Publications by authors named "Paul Franken"

70 Publications

Sub-minute prediction of brain temperature based on sleep-wake state in the mouse.

Elife 2021 Mar 8;10. Epub 2021 Mar 8.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Although brain temperature has neurobiological and clinical importance, it remains unclear which factors contribute to its daily dynamics and to what extent. Using a statistical approach, we previously demonstrated that hourly brain temperature values co-varied strongly with time spent awake (Hoekstra et al., 2019). Here we develop and make available a mathematical tool to simulate and predict cortical temperature in mice based on a 4-s sleep-wake sequence. Our model estimated cortical temperature with remarkable precision and accounted for 91% of the variance based on three factors: sleep-wake sequence, time-of-day ('circadian'), and a novel 'prior wake prevalence' factor, contributing with 74%, 9%, and 43%, respectively (including shared variance). We applied these optimized parameters to an independent cohort of mice and predicted cortical temperature with similar accuracy. This model confirms the profound influence of sleep-wake state on brain temperature, and can be harnessed to differentiate between thermoregulatory and sleep-wake-driven effects in experiments affecting both.
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http://dx.doi.org/10.7554/eLife.62073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939547PMC
March 2021

Circadian hepatocyte clocks keep synchrony in the absence of a master pacemaker in the suprachiasmatic nucleus or other extrahepatic clocks.

Genes Dev 2021 Mar 18;35(5-6):329-334. Epub 2021 Feb 18.

Department of Molecular Biology, Sciences III, University of Geneva, 1211 Geneva, Switzerland.

It has been assumed that the suprachiasmatic nucleus (SCN) synchronizes peripheral circadian oscillators. However, this has never been convincingly shown, since biochemical time series experiments are not feasible in behaviorally arrhythmic animals. By using long-term bioluminescence recording in freely moving mice, we show that the SCN is indeed required for maintaining synchrony between organs. Surprisingly, however, circadian oscillations persist in the livers of mice devoid of an SCN or oscillators in cells other than hepatocytes. Hence, similar to SCN neurons, hepatocytes can maintain phase coherence in the absence of Zeitgeber signals produced by other organs or environmental cycles.
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http://dx.doi.org/10.1101/gad.346460.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919413PMC
March 2021

Rapid fast-delta decay following prolonged wakefulness marks a phase of wake-inertia in NREM sleep.

Nat Commun 2020 06 19;11(1):3130. Epub 2020 Jun 19.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Sleep-wake driven changes in non-rapid-eye-movement sleep (NREM) sleep (NREMS) EEG delta (δ-)power are widely used as proxy for a sleep homeostatic process. Here, we noted frequency increases in δ-waves in sleep-deprived mice, prompting us to re-evaluate how slow-wave characteristics relate to prior sleep-wake history. We identified two classes of δ-waves; one responding to sleep deprivation with high initial power and fast, discontinuous decay during recovery sleep (δ2) and another unrelated to time-spent-awake with slow, linear decay (δ1). Reanalysis of previously published datasets demonstrates that δ-band heterogeneity after sleep deprivation is also present in human subjects. Similar to sleep deprivation, silencing of centromedial thalamus neurons boosted subsequent δ2-waves, specifically. δ2-dynamics paralleled that of temperature, muscle tone, heart rate, and neuronal ON-/OFF-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.
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http://dx.doi.org/10.1038/s41467-020-16915-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305232PMC
June 2020

Recent advances in understanding the genetics of sleep.

F1000Res 2020 27;9. Epub 2020 Mar 27.

Centre for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland.

Sleep is a ubiquitous and complex behavior in both its manifestation and regulation. Despite its essential role in maintaining optimal performance, health, and well-being, the genetic mechanisms underlying sleep remain poorly understood. Here, we review the forward genetic approaches undertaken in the last four years to elucidate the genes and gene pathways affecting sleep and its regulation. Despite an increasing number of studies and mining large databases, a coherent picture on "sleep" genes has yet to emerge. We highlight the results achieved by using unbiased genetic screens mainly in humans, mice, and fruit flies with an emphasis on normal sleep and make reference to lessons learned from the circadian field.
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http://dx.doi.org/10.12688/f1000research.22028.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104869PMC
August 2020

Sleep-wake-driven and circadian contributions to daily rhythms in gene expression and chromatin accessibility in the murine cortex.

Proc Natl Acad Sci U S A 2019 12 27;116(51):25773-25783. Epub 2019 Nov 27.

Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, CH-1015 Lausanne, Switzerland;

The timing and duration of sleep results from the interaction between a homeostatic sleep-wake-driven process and a periodic circadian process, and involves changes in gene regulation and expression. Unraveling the contributions of both processes and their interaction to transcriptional and epigenomic regulatory dynamics requires sampling over time under conditions of unperturbed and perturbed sleep. We profiled mRNA expression and chromatin accessibility in the cerebral cortex of mice over a 3-d period, including a 6-h sleep deprivation (SD) on day 2. We used mathematical modeling to integrate time series of mRNA expression data with sleep-wake history, which established that a large proportion of rhythmic genes are governed by the homeostatic process with varying degrees of interaction with the circadian process, sometimes working in opposition. Remarkably, SD caused long-term effects on gene-expression dynamics, outlasting phenotypic recovery, most strikingly illustrated by a damped oscillation of most core clock genes, including /, suggesting that enforced wakefulness directly impacts the molecular clock machinery. Chromatin accessibility proved highly plastic and dynamically affected by SD. Dynamics in distal regions, rather than promoters, correlated with mRNA expression, implying that changes in expression result from constitutively accessible promoters under the influence of enhancers or repressors. Serum response factor (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 and highlights the importance of the sleep-wake distribution to diurnal rhythmicity and circadian processes.
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http://dx.doi.org/10.1073/pnas.1910590116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925978PMC
December 2019

A multi-omics digital research object for the genetics of sleep regulation.

Sci Data 2019 10 31;6(1):258. Epub 2019 Oct 31.

Ludwig Cancer Research/CHUV-UNIL, Lausanne, Switzerland.

With the aim to uncover the molecular pathways underlying the regulation of sleep, we recently assembled an extensive and comprehensive systems genetics dataset interrogating a genetic reference population of mice at the levels of the genome, the brain and liver transcriptomes, the plasma metabolome, and the sleep-wake phenome. To facilitate a meaningful and efficient re-use of this public resource by others we designed, describe in detail, and made available a Digital Research Object (DRO), embedding data, documentation, and analytics. We present and discuss both the advantages and limitations of our multi-modal resource and analytic pipeline. The reproducibility of the results was tested by a bioinformatician not implicated in the original project and the robustness of results was assessed by re-annotating genetic and transcriptome data from the mm9 to the mm10 mouse genome assembly.
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http://dx.doi.org/10.1038/s41597-019-0171-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823400PMC
October 2019

Cold-inducible RNA-binding protein (CIRBP) adjusts clock-gene expression and REM-sleep recovery following sleep deprivation.

Elife 2019 02 5;8. Epub 2019 Feb 5.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Sleep depriving mice affects clock-gene expression, suggesting that these contribute to sleep homeostasis. The mechanisms linking extended wakefulness to clock-gene expression are, however, not well understood. We propose CIRBP to play a role because its rhythmic expression is i) sleep-wake driven and ii) necessary for high-amplitude clock-gene expression . We therefore expect knock-out (KO) mice to exhibit attenuated sleep-deprivation-induced changes in clock-gene expression, and consequently to differ in their sleep homeostatic regulation. Lack of CIRBP indeed blunted the sleep-deprivation incurred changes in cortical expression of , whereas it amplified the changes in and . Concerning sleep homeostasis, KO mice accrued only half the extra REM sleep wild-type (WT) littermates obtained during recovery. Unexpectedly, KO mice were more active during lights-off which was accompanied with faster theta oscillations compared to WT mice. Thus, CIRBP adjusts cortical clock-gene expression after sleep deprivation and expedites REM-sleep recovery.
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http://dx.doi.org/10.7554/eLife.43400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379088PMC
February 2019

Rocking Promotes Sleep in Mice through Rhythmic Stimulation of the Vestibular System.

Curr Biol 2019 02 24;29(3):392-401.e4. Epub 2019 Jan 24.

Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address:

Rocking has long been known to promote sleep in infants and, more recently, also in adults, increasing NREM sleep stage N2 and enhancing EEG slow waves and spindles. Nevertheless, whether rocking also promotes sleep in other species, and what the underlying mechanisms are, has yet to be explored. In the current study, C57BL/6J mice equipped with EEG and EMG electrodes were rocked laterally during their main sleep period, i.e., the 12-h light phase. We observed that rocking affected sleep in mice with a faster optimal rate than in humans (1.0 versus 0.25 Hz). Specifically, rocking mice at 1.0 Hz increased time spent in NREM sleep through the shortening of wake episodes and accelerated sleep onset. Although rocking did not increase EEG activity in the slow-wave and spindle-frequency ranges in mice, EEG theta activity (6-10 Hz) during active wakefulness shifted toward slower frequencies. To test the hypothesis that the rocking effects are mediated through the vestibular system, we used the otoconia-deficient tilted (tlt) mouse, which cannot encode linear acceleration. Mice homozygous for the tlt mutation were insensitive to rocking at 1.0 Hz, while the sleep and EEG response of their heterozygous and wild-type littermates resembled those of C57BL/6J mice. Our findings demonstrate that rocking also promotes sleep in the mouse and that this effect requires input from functional otolithic organs of the vestibule. Our observations also demonstrate that the maximum linear acceleration applied, and not the rocking rate per se, is key in mediating the effects of rocking on sleep.
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http://dx.doi.org/10.1016/j.cub.2018.12.007DOI Listing
February 2019

Whole-Night Continuous Rocking Entrains Spontaneous Neural Oscillations with Benefits for Sleep and Memory.

Curr Biol 2019 02 24;29(3):402-411.e3. Epub 2019 Jan 24.

