Circadian rhythm: how the clock actually works

The suprachiasmatic nucleus, a paired cluster of ~20,000 neurons in the anterior hypothalamus above the optic chiasm, is the central pacemaker. Lesion it and behavioral and hormonal rhythms collapse; transplant a donor SCN and rhythms return with the donor's period, which Ralph et al. 1990 (Science) demonstrated in hamsters. The clock runs on a transcription-translation feedback loop in which CLOCK and BMAL1 drive Period (PER1-3) and Cryptochrome (CRY1-2) expression, whose protein products feed back to inhibit their own transcription over roughly 24 hours. Dibner et al. 2010 (Annu Rev Physiol) describe this molecular loop as conserved across nearly every cell, with the SCN acting as the conductor that synchronizes the orchestra.

Of all the inputs that set the clock (a zeitgeber, German for time-giver), light is by far the strongest. The signal does not travel through the rod and cone system used for vision but through intrinsically photosensitive retinal ganglion cells expressing the photopigment melanopsin, which Berson et al. 2002 (Science) showed fire directly in response to light and project via the retinohypothalamic tract to the SCN. Melanopsin peaks near 480 nm (short-wavelength blue), so cool morning daylight drives entrainment more effectively per photon than warm light. This is why mice lacking rods and cones still entrain, but mice additionally lacking melanopsin signaling do not.

Left in constant dim light with no time cues, the human clock free-runs at its intrinsic period, which is slightly longer than a solar day. Czeisler et al. 1999 (Science) used forced desynchrony in 24 subjects to measure a mean intrinsic period of ~24.18 hours, tightly clustered (SD ~0.2h) and far more precise than the 25h figure from older studies that were contaminated by self-selected light exposure. Because the clock runs long, it must be reset ~0.2h earlier each day, and morning light provides exactly that phase-advancing correction. Without daily resetting, sleep timing would drift later by ~12 minutes per day.

Nearly every tissue (liver, gut, pancreas, fat) carries its own molecular clock, normally kept in phase by the SCN. Dibner et al. 2010 (Annu Rev Physiol) detail how these peripheral oscillators can be uncoupled from the SCN by non-light cues: feeding time is the dominant zeitgeber for the liver, so a shifted meal schedule can desynchronize peripheral clocks from the light-entrained master clock. Ambient temperature, scheduled exercise, and social cues act as weaker secondary zeitgebers. This SCN-versus-periphery split is the mechanistic basis for why mistimed eating (late-night meals) can produce metabolic disruption even when sleep timing is unchanged.

Three measurable outputs mark clock phase. Core body temperature reaches its daily minimum (CBTmin) roughly 2-3 hours before habitual wake; light before CBTmin delays the clock, light after it advances the clock, which is the axis of the phase response curve. Dim light melatonin onset (DLMO), the rise in pineal melatonin under dim conditions, occurs ~2-3 hours before sleep onset and is the gold-standard phase marker in chronobiology labs. The cortisol awakening response, a ~50% surge within 30-45 minutes of waking, is the clock's morning output. These three markers, not clock time on the wall, define where an individual's circadian phase actually sits.

Entrainment breaks in three characteristic ways. Phase delay: evening short-wavelength light (screens, bright indoor light after dusk) hits the delay region of the phase response curve and pushes the clock later, the dominant driver of late-modern sleep timing. Social jetlag: a term coined by Roenneberg et al. 2007 (Sleep Med Rev), the chronic mismatch between weekday alarm-driven schedules and weekend free-running schedules, which behaves like flying across time zones every week and tracks with worse metabolic and mood outcomes. Free-running: in totally blind people without functional light input, the clock runs at its ~24.2h period uncorrected, producing Non-24-Hour Sleep-Wake Disorder where sleep cycles drift progressively later.