Evidence for a biological dawn and dusk in the human circadian timing system

Abstract

1. Because individuals differ in the phase angle at which their circadian rhythms are entrained to external time cues, averaging group data relative to clock time sometimes obscures abrupt changes that are characteristic of waveforms of the rhythms in individuals. Such changes may have important implications for the temporal organization of human circadian physiology. 2. To control for variance in phase angle of entrainment, we used dual internal reference points--onset and offset of the nocturnal period of melatonin secretion--to calculate average profiles of circadian rhythm data from five previously published studies. 3. Onset and/or offset of melatonin secretion were found to coincide with switch-like transitions between distinct diurnal and nocturnal periods of circadian rhythms in core body temperature, sleepiness, power in the theta band of the wake EEG, sleep propensity and rapid eye movement (REM) sleep propensity. 4. Transitions between diurnal and nocturnal periods of sleep-wake and cortisol circadian rhythms were found to lag the other transitions by 1-3 h. 5. When the duration of the daily light period was manipulated experimentally, melatonin-onset-related transitions in circadian rhythms appeared to be entrained to the light-to-dark transition, while melatonin-offset-related transitions appeared to be entrained to the dark-to-light transition. 6. These results suggest a model of the human circadian timing system in which two states, one diurnal and one nocturnal, alternate with one another, and in which transitions between the states are switch-like and are separately entrained to dawn and dusk. 7. This description of the human circadian system is similar to the Pittendrigh-Daan model of the rodent circadian system, and it suggests that core features of the system in other mammals are conserved in humans.

Figures

Figure 1. Onset and offset of nocturnal melatonin secretion

Twenty-four hour profiles of plasma melatonin levels in summer (left panel) and winter (right panel) in nine men who remained awake and at rest in constant dim light. For each profile, arrows indicate when the onset and offset of nocturnal period of melatonin secretion were judged to have occurred. Simultaneous profiles of rectal temperature appear in Fig. 2. Group-average profiles appear in Fig. 3. Data are extracted from Wehr et al. (1995a).

Figure 2. Onsets of evening decline and morning rise of core body temperature

Twenty-four hour profiles of rectal temperature in summer (left panel) and winter (right panel) in nine men who remained awake and at rest in constant dim light. For each profile, arrows indicate when the temperature was judged to have begun a rapid decline from high daytime levels to low night-time levels and when it was judged to have begun a rapid rise from low night-time levels to high daytime levels. Simultaneous profiles of plasma melatonin levels appear in Fig. 1. Group-average profiles appear in Fig. 3. Data are extracted from Wehr et al. (1995a).

Figure 3. Simultaneous evening and morning transitions in melatonin and temperature circadian rhythms

Group-average 24 h profiles (±s.e.m.) of plasma melatonin levels and rectal temperature in winter and summer in individuals who remained awake and at rest in constant dim light. Onset of melatonin secretion coincides with the beginning of a rapid, exponential decline of temperature from high daytime values to low night-time values. Offset of melatonin secretion coincides with the beginning of a rapid, exponential rise of temperature from low night-time values to high daytime values. A and B, melatonin and temperature data in the left half of each circadian rhythm profile are averaged across subjects with reference to their time of onset of melatonin secretion (shown in Fig. 1). This reference point in average profiles is positioned over the abscissa at its average time of occurrence in the group, indicated by the left margin of the cross-hatched area delineating the period of nocturnal melatonin secretion. Melatonin and temperature data in the right half of each circadian rhythm profile are averaged across subjects with reference to their time of offset of melatonin secretion (shown in Fig. 1). This reference point in average profiles is positioned over the abscissa at its average time of occurrence in the group, indicated by the right margin of the cross-hatched area delineating the period of nocturnal melatonin secretion. Ninety-five per cent confidence intervals for onset of evening decline in temperature relative to onset of melatonin secretion, and onset of morning rise in temperature relative to offset of melatonin secretion, are shown. C, temperature data in the left half of each circadian rhythm profile are averaged across subjects with reference to their time of beginning of rapid decline in temperature from high daytime levels to low night-time levels (shown in Fig. 2). Temperature data in the right half of each circadian rhythm profile are averaged across subjects with reference to their time of beginning of rapid rise in temperature from low night-time levels to high daytime levels (shown in Fig. 2). These reference points in average profiles are positioned over the abscissa at their average time of occurrence in the group, indicated by arrows. Note that average times of corresponding reference points in temperature and melatonin rhythms coincide exactly. Since data in the right half of each melatonin profile were averaged across subjects with reference to a local maximum that was identified as the end of secretion, a local maximum has been preserved in the average profile at this point. Data are from nine pairs of profiles in nine subjects extracted from Wehr et al. (1995a).