Department of Neuroscience, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Center for Sleep Medicine, Geneva University Hospital, 1211 Geneva, Switzerland. Electronic address:

Sensory processing continues during sleep and can influence brain oscillations. We previously showed that a gentle rocking stimulation (0.25 Hz), during an afternoon nap, facilitates wake-sleep transition and boosts endogenous brain oscillations (i.e., EEG spindles and slow oscillations [SOs]). Here, we tested the hypothesis that the rhythmic rocking stimulation synchronizes sleep oscillations, a neurophysiological mechanism referred to as "neural entrainment." We analyzed EEG brain responses related to the stimulation recorded from 18 participants while they had a full night of sleep on a rocking bed. Moreover, because sleep oscillations are considered of critical relevance for memory processes, we also investigated whether rocking influences overnight declarative memory consolidation. We first show that, compared to a stationary night, continuous rocking shortened the latency to non-REM (NREM) sleep and strengthened sleep maintenance, as indexed by increased NREM stage 3 (N3) duration and fewer arousals. These beneficial effects were paralleled by an increase in SOs and in slow and fast spindles during N3, without affecting the physiological SO-spindle phase coupling. We then confirm that, during the rocking night, overnight memory consolidation was enhanced and also correlated with the increase in fast spindles, whose co-occurrence with the SO up-state is considered to foster cortical synaptic plasticity. Finally, supporting the hypothesis that a rhythmic stimulation entrains sleep oscillations, we report a temporal clustering of spindles and SOs relative to the rocking cycle. Altogether, these findings demonstrate that a continuous rocking stimulation strengthens deep sleep via the neural entrainment of intrinsic sleep oscillations.
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http://dx.doi.org/10.1016/j.cub.2018.12.028DOI Listing
February 2019

Bidirectional and context-dependent changes in theta and gamma oscillatory brain activity in noradrenergic cell-specific Hypocretin/Orexin receptor 1-KO mice.

Sci Rep 2018 10 19;8(1):15474. Epub 2018 Oct 19.

Department of Physiology, University of Lausanne, CH-1005, Lausanne, Switzerland.

Noradrenaline (NA) and hypocretins/orexins (HCRT), and their receptors, dynamically modulate the circuits that configure behavioral states, and their associated oscillatory activities. Salient stimuli activate spiking of locus coeruleus noradrenergic (NA) cells, inducing NA release and brain-wide noradrenergic signalling, thus resetting network activity, and mediating an orienting response. Hypothalamic HCRT neurons provide one of the densest input to NA cells. To functionally address the HCRT-to-NA connection, we selectively disrupted the Hcrtr1 gene in NA neurons, and analyzed resulting (Hcrtr1) mice', and their control littermates' electrocortical response in several contexts of enhanced arousal. Under enforced wakefulness (EW), or after cage change (CC), Hcrtr1 mice exhibited a weakened ability to lower infra-θ frequencies (1-7 Hz), and mount a robust, narrow-bandwidth, high-frequency θ rhythm (~8.5 Hz). A fast-γ (55-80 Hz) response, whose dynamics closely parallelled θ, also diminished, while β/slow-γ activity (15-45 Hz) increased. Furthermore, EW-associated locomotion was lower. Surprisingly, nestbuilding-associated wakefulness, inversely, featured enhanced θ and fast-γ activities. Thus HCRT-to-NA signalling may fine-tune arousal, up in alarming conditions, and down during self-motivated, goal-driven behaviors. Lastly, slow-wave-sleep following EW and CC, but not nestbuilding, was severely deficient in slow-δ waves (0.75-2.25 Hz), suggesting that HCRT-to-NA signalling regulates the slow-δ rebound characterizing sleep after stress-associated arousal.
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http://dx.doi.org/10.1038/s41598-018-33069-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195537PMC
October 2018

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

PLoS Biol 2018 08 9;16(8):e2005750. Epub 2018 Aug 9.

Center for Integrative Genomics, University of Lausanne, Switzerland.

Sleep is essential for optimal brain functioning and health, but the biological substrates through which sleep delivers these beneficial effects remain largely unknown. We used a systems genetics approach in the BXD genetic reference population (GRP) of mice and assembled a comprehensive experimental knowledge base comprising a deep "sleep-wake" phenome, central and peripheral transcriptomes, and plasma metabolome data, collected under undisturbed baseline conditions and after sleep deprivation (SD). We present analytical tools to interactively interrogate the database, visualize the molecular networks altered by sleep loss, and prioritize candidate genes. We found that a one-time, short disruption of sleep already extensively reshaped the systems genetics landscape by altering 60%-78% of the transcriptomes and the metabolome, with numerous genetic loci affecting the magnitude and direction of change. Systems genetics integrative analyses drawing on all levels of organization imply α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and fatty acid turnover as substrates of the negative effects of insufficient sleep. Our analyses demonstrate that genetic heterogeneity and the effects of insufficient sleep itself on the transcriptome and metabolome are far more widespread than previously reported.
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http://dx.doi.org/10.1371/journal.pbio.2005750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085075PMC
August 2018

Omics Approaches in Sleep-Wake Regulation.

Handb Exp Pharmacol 2019 ;253:59-81

Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.

