology of a mouse model of limb-girdle muscular dystrophy r1 (calpainopathy)

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Exercise-specific effects on the motor performance, glycemia regulation and muscle histology of a mouse model of limb-girdle muscular dystrophy r1 (calpainopathy)

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Impact of total sleep deprivation and related mood changes on approach-avoidance decisions to threat-related facial displays

International audienceStudy Objectives: Total sleep deprivation is known to have significant detrimental effects on cognitive and socio-emotional functioning. Nonetheless, the mechanisms by which total sleep loss disturbs decision-making in social contexts are poorly understood. Here, we investigated the impact of total sleep deprivation on approach/avoidance decisions when faced with threatening individuals, as well as the potential moderating role of sleep-related mood changes. Methods: Participants (n = 34) made spontaneous approach/avoidance decisions in the presence of task-irrelevant angry or fearful individuals, while rested or totally sleep deprived (27 h of continuous wakefulness). Sleep-related changes in mood and sustained attention were assessed using the Positive and Negative Affective Scale and the psychomotor vigilance task, respectively. Results: Rested participants avoided both fearful and angry individuals, with stronger avoidance for angry individuals, in line with previous results. On the contrary, totally sleep deprived participants favored neither approach nor avoidance of fearful individuals, while they still comparably avoided angry individuals. Driftdiffusion models showed that this effect was accounted for by the fact that total sleep deprivation reduced value-based evidence accumulation toward avoidance during decision making. Finally, the reduction of positive mood after total sleep deprivation positively correlated with the reduction of fearful display avoidance. Importantly, this correlation was not mediated by a sleep-related reduction in sustained attention. Conclusions: All together, these findings support the underestimated role of positive mood-state alterations caused by total sleep loss on approach/avoidance decisions when facing ambiguous socio-emotional displays, such as fear

Genotyping on blood and buccal cells using loop-mediated isothermal amplification in healthy humans

International audienceGenetic variations contribute to phenotypic individual vulnerabilities to sleep debt, particularly for five single nucleotide polymorphisms (SNPs). Loop-mediated isothermal amplification and melting curve analysis (LAMP-MC) is a recently developed method to characterize SNPs. The aim of present study was to evaluate the LAMP-MC method on blood and buccal cells for detection of five SNPs of interest in healthy humans. We first analyzed signals obtained from LAMP-MC method on 42 samples. Then we compared the results with those of referent TaqMan method. The LAMP-MC method produced specific melting curves for the five SNPs. A high concordance of genotyping results was observed between the two methods for rs5751876_ADORA2A, rs1800629_TNF-α, rs73598374_ADA and rs228697_PER3 in blood and saliva (Cohen’s kappa coefficient >0.80). A good agreement ( = 0.61) was observed for rs4680_COMT in blood only. LAMP-MC is a simple and reliable method to study genetic influences on health, sleep debt-related performance impairments and countermeasures

Relationship between Habitual Caffeine Consumption, Attentional Performance, and Individual Alpha Frequency during Total Sleep Deprivation

International audience(1) Background: Caffeine is a psychostimulant that is well known to mitigate the deleterious effects of sleep debt. Our aim was to assess the effects of acute caffeine intake on cognitive vulnerability and brain activity during total sleep deprivation (TSD), taking into account habitual caffeine consumption. (2) Methods: Thirty-seven subjects were evaluated in a double-blind, crossover, total sleep deprivation protocol with caffeine or placebo treatment. Vigilant attention was evaluated every six hours during TSD using the psychomotor vigilance test (PVT) with EEG recordings. The influence of habitual caffeine consumption was analyzed by categorizing subjects into low, moderate, and high consumers. (3) Results: The PVT reaction time (RT) increased during TSD and was lower in the caffeine condition vs. the placebo condition. The RT was shorter in the low-caffeine consumers compared to moderate and high consumers, regardless of conditions and treatments. The TSD-related increase in EEG power was attenuated by acute caffeine intake independently of habitual caffeine consumption, and the individual alpha frequency (IAF) was lower in the high-consumption group. The IAF was negatively correlated with daytime sleepiness. Moreover, a correlation analysis showed that the higher the daily caffeine consumption, the higher the RT and the lower the IAF. (4) Conclusions: A high level of habitual caffeine consumption decreases attentional performance and alpha frequencies, decreasing tolerance to sleep deprivation

Relationship between genetic polymorphisms of cytokines and self-reported sleep complaints and habitual caffeine consumption

International audiencePro-inflammatory cytokines are involved in sleep-wake regulation and are associated with caffeine consumption. This is a cross-sectional study in 1023 active French workers investigating associations between self-reported sleep complaints (>3months) and total sleep time (TST) with nine single-nucleotide-polymorphisms (SNPs) including pro-inflammatory cytokines, according to caffeine consumption. Participants were characterized as low, moderate and high (0–50, 51–300, and >300 mg/day) caffeine consumers. After adjusting the odd ratios (OR) for age, gender, and smoking, the risk of sleep complaints was higher in subjects with genetic mutations in tumor necrosis factor alpha (TNF-α, rs 1800629) (ORa [95%CI] = 1.43 [1.07–1.92] for both G/A and A/A aggregate genotypes) or interleukin-1 beta (IL-1β, rs1143627) (ORa = 1.61 [1.08–2.44] for homozygous A/A genotype), and the risk was higher when subjects carry the mutations in TNF-α plus IL-1β regardless of caffeine consumption. When stratified with caffeine consumption, the risk of sleep complaints was higher in TNF-α A allele carriers in high caffeine consumers, and in homozygous A/A genotype of IL-1β in moderate and high consumers. None of the nine SNPs influence TST, with the exception of the mutation on CYP1A2 and only when stratified with caffeine consumption. Our results also indicated more caffeine side-effects when carrying mutation on IL1β. This study showed that polymorphisms in TNF-α and/or IL-1β influenced sleep complaints but did not influence total sleep time. This suggests that management of sleep complaints, which can be addressed by clinical interventions, should consider the influence of the genetic profile of pro-inflammatory cytokines