Figure 4. Simultaneous evening and morning transitions in melatonin and sleepiness circadian rhythms

Group-average 24 h profiles (±s.e.m.) of plasma melatonin levels and self-ratings of sleepiness on the Stanford Sleepiness Scale in individuals who remained awake and at rest in constant dim light. Onset and offset of melatonin secretion coincide with onset and offset of nocturnal period of increasing sleepiness. The hatched area delineates the nocturnal period of melatonin secretion. Ninety-five per cent confidence intervals are shown for onset and offset of the nocturnal period of increasing sleepiness, relative to onset and offset, respectively, of melatonin secretion. 24 h profiles are constructed as described for A and B in Fig. 3. Data are from 18 pairs of rhythm profiles in 18 subjects extracted from Wehr et al. (1993) and Wehr et al. (1995a).

Figure 6. Simultaneous evening transitions in melatonin and EEG theta activity circadian rhythms

Group-average 24 h profiles (±s.e.m.) of plasma melatonin levels and power density in the theta band of wake EEG in individuals who remained awake and at rest in constant dim light. The wake-dependent component that was approximated by a saturating exponential function was removed from the theta profile. The hatched area delineates the nocturnal period of melatonin secretion. The onset of melatonin secretion coincides with the transition from the diurnal period of decreasing theta power density to the nocturnal period of increasing power density. The 24 h profiles are constructed as described for the left half of A and B in Fig. 3. Ninety-five per cent confidence intervals are shown for onset of the nocturnal period of increasing theta power, relative to onset of melatonin secretion. Data are from 10 rhythm profiles in 10 subjects extracted from Aeschbach et al. (1999).

Figure 7. Simultaneous morning transitions in melatonin and REM sleep propensity circadian rhythms

Group-average 24 h profiles (±s.e.m.) of plasma melatonin levels and amount of REM sleep in individuals who slept during a 14 h dark period from 6 p.m. to 8 a.m. for several weeks. The hatched area delineates the nocturnal period of melatonin secretion. Offset of melatonin secretion coincides with the transition from the nocturnal period of increasing frequency of REM sleep to the diurnal period of decreasing frequency of REM sleep (as a percentage of recording time). 24 h profiles are constructed as described for A and B in Fig. 3. Ninety-five per cent confidence intervals are shown for offset of the nocturnal period of increasing frequency of REM sleep, relative to offset of melatonin secretion. Data are from 10 six-night-average REM sleep profiles in 10 subjects extracted from Wehr et al. (1993).

Figure 5. Simultaneous evening transitions in melatonin and sleep propensity circadian rhythms

Group-average 24 h profiles (±s.e.m.) of plasma melatonin levels and sleep propensity in individuals who were given a 10 min sleep opportunity every 30 min. The hatched area delineates the nocturnal period of melatonin secretion. Onset of melatonin secretion coincides with onset of the nocturnal period of increasing sleep propensity. Ninety-five per cent confidence intervals are shown for onset and offset of the nocturnal period of increasing sleep propensity, relative to onset and offset, respectively, of melatonin secretion. 24 h profiles are constructed as described for A and B in Fig. 3. Data from six pairs of rhythm profiles in six subjects are extracted from Wehr (1996).