Although sleep seems an obvious and simple behaviour, it is extremely complex involving numerous interactions both at the neuronal and the molecular levels. While we have gained detailed insight into the molecules and neuronal networks responsible for the circadian organization of sleep and wakefulness, the molecular underpinnings of the homeostatic aspect of sleep regulation are still unknown and the focus of a considerable research effort. In the last 20 years, the development of techniques allowing the simultaneous measurement of hundreds to thousands of molecular targets (i.e. 'omics' approaches) has enabled the unbiased study of the molecular pathways regulated by and regulating sleep. In this chapter, we will review how the different omics approaches, including transcriptomics, epigenomics, proteomics, and metabolomics, have advanced sleep research. We present relevant data in the framework of the two-process model in which circadian and homeostatic processes interact to regulate sleep. The integration of the different omics levels, known as 'systems genetics', will eventually lead to a better understanding of how information flows from the genome, to molecules, to networks, and finally to sleep both in health and disease.
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http://dx.doi.org/10.1007/164_2018_125DOI Listing
September 2019

: A New Open-Access Journal to Publish Your Circadian and Sleep Research Results.

Clocks Sleep 2019 Mar 18;1(1):1-2. Epub 2018 Apr 18.

University of Lausanne, Center for Integrative Genomics, Genopode Building, CH-1015 Lausanne-Dorigny, Switzerland.

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http://dx.doi.org/10.3390/clockssleep1010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509667PMC
March 2019

Clock-dependent chromatin topology modulates circadian transcription and behavior.

Genes Dev 2018 03 23;32(5-6):347-358. Epub 2018 Mar 23.

School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.

The circadian clock in animals orchestrates widespread oscillatory gene expression programs, which underlie 24-h rhythms in behavior and physiology. Several studies have shown the possible roles of transcription factors and chromatin marks in controlling cyclic gene expression. However, how daily active enhancers modulate rhythmic gene transcription in mammalian tissues is not known. Using circular chromosome conformation capture (4C) combined with sequencing (4C-seq), we discovered oscillatory promoter-enhancer interactions along the 24-h cycle in the mouse liver and kidney. Rhythms in chromatin interactions were abolished in arrhythmic knockout mice. Deleting a contacted intronic enhancer element in the () gene was sufficient to compromise the rhythmic chromatin contacts in tissues. Moreover, the deletion reduced the daily dynamics of transcriptional burst frequency and, remarkably, shortened the circadian period of locomotor activity rhythms. Our results establish oscillating and clock-controlled promoter-enhancer looping as a regulatory layer underlying circadian transcription and behavior.
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http://dx.doi.org/10.1101/gad.312397.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900709PMC
March 2018

Cerebral mGluR5 availability contributes to elevated sleep need and behavioral adjustment after sleep deprivation.

Elife 2017 10 5;6. Epub 2017 Oct 5.

Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.

Increased sleep time and intensity quantified as low-frequency brain electrical activity after sleep loss demonstrate that sleep need is homeostatically regulated, yet the underlying molecular mechanisms remain elusive. We here demonstrate that metabotropic glutamate receptors of subtype 5 (mGluR5) contribute to the molecular machinery governing sleep-wake homeostasis. Using positron emission tomography, magnetic resonance spectroscopy, and electroencephalography in humans, we find that increased mGluR5 availability after sleep loss tightly correlates with behavioral and electroencephalographic biomarkers of elevated sleep need. These changes are associated with altered cortical myo-inositol and glycine levels, suggesting sleep loss-induced modifications downstream of mGluR5 signaling. Knock-out mice without functional mGluR5 exhibit severe dysregulation of sleep-wake homeostasis, including lack of recovery sleep and impaired behavioral adjustment to a novel task after sleep deprivation. The data suggest that mGluR5 contribute to the brain's coping mechanisms with sleep deprivation and point to a novel target to improve disturbed wakefulness and sleep.
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http://dx.doi.org/10.7554/eLife.28751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644949PMC
October 2017

Hypocretin (orexin) is critical in sustaining theta/gamma-rich waking behaviors that drive sleep need.

Proc Natl Acad Sci U S A 2017 07 19;114(27):E5464-E5473. Epub 2017 Jun 19.

Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland.

gene inactivation in mice leads to behavioral state instability, abnormal transitions to paradoxical sleep, and cataplexy, hallmarks of narcolepsy. Sleep homeostasis is, however, considered unimpaired in patients and narcoleptic mice. We find that whereas mice respond to 6-h sleep deprivation (SD) with a slow-wave sleep (SWS) EEG δ (1.0 to 4.0 Hz) power rebound like littermates, spontaneous waking fails to induce a δ power reflecting prior waking duration. This correlates with impaired θ (6.0 to 9.5 Hz) and fast-γ (55 to 80 Hz) activity in prior waking. We algorithmically identify a theta-dominated wakefulness (TDW) substate underlying motivated behaviors and typically preceding cataplexy in mice. mice fully implement TDW when waking is enforced, but spontaneous TDW episode duration is greatly reduced. A reformulation of the classic sleep homeostasis model, where homeostatic pressure rises exclusively in TDW rather than all waking, predicts δ power dynamics both in and mouse baseline and recovery SWS. The low homeostatic impact of mouse spontaneous waking correlates with decreased cortical expression of neuronal activity-related genes (notably , /, and ). Thus, spontaneous TDW stability relies on Hcrt to sustain θ/fast-γ network activity and associated plasticity, whereas other arousal circuits sustain TDW during SD. We propose that TDW identifies a discrete global brain activity mode that is regulated by context-dependent neuromodulators and acts as a major driver of sleep homeostasis. Hcrt loss in mice causes impaired TDW maintenance in baseline wake and blunted δ power in SWS, reproducing, respectively, narcolepsy excessive daytime sleepiness and poor sleep quality.
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http://dx.doi.org/10.1073/pnas.1700983114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502606PMC
July 2017

frees mice from the repression of active wake behaviors by light.

