Abstract
Circadian rhythms (CRs) are entrainable endogenous rhythms that respond to external
stimuli and regulate physiological functions. The suprachiasmatic nucleus (SCN) in
the hypothalamus is the mammalian master clock that synchronizes all other tissue-specific
peripheral clocks, primarily through gamma-aminobutyric acid (GABA) and vasoactive
intestinal polypeptide (VIP). The SCN follows Earth's 24-hour cycle by light entrainment
through the retinohypothalamic tract. At the cellular level, the core clock genes
CLOCK, BMAL1, PER1–PER3, CRY1, and CRY2 regulate CRs in a negative feedback loop. The circadian disruption of the sleep–wake
cycle manifests in at least six distinct clinical conditions. These are the circadian
rhythm sleep–wake disorders (CRSWDs). Their diagnosis is made by history, sleep diaries,
and actigraphy. Treatment involves a combination of timed light exposure, melatonin/melatonin
agonists, and behavioral interventions. In addition, CR disturbances and subsequent
misalignment can increase the risk of a variety of illnesses. These include infertility
and menstrual irregularities as well as diabetes, obesity, fatty liver disease, and
other metabolic syndromes. In addition, a disruption in the gut microbiome creates
a proinflammatory environment. CR disturbances increase the risk for mood disorders,
hence the utility of light-based therapies in depression. People with neurodegenerative
disorders demonstrate significant disturbances in their CRs, and in their sleep–wake
cycles. Circadian realignment therapies can also help decrease the symptomatic burden
of these disorders. Certain epilepsy syndromes, such as juvenile myoclonic epilepsy
(JME), have a circadian pattern of seizures. Circadian disturbances in epilepsy can
be both the consequence and cause for breakthrough seizures. The immune system has
its own CR. Disturbances in these due to shift work, for instance, can increase the
risk of infections. CR disturbances can also increase the risk of cancer by impacting
DNA repair, apoptosis, immune surveillance, and cell cycle regulation. Moreover, the
timing of chemotherapeutic agents has been shown to increase their therapeutic impact
in certain cancers.
Keywords
circadian rhythms - circadian rhythm sleep–wake disorders - chronobiology - suprachiasmatic
nucleus - CLOCK genes - metabolism - mood disorders - immune disturbances - neurodegeneration
- cancer - epilepsy