Figure 8. One to three hour lag between evening and morning transitions of cortisol and sleep-wake circadian rhythms relative to those of melatonin circadian rhythm

Group-average 24 h profiles (±s.e.m.) of plasma melatonin levels and plasma cortisol levels in individuals who remained awake and at rest in constant dim light. Onset and offset of the nocturnal period of increasing cortisol levels lag by 1-3 h onset and offset, respectively, of nocturnal melatonin secretion. The hatched area delineates the nocturnal period of melatonin secretion. Ninety-five per cent confidence intervals are shown for onset and offset of the nocturnal period of increasing cortisol levels, relative to onset and offset, respectively, of melatonin secretion. A and B, 24 h profiles constructed as described for A and B in Fig. 3. C, sleep and cortisol data in the left half of the graph are averaged across subjects with reference to their time of onset of sleep. Sleep and cortisol data in the right half of the graph are averaged across subjects with reference to their time of offset of sleep. These reference points in average profiles are positioned over the abscissa at their average times of occurrence in the group, indicated by dotted lines on the left and right, respectively. Ninety-five per cent confidence intervals are shown for onset and offset of the nocturnal period of increasing cortisol levels, relative to onset and offset respectively, of sleep. Data are from nine pairs of rhythm profiles in nine subjects extracted from Wehr et al. (1993).

Figure 9. Morning and evening transitions in circadian rhythms separately entrained to dawn and dusk

Group-average 24 h profiles (±s.e.m.) of plasma melatonin levels, sleepiness self-ratings (Stanford Scale), and plasma cortisol levels in individuals who remained awake and at rest in constant dim light after they were chronically exposed to short artificial ‘nights’ (left panel) and to long artificial ‘nights’ (right panel). Group-average profiles (±s.e.m.) of the prior sleep period are also shown. Nocturnal periods of melatonin secretion, increasing sleepiness and increasing cortisol were longer after exposure to long nights compared with short nights. The black horizontal bars indicate duration of nightly periods of darkness. The hatched areas delineate nocturnal periods of melatonin secretion. Ninety-five per cent confidence intervals are shown for onset and offset of nocturnal periods of increasing sleepiness and increasing plasma cortisol levels relative to onset and offset, respectively, of melatonin secretion. A and B, 24 h profiles of rhythms constructed as described for A and B in Fig. 3. C, 24 h profiles of rhythms constructed as described for C in Fig. 8. Data are from nine pairs of rhythm profiles in nine subjects extracted from Wehr et al. (1993).

Figure 11. Group-average 24 h melatonin profiles referenced to external clock-time and internal circadian time

Group-average 24 h profiles (±s.e.m.) of plasma melatonin levels in constant dim light in 55 healthy individuals (23 men and 32 women) who slept according to their habitual sleep schedules and remained in constant dim (< 1 lx) light when they were awake. A,melatonin data are averaged across subjects with reference to clock-time. B, same data averaged with reference to onset (up-arrow) and offset (down-arrow) of melatonin secretion (B), as described for A and B in Fig. 3. Because individuals differ in schedules to which their circadian rhythms are entrained and in phase angles at which their circadian rhythms are entrained to these schedules, abrupt changes that are characteristic of rhythm waveforms in individuals, such as onset of melatonin secretion (see examples in Fig. 1), are obscured when data are averaged relative to external phase markers (A). These features are preserved when data are averaged relative to internal phase markers (B). Data extracted from Wehr et al. (2001).

Figure 10. Temporal organization of the human circadian timing system

Profiles of a number of circadian rhythms in humans exhibit distinct diurnal and nocturnal states with abrupt switch-like transitions between them. These states and transitions can be conceptualized as a biological day and night and a biological dawn and dusk. They are generated within the organism and mirror and anticipate features of the solar day to which they correspond, and with which they are synchronized.