Elife 2017 05 26;6. Epub 2017 May 26.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Besides its role in vision, light impacts physiology and behavior through circadian and direct ( 'masking') mechanisms. In Smith-Magenis syndrome (SMS), the dysregulation of both sleep-wake behavior and melatonin production strongly suggests impaired non-visual light perception. We discovered that mice haploinsufficient for the SMS causal gene, (), were hypersensitive to light such that light eliminated alert and active-wake behaviors, while leaving time-spent-awake unaffected. Moreover, variables pertaining to circadian rhythm entrainment were activated more strongly by light. At the input level, the activation of rod/cone and suprachiasmatic nuclei (SCN) by light was paradoxically greatly reduced, while the downstream activation of the ventral-subparaventricular zone (vSPVZ) was increased. The vSPVZ integrates retinal and SCN input and, when activated, suppresses locomotor activity, consistent with the behavioral hypersensitivity to light we observed. Our results implicate as a novel and central player in processing non-visual light information, from input to behavioral output.
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http://dx.doi.org/10.7554/eLife.23292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464769PMC
May 2017

Development of Circadian Sleep Regulation in the Rat: A Longitudinal Study Under Constant Conditions.

Sleep 2017 Mar;40(3)

Department of Biology, Stanford University, Stanford, CA.

Study Objectives: To better understand the development of sleep, we characterized the development of circadian rhythms in sleep and wakefulness in the artificially-reared, isolated rat pup using an experimental design that minimized the effects of maternal separation.

Methods: Neonatal rats were reared in constant conditions (dim red light) while electroencephalographic and electromyographic signals were continuously recorded for up to 3 weeks. This time period spanned the preweaned and weaned ages. The distribution of sleep-wake states was analyzed to estimate the emergence of circadian rhythms.

Results: Overt ~24-hour rhythms in time spent awake and asleep appear by postnatal day (P)17. A marked bi-modal sleep-wake pattern was also observed, evidenced by the appearance of a pronounced ~12-hour component in the periodogram over the subsequent 3 days (P17-P21). This suggested the presence of two ~24-hour components consistent with the dual-oscillator concept. During this 3-day time window, waking bouts became longer resulting in a repartition of the duration of intervals without non-rapid-eye movement (NREM) sleep into short (<30 minutes) and longer inter-NREM sleep episodes. These longer waking bouts did not immediately result in an increase in NREM sleep delta (0.5-4.0 Hz) power, which is an index of sleep homeostasis in adult mammals. The sleep homeostatic response did not fully mature until P25.

Conclusions: These results demonstrate that the maturation of circadian organization of sleep-wake behavior precedes the expression of mature sleep homeostasis.
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http://dx.doi.org/10.1093/sleep/zsw077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251512PMC
March 2017

Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing.

Nat Genet 2016 08 4;48(8):912-8. Epub 2016 Jul 4.

Wellcome Trust Centre for Human Genetics, Oxford, UK.

Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations.
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http://dx.doi.org/10.1038/ng.3595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966644PMC
August 2016

Clock-Talk: Interactions between Central and Peripheral Circadian Oscillators in Mammals.

Cold Spring Harb Symp Quant Biol 2015 18;80:223-32. Epub 2015 Dec 18.

Center of Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland.

In mammals, including humans, nearly all physiological processes are subject to daily oscillations that are governed by a circadian timing system with a complex hierarchical structure. The central pacemaker, residing in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus, is synchronized daily by photic cues transmitted from the retina to SCN neurons via the retinohypothalamic tract. In turn, the SCN must establish phase coherence between self-sustained and cell-autonomous oscillators present in most peripheral cell types. The synchronization signals (Zeitgebers) can be controlled more or less directly by the SCN. In mice and rats, feeding-fasting rhythms, which are driven by the SCN through rest-activity cycles, are the most potent Zeitgebers for the circadian oscillators of peripheral organs. Signaling through the glucocorticoid receptor and the serum response factor also participate in the phase entrainment of peripheral clocks, and these two pathways are controlled by the SCN independently of feeding-fasting rhythms. Body temperature rhythms, governed by the SCN directly and indirectly through rest-activity cycles, are perhaps the most surprising cues for peripheral oscillators. Although the molecular makeup of circadian oscillators is nearly identical in all cells, these oscillators are used for different purposes in the SCN and in peripheral organs.
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http://dx.doi.org/10.1101/sqb.2015.80.027490DOI Listing
January 2018

Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions.

Sleep 2015 Dec 1;38(12):1849-60. Epub 2015 Dec 1.

