A systems genetics resource and analysis of sleep regulation in the mouse

Diessler, Shanaz; M, Jan; Emmenegger, Yann; Guex, Nicolas; Middleton, Benita; Skene, Debra J.; Ibberson, Mark; Burdet, Frédéric; Götz, Lou; Pagni, Marco; Sankar, Martial; Liechti, Robin; Hor, Charlotte N.; Xénarios, Ioannis; Franken, Paul

doi:10.1371/journal.pbio.2005750

Cited by 60 publications

(53 citation statements)

References 120 publications

(142 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1B, S2A-E). The similarity of the sleepwake driven dynamics in SW-slope and -amplitude was substantiated by high correlations both during baseline [R 2 =0.849, n=684 percentiles (38 mice of 18 percentiles), p<0.000001], and SD recovery [R 2 =0.874, n=532 percentiles, p<0.000001; linear regression of all NREMS percentiles, including 32 additional mice from previous studies (Diessler et al, 2018, Hoekstra et al, 2019 with frontal-parietal derivation only; Figs. 1C,D; S2G)].…”

Section: Results: Nrems Slow-waves Accelerate After Prolonged Periodsmentioning

confidence: 58%

Reassessing the validity of slow-wave dynamics as a proxy for NREM sleep homeostasis

Hubbard

Gent

Hoekstra

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Sleep-wake driven changes in NREM sleep (NREMS) EEG delta (δ: ~0.75-4.5Hz) power are widely used as proxy for a sleep homeostatic process. We noted frequency increases in δ-waves in sleep-deprived (SD) mice, prompting us to re-evaluate how slow-wave characteristics relate to prior sleep-wake history. We discovered two types of δ-waves; one responding to SD with high initial power and fast, discontinuous decay (δ2: ~2.5-3.5Hz) and another unrelated to time-spentawake with slow, linear decays (δ1: ~0.75-1.75Hz). Human experiments confirmed this δ-band heterogeneity. Similar to SD, silencing of centromedial thalamus neurons boosted δ2-waves, specifically. δ2-dynamics paralleled that of temperature, muscle tone, heart-rate, and neuronal UP/DOWN state lengths, all reverting to characteristic NREMS levels within the first recovery hour. Thus, prolonged waking seems to necessitate a physiological recalibration before typical NREMS can be reinstated. These short-lasting δ2-dynamics challenge accepted models of sleep regulation and function based on the merged δ-band as sleep-need proxy.

show abstract

Section: Results: Nrems Slow-waves Accelerate After Prolonged Periodsmentioning

confidence: 58%

Reassessing the validity of slow-wave dynamics as a proxy for NREM sleep homeostasis

Hubbard

Gent

Hoekstra

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…for Nr1d1), meaning the clock genes were assigned to C A either unequivocally, or with a close call to the more complex models S+C and S+C A (Table S4). Model C A also contained genes with increased amplitudes (331/794; 42%) after SD, such as Erbb3, Eva1b, Zfp473 and Akr1cl ( Fig 5B, Fig S2 pages [12][13][14][15]. Interestingly, the phases of expression differed between the genes with increased vs. decreased amplitudes, the former group having a similar distribution of phases to those of model C genes ( Fig 5A).…”

Section: Model S Recapitulates Known Sleep-wake Driven Genes and Closmentioning

confidence: 90%

“…The EEG cohort consisted of 12 male C57BL/6J mice 10-12 weeks at the time of SD that were part of another study (12). Surgical implantation of electrodes, EEG recording and data collection were performed according to our standard procedure 25 (see (19) for details).…”

Section: Surgery and Eeg Recordingmentioning

confidence: 99%

“…5 SD experiments aiming at identifying genes associated with the sleep homeostatic process follow the rationale that causing mice to stay awake during a time when they normally sleep will induce an acute response in sleep-wake driven genes. Indeed, studies comparing gene expression levels immediately after SD with controls collected at the same time-of-day have identified many differentially expressed genes (10)(11)(12)(13), and a few studies have probed the punctual effect of SD at different times of the 24h cycle in mice (13,14), or expression dynamics in blood during SD in humans (15,16). However, assessing the respective contributions of the two processes requires measuring gene expression over multiple time points, not only under SD, i.e.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Simple and complex interactions between sleep-wake driven and circadian processes shape daily genome regulatory dynamics in the mouse

