Health Consequences of Circadian Disruption in Humans and Animal Models - Progress in Molecular Biology and Translational Science - page 285

2. CIRCADIAN REGULATION

In mammals, the circadian system is a hierarchical collection of bio-
logical clocks controlled by a master pacemaker within the suprachiasmatic
nucleus (SCN) of the anterior hypothalamus. 1 The SCN is synchronized by
light and, in turn, coordinates downstream tissues so that they adopt specific
temporal relationships to the external environment and to one another. In
addition to monosynaptic and polysynaptic neural projections from the
SCN to downstream targets, the SCN also controls overt rhythms such as
body temperature, feeding, and hormone release, which can act to synchro-
nize peripheral clocks. Individual cells within central and peripheral clocks
contain molecular oscillators that generate circadian rhythms in protein
expression and metabolic state. 2 Coordination at both the molecular and sys-
tems level is important for circadian function, as is synchronization to the
24 h environment and local time. 3
The SCN receives a direct retinal projection from a population of intrin-
sically photoresponsive retinal ganglion cells expressing the photopigment
melanopsin. 4 Circadian responses to light are time-dependent, with light
at night causing the release of glutamate and PACAP to reset the phase of
the SCN. 5 Light at night also produces acute effects, including changes in
sleep, alertness, SCN electrical activity and gene expression, and melatonin
levels. While the circadian visual system in humans has typically been
viewed as having a relatively high photic threshold compared to the classic
image-forming visual system, recent work indicates that the human circa-
dian system can be affected by even low levels of illumination at night. 6,7
This suggests that even the use of low levels of artificial lighting at home
and work may alter circadian function.
At the molecular level, circadian rhythms are controlled by
autoregulatory feedback loops that control the transcription and translation
of clock genes. 8 Within the core molecular loop, CLOCK and BMAL1 form
a heterodimer that activates transcription of period ( per1 , per2 ) and cryptochrome
( cry1 , cry2 ) genes, which form proteins that complex with casein kinase 1 e
and translocate back into the nucleus to inhibit CLOCK/BMAL1-mediated
transcription. Degradation of PER/CRY repressor elements relieves the
inhibition on CLOCK/BMAL1 transcription allowing the cycle to begin
anew once every

24 h, and this oscillatory process operates in nearly every
cell of the body to control both ubiquitous and tissue-specific function.
Additional loops involving other clock gene elements modulate clock