Department of Integrative Physiology, University of Colorado, Boulder, CO.

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.
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http://dx.doi.org/10.5665/sleep.5226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667373PMC
December 2015

Altered Sleep Homeostasis in Rev-erbα Knockout Mice.

Sleep 2016 Mar 1;39(3):589-601. Epub 2016 Mar 1.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Study Objectives: The nuclear receptor REV-ERBα is a potent, constitutive transcriptional repressor critical for the regulation of key circadian and metabolic genes. Recently, REV-ERBα's involvement in learning, neurogenesis, mood, and dopamine turnover was demonstrated suggesting a specific role in central nervous system functioning. We have previously shown that the brain expression of several core clock genes, including Rev-erbα, is modulated by sleep loss. We here test the consequences of a loss of REV-ERBα on the homeostatic regulation of sleep.

Methods: EEG/EMG signals were recorded in Rev-erbα knockout (KO) mice and their wild type (WT) littermates during baseline, sleep deprivation, and recovery. Cortical gene expression measurements after sleep deprivation were contrasted to baseline.

Results: Although baseline sleep/wake duration was remarkably similar, KO mice showed an advance of the sleep/wake distribution relative to the light-dark cycle. After sleep onset in baseline and after sleep deprivation, both EEG delta power (1-4 Hz) and sleep consolidation were reduced in KO mice indicating a slower increase of homeostatic sleep need during wakefulness. This slower increase might relate to the smaller increase in theta and gamma power observed in the waking EEG prior to sleep onset under both conditions. Indeed, the increased theta activity during wakefulness predicted delta power in subsequent NREM sleep. Lack of Rev-erbα increased Bmal1, Npas2, Clock, and Fabp7 expression, confirming the direct regulation of these genes by REV-ERBα also in the brain.

Conclusions: Our results add further proof to the notion that clock genes are involved in sleep homeostasis. Because accumulating evidence directly links REV-ERBα to dopamine signaling the altered homeostatic regulation of sleep reported here are discussed in that context.
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http://dx.doi.org/10.5665/sleep.5534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763348PMC
March 2016

Twist1 Is a TNF-Inducible Inhibitor of Clock Mediated Activation of Period Genes.

PLoS One 2015 11;10(9):e0137229. Epub 2015 Sep 11.

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Background: Activation of the immune system affects the circadian clock. Tumor necrosis factor (TNF) and Interleukin (IL)-1β inhibit the expression of clock genes including Period (Per) genes and the PAR-bZip clock-controlled gene D-site albumin promoter-binding protein (Dbp). These effects are due to cytokine-induced interference of E-box mediated transcription of clock genes. In the present study we have assessed the two E-box binding transcriptional regulators Twist1 and Twist2 for their role in cytokine induced inhibition of clock genes.

Methods: The expression of the clock genes Per1, Per2, Per3 and of Dbp was assessed in NIH-3T3 mouse fibroblasts and the mouse hippocampal neuronal cell line HT22. Cells were treated for 4h with TNF and IL-1β. The functional role of Twist1 and Twist2 was assessed by siRNAs against the Twist genes and by overexpression of TWIST proteins. In luciferase (luc) assays NIH-3T3 cells were transfected with reporter gene constructs, which contain a 3xPer1 E-box or a Dbp E-box. Quantitative chromatin immunoprecipitation (ChIP) was performed using antibodies to TWIST1 and CLOCK, and the E-box consensus sequences of Dbp (CATGTG) and Per1 E-box (CACGTG).

Results: We report here that siRNA against Twist1 protects NIH-3T3 cells and HT22 cells from down-regulation of Period and Dbp by TNF and IL-1β. Overexpression of Twist1, but not of Twist2, mimics the effect of the cytokines. TNF down-regulates the activation of Per1-3xE-box-luc, the effect being prevented by siRNA against Twist1. Overexpression of Twist1, but not of Twist2, inhibits Per1-3xE-box-luc or Dbp-E-Box-luc activity. ChIP experiments show TWIST1 induction by TNF to compete with CLOCK binding to the E-box of Period genes and Dbp.

Conclusion: Twist1 plays a pivotal role in the TNF mediated suppression of E-box dependent transactivation of Period genes and Dbp. Thereby Twist1 may provide a link between the immune system and the circadian timing system.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137229PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567340PMC
May 2016

A neuron-specific deletion of the microRNA-processing enzyme DICER induces severe but transient obesity in mice.