Yeung

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

The timing and duration of sleep results from the interaction between a sleepwake driven, or homeostatic, process (S) and a circadian process (C), and involves changes in gene expression and genomic regulation. Unraveling the respective contributions of S and C, and their interaction, to transcriptional and epigenomic regulatory dynamics requires sampling over time under unperturbed conditions and conditions of perturbed sleep. Here, we profiled mRNA expression and chromatin accessibility in the cerebral cortex of mice over a three-day period, including a 6-hour sleep deprivation (SD) on day two. Mathematical modeling established that a large proportion of rhythmic genes are actually governed by Process S with varying degrees of interaction with Process C, sometimes working in opposition. Remarkably, SD causes long-term effects on gene expression dynamics, outlasting phenotypic recovery, most strikingly illustrated by a dampening of the oscillation of most core clock genes, including Bmal1, suggesting that enforced wakefulness directly impacts the molecular clock machinery. Chromatin accessibility proved highly plastic and dynamically affected by SD. Distal regions, rather than promoters, display dynamics corresponding to gene transcription, implying that changes in mRNA expression result from constantly accessible promoters under the influence of distal enhancers or repressors. Srf was predicted as a transcriptional regulator driving immediate response, suggesting that Srf activity mirrors the build-up and release of sleep pressure. Our results demonstrate that a single, short SD has long-term aftereffects at the genomic regulatory level. Such effects might accumulate with repeated sleep restrictions, thereby contributing to their adverse health effects. Significance statementWhen and how long we sleep is determined by the time-of-day and how long we have been awake, which are tracked molecularly by a circadian and a sleep-wake driven process, respectively. We measured the long-term consequences of a short-term sleep deprivation (SD) on gene expression and regulation in the mouse brain, and used mathematical models to determine the relative contributions of the circadian and sleep-wake driven processes. We find that many genes, including most of the genes that constitute the molecular circadian clock, are perturbed by SD long after the mice ceased showing behavioral signs of sleep loss. Our results have implications for human health, given the high prevalence of insufficient and poor quality sleep in our contemporary society. 4

show abstract

“…It has been proposed that sleep aids metabolite clearance (1), synaptic down-scaling (2), stress reduction (3) and protection of the heart (4). Disruption of sleep causes many changes in brain gene expression and the blood plasma metabolome (5)(6)(7). Perhaps reflecting the fundamental restorative purpose(s) of sleep, the urge to sleep, known as the homeostatic drive, increases with the time spent awake and dissipates during sleep (8).…”

Section: Introductionmentioning

confidence: 99%

Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

Ma¹,

Miracca²,

Yu³

et al. 2019

Preprint

View full text Add to dashboard Cite

Sleep deprivation induces a characteristic rebound in NREM sleep accompanied by an immediate increase in the power of delta (0.5 -4 Hz) oscillations, proportional to the prior time awake. To test the idea that galanin neurons in the mouse lateral preoptic hypothalamus (LPO) regulate this sleep homeostasis, they were selectively genetically ablated. The baseline sleep architecture of LPO-DGal mice became heavily fragmented, their average core body temperature permanently increased (by about 2°C) and the diurnal variations in body temperature across the sleep-wake cycle also markedly increased. Additionally, LPO-DGal mice showed a striking spike in body temperature and increase in wakefulness at a time (ZT24) when control mice were experiencing the opposite -a decrease in body temperature and becoming maximally sleepy (start of "lights on"). After sleep deprivation sleep homeostasis was largely abolished in LPO-DGal mice: the characteristic increase in the delta power of NREM sleep following sleep deprivation was absent, suggesting that LPO galanin neurons track the time spent awake. Moreover, the amount of recovery sleep was substantially reduced over the following hours. We also found that the a2 adrenergic agonist dexmedetomidine, used for long-term sedation during intensive care, requires LPO galanin neurons to induce both the NREM-like state with increased delta power and the reduction in body temperature, characteristic features of this drug. This suggests that dexmedetomidine over-activates the natural sleep homeostasis pathway via galanin neurons. Collectively, the results emphasize that NREM sleep and the concurrent reduction in body temperature are entwined at the circuit level. 3 Significance Catching up on lost sleep (sleep homeostasis) is a common phenomenon in mammals, but there is no circuit explanation for how this occurs. We have discovered that galanin neurons in the hypothalamus are essential for sleep homeostasis as well as for the control of body temperature. This is the first time that a neuronal cell type has been identified that underlies sleep homeostasis. Moreover, we show that activation of these galanin neurons are also essential for the actions of the a2 adrenergic agonist dexmedetomidine, which induces both hypothermia together with powerful delta oscillations resembling NREM sleep. Thus, sleep homeostasis, temperature control and sedation by a2 adrenergic agonists can all be linked at the circuit level by hypothalamic galanin neurons.

show abstract

A systems genetics resource and analysis of sleep regulation in the mouse

Cited by 60 publications

References 120 publications

Reassessing the validity of slow-wave dynamics as a proxy for NREM sleep homeostasis

Reassessing the validity of slow-wave dynamics as a proxy for NREM sleep homeostasis

Simple and complex interactions between sleep-wake driven and circadian processes shape daily genome regulatory dynamics in the mouse

Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

Contact Info

Product

Resources

About