Human Melatonin and Alerting Response to Blue-Enriched Light Depend on a Polymorphism in the Clock Gene PER3

Chellappa, Sarah Laxhmi; Viola, Antoine; Schmidt, Christina; Bachmann, Valérie; Gabel, Virginie; Maire, Micheline; Reichert, Carolin; Valomon, Amandine; Götz, Thomas; Landolt, Hans‐Peter; Cajochen, Christian

doi:10.1210/jc.2011-2391

Cited by 85 publications

(83 citation statements)

References 17 publications

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“…Moreover, the sleepreducing effects of mutant PER3 are light dependent (observed only in LD and not in DD). Consistent with our findings, it has been suggested that a polymorphism in PER3 is involved in modulating the alerting effects of light and the influence of light on sleep in human subjects (38,39).…”

Section: Discussionsupporting

confidence: 92%

A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait

Zhang

Hirano

Hsu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

144

134

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In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes. I n human populations, alterations in circadian timing can result in mood-related problems (1). An example of this is seasonal affective disorder, also known as "winter depression," which is among the most common mood disorders, with a reported prevalence of 1.5-9%, depending on latitude (2). In addition, shift work has been suggested as a risk factor for major depressive disorder (3), and depression severity correlates with the degree of circadian misalignment (4, 5). A number of genetic variants in core clock genes have been reported as statistically associated with mood disorders, including seasonal affective disorder and major depressive disorder (6-14), but to date none has been causally related with an understanding of specific molecular links.Familial advanced sleep phase (FASP) is a human behavioral phenotype defined by early sleep time and early morning awakening (15). We previously identified mutations in core clock genes that cause FASP by linkage analysis/positional cloning (16) and candidate gene sequencing (17, 18). Here we identify two rare missense variants in PER3 (PER3-P415A/H417R) that cause FASP and are associated with elevated Beck Depression Inventory (BDI) and seasonality scores. Transgenic mice carrying human PER3-P415A/H417R exhibit delayed phase in a short photoperiod and a lengthened period of wheel-running rhythms in constant light. At a molecular level, the rare variants lead to decreased PER3 protein levels, likely due to decreased protein stability. Moreover, we found that PER3-P415A/H417R can exert effects on the clock (at least in part) by reducing its stabilizing effect on PER1 and PER2. Although hPER3-P415A/H417R transgenic mice display mild measures of depression-like phenotype, Per3 −/− mice exhibit consistent depression-like behaviors in multiple tests. The differences are particularly evident in short photoperiods, implying a role for PER3 in mood regulation. Taken together, these results support a role for PER3 in ...

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Section: Discussionsupporting

confidence: 92%

A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait

Zhang

Hirano

Hsu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

144

134

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“…Short wavelengths are very effective in suppressing melatonin production, which is wavelength dependent [55,56]. In human [57,58] and animals [59,60], pineal melatonin production is highly photosensitive to light of short wavelength (i.e. blue light).…”

Section: Melatonin Suppressionmentioning

confidence: 99%

Artificial light at night: melatonin as a mediator between the environment and epigenome

Haim

Zubidat

2015

Phil. Trans. R. Soc. B

107

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The adverse effects of excessive use of artificial light at night (ALAN) are becoming increasingly evident and associated with several health problems including cancer. Results of epidemiological studies revealed that the increase in breast cancer incidents co-distribute with ALAN worldwide. There is compiling evidence that suggests that melatonin suppression is linked to ALAN-induced cancer risks, but the specific genetic mechanism linking environmental exposure and the development of disease is not well known. Here we propose a possible genetic link between environmental exposure and tumorigenesis processes. We discuss evidence related to the relationship between epigenetic remodelling and oncogene expression. In breast cancer, enhanced global hypomethylation is expected in oncogenes, whereas in tumour suppressor genes local hypermethylation is recognized in the promoter CpG chains. A putative mechanism of action involving epigenetic modifications mediated by pineal melatonin is discussed in relation to cancer prevalence. Taking into account that ALAN-induced epigenetic modifications are reversible, early detection of cancer development is of great significance in the treatment of the disease. Therefore, new biomarkers for circadian disruption need to be developed to prevent ALAN damage.

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“…Together with light's wavelength, other properties, such as intensity, duration, and timing, are crucial in determining its effects on human physiology and behavior (for a review, see Cajochen, 2007). Nighttime light exposure triggers melatonin suppression with concomitant reduction of subjective sleepiness and objective markers of sleepiness (e.g., waking electroencephalographic [EEG] theta activity, incidence of slow eye movements) (Cajochen et al, 2000;Chellappa et al, 2011bChellappa et al, , 2012Lockley et al, 2006;Ruger et al, 2005). It has been suggested that these effects are mediated through melatonin's alerting effects and/or its resetting properties on the endogenous circadian pacemaker (Chellappa et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%

Effects of Artificial Dawn and Morning Blue Light on Daytime Cognitive Performance, Well-being, Cortisol and Melatonin Levels

Gabel

Maire

Reichert

et al. 2013

Chronobiology International

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134

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Light exposure elicits numerous effects on human physiology and behavior, such as better cognitive performance and mood. Here we investigated the role of morning light exposure as a countermeasure for impaired cognitive performance and mood under sleep restriction (SR). Seventeen participants took part of a 48h laboratory protocol, during which three different light settings (separated by 2 wks) were administered each morning after two 6-h sleep restriction nights: a blue monochromatic LED (light-emitting diode) light condition (BL; 100 lux at 470 nm for 20 min) starting 2 h after scheduled wake-up time, a dawn-simulating light (DsL) starting 30 min before and ending 20 min after scheduled wake-up time (polychromatic light gradually increasing from 0 to 250 lux), and a dim light (DL) condition for 2 h beginning upon scheduled wake time (58 lux). Cognitive tasks were performed every 2 h during scheduled wakefulness, and questionnaires were administered hourly to assess subjective sleepiness, mood, and wellbeing. Salivary melatonin and cortisol were collected throughout scheduled wakefulness in regular intervals, and the effects on melatonin were measured after only one light pulse. Following the first SR, analysis of the time course of cognitive performance during scheduled wakefulness indicated a decrease following DL, whereas it remained stable following BL and significantly improved after DsL. Cognitive performance levels during the second day after SR were not significantly affected by the different light conditions. However, after both SR nights, mood and well-being were significantly enhanced after exposure to morning DsL compared with DL and BL. Melatonin onset occurred earlier after morning BL exposure, than after morning DsL and DL, whereas salivary cortisol levels were higher at wake-up time after DsL compared with BL and DL. Our data indicate that exposure to an artificial morning dawn simulation light improves subjective well-being, mood, and cognitive performance, as compared with DL and BL, with minimal impact on circadian phase. Thus, DsL may provide an effective strategy for enhancing cognitive performance, wellbeing, and mood under mild sleep restriction.

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Human Melatonin and Alerting Response to Blue-Enriched Light Depend on a Polymorphism in the Clock Gene PER3

Cited by 85 publications

References 17 publications

A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait

A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait

Artificial light at night: melatonin as a mediator between the environment and epigenome

Effects of Artificial Dawn and Morning Blue Light on Daytime Cognitive Performance, Well-being, Cortisol and Melatonin Levels

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