PLoS One 2015 28;10(1):e0116760. Epub 2015 Jan 28.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression post-transcriptionally. MiRNAs are implicated in various biological processes associated with obesity, including adipocyte differentiation and lipid metabolism. We used a neuronal-specific inhibition of miRNA maturation in adult mice to study the consequences of miRNA loss on obesity development. Camk2a-CreERT2 (Cre+) and floxed Dicer (Dicerlox/lox) mice were crossed to generate tamoxifen-inducible conditional Dicer knockouts (cKO). Vehicle- and/or tamoxifen-injected Cre+;Dicerlox/lox and Cre+;Dicer+/+ served as controls. Four cohorts were used to a) measure body composition, b) follow food intake and body weight dynamics, c) evaluate basal metabolism and effects of food deprivation, and d) assess the brain transcriptome consequences of miRNA loss. cKO mice developed severe obesity and gained 18 g extra weight over the 5 weeks following tamoxifen injection, mainly due to increased fat mass. This phenotype was highly reproducible and observed in all 38 cKO mice recorded and in none of the controls, excluding possible effects of tamoxifen or the non-induced transgene. Development of obesity was concomitant with hyperphagia, increased food efficiency, and decreased activity. Surprisingly, after reaching maximum body weight, obese cKO mice spontaneously started losing weight as rapidly as it was gained. Weight loss was accompanied by lowered O2-consumption and respiratory-exchange ratio. Brain transcriptome analyses in obese mice identified several obesity-related pathways (e.g. leptin, somatostatin, and nemo-like kinase signaling), as well as genes involved in feeding and appetite (e.g. Pmch, Neurotensin) and in metabolism (e.g. Bmp4, Bmp7, Ptger1, Cox7a1). A gene cluster with anti-correlated expression in the cerebral cortex of post-obese compared to obese mice was enriched for synaptic plasticity pathways. While other studies have identified a role for miRNAs in obesity, we here present a unique model that allows for the study of processes involved in reversing obesity. Moreover, our study identified the cortex as a brain area important for body weight homeostasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116760PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309537PMC
October 2015

In Vivo Imaging of the Central and Peripheral Effects of Sleep Deprivation and Suprachiasmatic Nuclei Lesion on PERIOD-2 Protein in Mice.

Sleep 2015 Sep 1;38(9):1381-94. Epub 2015 Sep 1.

Center for Integrative Genomics, University of Lausanne, Switzerland.

Study Objectives: That sleep deprivation increases the brain expression of various clock genes has been well documented. Based on these and other findings we hypothesized that clock genes not only underlie circadian rhythm generation but are also implicated in sleep homeostasis. However, long time lags have been reported between the changes in the clock gene messenger RNA levels and their encoded proteins. It is therefore crucial to establish whether also protein levels increase within the time frame known to activate a homeostatic sleep response. We report on the central and peripheral effects of sleep deprivation on PERIOD-2 (PER2) protein both in intact and suprachiasmatic nuclei-lesioned mice.

Design: In vivo and in situ PER2 imaging during baseline, sleep deprivation, and recovery.

Settings: Mouse sleep-recording facility.

Participants: Per2::Luciferase knock-in mice.

Interventions: N/A.

Measurements And Results: Six-hour sleep deprivation increased PER2 not only in the brain but also in liver and kidney. Remarkably, the effects in the liver outlasted those observed in the brain. Within the brain the increase in PER2 concerned the cerebral cortex mainly, while leaving suprachiasmatic nuclei (SCN) levels unaffected. Against expectation, sleep deprivation did not increase PER2 in the brain of arrhythmic SCN-lesioned mice because of higher PER2 levels in baseline. In contrast, liver PER2 levels did increase in these mice similar to the sham and partially lesioned controls.

Conclusions: Our results stress the importance of considering both sleep-wake dependent and circadian processes when quantifying clock-gene levels. Because sleep deprivation alters PERIOD-2 in the brain as well as in the periphery, it is tempting to speculate that clock genes constitute a common pathway mediating the shared and well-known adverse effects of both chronic sleep loss and disrupted circadian rhythmicity on metabolic health.
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http://dx.doi.org/10.5665/sleep.4974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531406PMC
September 2015

Evaluation of a piezoelectric system as an alternative to electroencephalogram/ electromyogram recordings in mouse sleep studies.

Sleep 2014 Aug 1;37(8):1383-92. Epub 2014 Aug 1.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Study Objectives: Traditionally, sleep studies in mammals are performed using electroencephalogram/electromyogram (EEG/EMG) recordings to determine sleep-wake state. In laboratory animals, this requires surgery and recovery time and causes discomfort to the animal. In this study, we evaluated the performance of an alternative, noninvasive approach utilizing piezoelectric films to determine sleep and wakefulness in mice by simultaneous EEG/EMG recordings. The piezoelectric films detect the animal's movements with high sensitivity and the regularity of the piezo output signal, related to the regular breathing movements characteristic of sleep, serves to automatically determine sleep. Although the system is commercially available (Signal Solutions LLC, Lexington, KY), this is the first statistical validation of various aspects of sleep.

Design: EEG/EMG and piezo signals were recorded simultaneously during 48 h.

Setting: Mouse sleep laboratory.

Participants: Nine male and nine female CFW outbred mice.

Interventions: EEG/EMG surgery.

Measurements And Results: The results showed a high correspondence between EEG/EMG-determined and piezo-determined total sleep time and the distribution of sleep over a 48-h baseline recording with 18 mice. Moreover, the piezo system was capable of assessing sleep quality (i.e., sleep consolidation) and interesting observations at transitions to and from rapid eye movement sleep were made that could be exploited in the future to also distinguish the two sleep states.

Conclusions: The piezo system proved to be a reliable alternative to electroencephalogram/electromyogram recording in the mouse and will be useful for first-pass, large-scale sleep screens for genetic or pharmacological studies.

