Circadian

The term circadian literally means “around a day,” and is a descriptive word that indicates that an entity functions on an approximately 24-hour cycle. All living cells [Page 413]have an inherent and endogenously active chronological system that helps them synchronize their physiology and behavior to cues from the environment.

These circadian rhythms are highly conserved across species and are genetically programmed. Molecular and genetic evidence of circadian rhythms has been observed in species as varied as photosynthetic bacteria, fungi, plants, mice, and humans. It is hypothesized that the 24-hour period is not arbitrary but developed in accordance with the needs of the first primitive unicellular organisms to prevent DNA damage from sunlight approximately 2 billion years ago. Additionally, recognition of night and day would have helped primitive cells more efficiently demarcate appropriate periods for nitrogen fixation and photosynthesis. As an essential feature of cellular life, chronicity and the specific manner of splicing time may have developed in response and relation to the periodicity of the earth's rotation around its axis.

With natural environment cues of sunlight and sunset, human circadian rhythms occur at almost exactly 24-hour periods. However, when animals are placed in constant light or constant darkness, and with natural environmental cues absent, the endogenous circadian system is said to “free run.” Within these somewhat artificial conditions, circadian rhythms still function at periods of approximately 24 hours, although the exact free-running period varies from species to species. In humans, the free-running rhythm is 25 hours, and variation from person to person is no more than a few minutes. The endogenous circadian rhythm is independent from homeostatic mechanisms such as temperature control and does not change in different environmental temperatures.

It would be a mistake to assume that just because circadian rhythms are under genetic control and are evolutionarily conserved that they are impervious to changes in the environment. In a free-running environment (such as having been awake all night in a hospital), a circadian rhythm can be reset by even brief contact with sunlight. Blue light seems to create the most powerful effect. This does not mean that the 24-hour period changes but that the phase (“day”/“night”) within that period can be subjectively reset. The extent and direction of the phase shift will vary depending on where one is in the 24-hour cycle (i.e., subjective “day” or “night,” the early or late night, etc.). For example, if one is in one's subjective “day” phase, sunlight will not significantly change the phase one is in, but if one is shown sunlight in the late phase of “night,” a phase advance will occur and the internal clock will be reset via a projection directly from the retina to pacemaker cells in the hypothalamus. These are the foundations of the adaptive mechanisms underlying the phase delay and phase advancement that can occur when organisms are placed in nonsymmetric day and night environments. It should be noted that many nonphotic effectors of the internal clock (melatonin, leptin, opioids, etc.) exist as well.

Circadian rhythmicity is a self-sustaining property that emerges at the level of the cell itself. Circadian rhythms are produced by the selective expression and regulation a variety of evolutionarily conserved “clock” genes (clock, Bmal1/Mop3, Per1, Per2, Per3, etc.) and their positive and negative transcriptional/translational feedback loops. The regulation of these protein products produces cyclical variation in important intracellular molecules. In mammals, the superchiasmatic nucleus (SCN) of the hypothalamus, acting as “conductor” of a symphony of peripheral extrahypothalamic oscillators, is centrally important in producing circadian activity and behavior.

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