1.9 Chronobiology
89
light acutely suppresses elevated melatonin levels, immediately
decreasing them to baseline levels. Second, light shifts the phase
of the circadian rhythm of melatonin synthesis. Because melato-
nin can be assayed easily, it provides a convenient window into
the state of the circadian pacemaker. Any perturbation of the
clock is reflected in the melatonin profile; thus melatonin offers
an output that can be used to study the regulation of the central
circadian pacemaker.
Sleep and Circadian Rhythms
Sleep Regulation
Restful consolidated sleep is most appreciated when sleep dis-
turbances are experienced. Sleep is the integrated product of two
oscillatory processes. The first process, frequently referred to as
the
sleep homeostat,
is an oscillation that stems from the accu-
mulation and dissipation of sleep debt. The biological substrates
encoding sleep debt are not known, although adenosine is emerg-
ing as a primary candidate neuromodulator of the sleep homeo-
stat. The second oscillatory process is governed by the circadian
clock and controls a daily rhythm in sleep propensity or, con-
versely, arousal. These interacting oscillations can be dissociated
by housing subjects in a timeless environment for several weeks.
The circadian cycle in arousal (wakefulness) steadily
increases throughout the day, reaching a maximum immediately
before the circadian increase in plasma melatonin (Fig. 1.9-1).
Arousal subsequently decreases to coincide with the circadian
trough in core body temperature. Experiments imposing forced
sleep schedules throughout the circadian day have shown that an
uninterrupted 8-hour bout of sleep can only be obtained if sleep
is initiated approximately 6 hours before the temperature nadir.
This nadir typically occurs at approximately 5:00 am to 6:00 am.
In healthy individuals, initiating sleep between 11:00 pm and
12:00 am affords the highest probability of getting 8 solid hours
of sleep.
It should be stressed that diurnal preference varies among indi-
viduals as a function of age, endogenous circadian periods, and
other factors. This variability is paralleled by physiology. Clinically,
diurnal preference can be quantified using the Horne–Östberg
(HO) Morningness-Eveningness Questionnaire (MEQ). In qualita-
tive terms,
morning people
or
morning larks
tend to awaken earlier
and experience the core body temperature minimum at an earlier
clock time relative to
night people
or
night owls.
Sleep depriva-
tion studies have shown that the homeostatic component of sleep is
remarkably similar among individuals of similar age. (It should be
noted that there is a well-established age-dependent decline in sleep
need.) Therefore, diurnal preference is dictated almost exclusively
by the circadian component of sleep regulation.
Circadian Sleep Disorders
Advanced sleep phase syndrome (ASPS) is a pathological
extreme of the morning lark phenotype. An autosomal-domi-
nant familial form of ASPS (FASPS) recently has been geneti-
cally characterized. Afflicted family members exhibit a striking
4-hour advance of the daily sleep–wake rhythm. They typi-
cally fall asleep at approximately 7:30 pm and spontaneously
awaken at approximately 4:30 am. Affected individuals have a
single nucleotide polymorphism in the gene encoding hPER2,
the human homolog of the mouse
Per2
clock gene. This ade-
nine-to-guanine nucleotide polymorphism results in serine-
to-glycine amino acid substitution that causes the mutant pro-
tein to be inefficiently phosphorylated by casein kinase I
e
,
an
established component of the circadian molecular clockwork.
Similarly, delayed sleep phase syndrome (DSPS) has been
shown to be influenced by genetics. A length polymorphism
in a repeat region of the
hPER3
gene appears to be associated
with diurnal preference in patients with DSPS, the shorter allele
being associated with evening preference.
The advent of the light bulb has extended the human day
into the natural night. This encroachment on the night, although
increasing productivity, has affected human sleep patterns
(Fig. 1.9-2). Typical use of artificial lights results in a single,
consolidated bout of sleep lasting approximately 8 hours. This
pattern of sleep is uncommon among most other mammals,
which typically experience more fractured sleep. Human sleep
under more natural photoperiods, where the duration of the
night is longer, becomes decompressed. Specifically, a bimodal
distribution of sleep is observed; bouts of sleep occur in early
and late night. Periods of
quiet wakefulness
are interspersed
between the two primary bouts of sleep. This natural sleep pat-
tern is more similar to the sleep patterns of other mammals.
Seasonality
The 24-hour period of the Earth’s rotation around its axis is
unchanging. However, the Earth’s axis is tilted 23.45 degrees
Figure 1.9-1
Relative phase relationship of sleep in young adults to other circa-
dian phase markers. (From Dijk D-J, Lockley SW. Invited review:
Integration of human sleep-wake regulation and circadian rhyth-
micity.
J Appl Physiol.
2002;92:852, with permission.)