Citation: Mang GM, Nicod J, Emmenegger Y, Donohue KD, O'Hara BF, Franken P. Evaluation of a piezoelectric system as an alternative to electroencephalogram/electromyogram recordings in mouse sleep studies.
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http://dx.doi.org/10.5665/sleep.3936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096208PMC
August 2014

Genetic dissection of sleep homeostasis.

Curr Top Behav Neurosci 2015 ;25:25-63

Center for Integrative Genomics, University of Lausanne, Genopode Building, 1015, Lausanne-Dorigny, Switzerland,

Sleep is a complex behavior both in its manifestation and regulation, that is common to almost all animal species studied thus far. Sleep is not a unitary behavior and has many different aspects, each of which is tightly regulated and influenced by both genetic and environmental factors. Despite its essential role for performance, health, and well-being, genetic mechanisms underlying this complex behavior remain poorly understood. One important aspect of sleep concerns its homeostatic regulation, which ensures that levels of sleep need are kept within a range still allowing optimal functioning during wakefulness. Uncovering the genetic pathways underlying the homeostatic aspect of sleep is of particular importance because it could lead to insights concerning sleep's still elusive function and is therefore a main focus of current sleep research. In this chapter, we first give a definition of sleep homeostasis and describe the molecular genetics techniques that are used to examine it. We then provide a conceptual discussion on the problem of assessing a sleep homeostatic phenotype in various animal models. We finally highlight some of the studies with a focus on clock genes and adenosine signaling molecules.
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http://dx.doi.org/10.1007/7854_2013_270DOI Listing
October 2015

Tumor necrosis factor and transforming growth factor β regulate clock genes by controlling the expression of the cold inducible RNA-binding protein (CIRBP).

J Biol Chem 2014 Jan 11;289(5):2736-44. Epub 2013 Dec 11.

From the Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.

The circadian clock drives the rhythmic expression of a broad array of genes that orchestrate metabolism, sleep wake behavior, and the immune response. Clock genes are transcriptional regulators engaged in the generation of circadian rhythms. The cold inducible RNA-binding protein (CIRBP) guarantees high amplitude expression of clock. The cytokines TNF and TGFβ impair the expression of clock genes, namely the period genes and the proline- and acidic amino acid-rich basic leucine zipper (PAR-bZip) clock-controlled genes. Here, we show that TNF and TGFβ impair the expression of Cirbp in fibroblasts and neuronal cells. IL-1β, IL-6, IFNα, and IFNγ do not exert such effects. Depletion of Cirbp is found to increase the susceptibility of cells to the TNF-mediated inhibition of high amplitude expression of clock genes and modulates the TNF-induced cytokine response. Our findings reveal a new mechanism of cytokine-regulated expression of clock genes.
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http://dx.doi.org/10.1074/jbc.M113.508200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908406PMC
January 2014

Real-time recording of circadian liver gene expression in freely moving mice reveals the phase-setting behavior of hepatocyte clocks.

Genes Dev 2013 Jul;27(13):1526-36

Department of Molecular Biology, Sciences III, University of Geneva, Switzerland.

The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) in the hypothalamus, which is thought to set the phase of slave oscillators in virtually all body cells. However, due to the lack of appropriate in vivo recording technologies, it has been difficult to study how the SCN synchronizes oscillators in peripheral tissues. Here we describe the real-time recording of bioluminescence emitted by hepatocytes expressing circadian luciferase reporter genes in freely moving mice. The technology employs a device dubbed RT-Biolumicorder, which consists of a cylindrical cage with reflecting conical walls that channel photons toward a photomultiplier tube. The monitoring of circadian liver gene expression revealed that hepatocyte oscillators of SCN-lesioned mice synchronized more rapidly to feeding cycles than hepatocyte clocks of intact mice. Hence, the SCN uses signaling pathways that counteract those of feeding rhythms when their phase is in conflict with its own phase.
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http://dx.doi.org/10.1101/gad.221374.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713432PMC
July 2013

A role for clock genes in sleep homeostasis.

Authors:
Paul Franken

Curr Opin Neurobiol 2013 Oct 4;23(5):864-72. Epub 2013 Jun 4.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. Electronic address:

The timing and quality of both sleep and wakefulness are thought to be regulated by the interaction of two processes. One of these two processes keeps track of the prior sleep-wake history and controls the homeostatic need for sleep while the other sets the time-of-day that sleep preferably occurs. The molecular pathways underlying the latter, circadian process have been studied in detail and their key role in physiological time-keeping has been well established. Analyses of sleep in mice and flies lacking core circadian clock gene proteins have demonstrated, however, that besides disrupting circadian rhythms, also sleep homeostatic processes were affected. Subsequent studies revealed that sleep loss alters both the mRNA levels and the specific DNA-binding of the key circadian transcriptional regulators to their target sequences in the mouse brain. The fact that sleep loss impinges on the very core of the molecular circadian circuitry might explain why both inadequate sleep and disrupted circadian rhythms can similarly lead to metabolic pathology. The evidence for a role for clock genes in sleep homeostasis will be reviewed here.
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http://dx.doi.org/10.1016/j.conb.2013.05.002DOI Listing
October 2013