Human Chronotype Is Determined in Bodily Cells Under Real-Life Conditions

Abstract

Individuals differ in their preferred timing of sleep and activity, which is referred to as a chronotype. The timing shows a wide distribution; extremely early chronotypes may wake up when the extremely late chronotypes fall asleep. The chronotype is supposed to be determined by the central circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus because the phasing of the pineal melatonin rhythm, which is driven by the SCN, correlates with the sleep timing preference. In addition to the SCN, circadian oscillators are also present in most if not all bodily cells. These peripheral clocks are synchronized by the central SCN clock and by other tissue-specific entraining cues. At the molecular level, the circadian oscillations are based on a complex, self-sustaining mechanism that drives the rhythmical expression of clock genes and their proteins. The aim of the present field study was to elucidate whether the changes in the internal timing of early and late chronotypes, as expressed by changes in the phases of their mid-sleep and melatonin secretion, can also be detected at the molecular clockwork level in subjects examined under real-life conditions. Ninety-five adult volunteers were chronotyped using an adapted Munich chronotype questionnaire to assess their mid-sleep phase, and 6 subjects with early chronotypes and 6 with late chronotypes were chosen for the study. For the assessment of the circadian phase, the subjects provided samples of saliva for the melatonin assay and samples of oral mucosa for the determination of clock gene Per1, Per2, and Reverbα mRNA levels every 4 h during a 24-h period. The significant correlation between the phase of the melatonin profile and timing of mid-sleep confirmed the classification of the subjects according to their chronotype. The circadian phases of the Per1, Per2, and Rev-erbα expression profiles in the oral mucosa were advanced in the early chronotypes compared with those in the late chronotypes ( p < .001) and correlated significantly with the mid-sleep phase of the individual subjects. Moreover, the circadian phases of the Per1 expression profiles of individual subjects correlated significantly with the phases of their melatonin profiles ( p < .05), whereas the correlation for the Per2 and Rev-erbα phases was nonsignificant, although the trend was the same. Our results demonstrate that the individual chronotype in humans living in real-life conditions affects not only the phasing of the daily melatonin rhythm in saliva but also the phasing of Per1, Per2, and Rev-erbα clock gene expression profiles in buccal mucosa cells. This report represents the first demonstration that the human peripheral circadian clock may sense the individual's chronotype under field study conditions. The data contribute to our understanding of the mechanisms underlying human chronotypes in real life. (Author correspondence: sumova@biomed.cas.cz)

Motor-Activity Markers of Circadian Timekeeping Are Related to Ketamine’s Rapid Antidepressant Properties

“…CLOCK gene variants alter circadian amplitude and phase (55, 56), biomarkers also associated with morning-evening variation in chronotypes (57), suggesting that such gene mutations might mediate rapid antidepressant response to ketamine (Table 3), and that their markers (amplitude and phase) may also be useful for predicting ketamine response per se .…”

Altered Phase-Relationship between Peripheral Oscillators and Environmental Time in Cry1 or Cry2 Deficient Mouse Models for Early and Late Chronotypes

“…LD 12∶12) are phase advanced in comparison to that of wild type animals, while oppositely, these peripheral clocks are phase delayed in long period Cry2 -/- mice in a tissue specific manner. The resulting dissonance between body time and environmental time likely mimics the condition encountered by human “larks” and “owls”, whose morningness and eveningness chronotype has been associated with alterations in the period and phase of their molecular circadian oscillator [46], [47]. Recent studies indicate that indeed the physiological period length of the human clock in vivo correlates with the period of the peripheral molecular oscillator in cultured fibroblasts from the same individuals [24], [25], [48].…”

Physical activity, and not fat mass is a primary predictor of circadian parameters in young men

“…These temperature rhythms have been shown to correlate with changes in dim light melatonin onset, a standard for determining circadian phase in people (Nováková et al, 2013). Despite the aforementioned studies, assessment of wrist temperature rhythms in healthy college age men with variable sleep/wake/activity schedules has not been performed.…”

“…Early studies using this approach validated it against dim light melatonin measures and found that the rise in wrist temperature occurred in anticipation of the evening increase in melatonin. Decreases in activity, changes in body position and increases in declared sleep propensity were delayed with respect to increases in dim light melatonin (Bonmati-Carrion et al, 2014; Corbalán-Tutau et al, 2011; Gompper et al, 2010; Kripke et al, 2005; Morgan et al, 1998; Nováková et al, 2013; Sarabia et al, 2008; van Marken Lichtenbelt et al, 2006). Furthermore, wrist skin temperature measures have been reported to be inversely correlated and phase-advanced with the oscillations of core body temperature, thus making this non-intrusive measurement method a reliable candidate to examine circadian rhythmicity (Marotte & Timbal, 1981; Sarabia et al, 2008).…”