Circadian Rhythms

Circadian rhythms (from circa [approximately] and dies (day)) are internally generated, near-24-hour fluctuations in physiology, performance, and behavior. Circadian rhythms have been identified in nearly every species in which they have been examined, from unicells to plants to mammals. Circadian rhythms are thought to provide an adaptive advantage to the organism by providing it a means to anticipate regular periodic changes in the environment, and such daily oscillations are thought to have arisen through the process of natural selection that took place in the presence of a regular 24-hour environmental alteration of day and night.

In the early 1970s, the neural structure responsible for synchronizing circadian rhythms in mammals was localized to the suprachiasmatic nucleus (SCN), a small structure located in the brain's hypothalamus. This structure was first identified in studies in which the SCN was lesioned. SCN lesions, resulted in behavior that no longer occurred at regular, near-24-hour intervals but instead was arrhythmic. After the SCN was identified, additional studies in which the electrical activity of the SCN was recorded revealed that part of the brain has a 24-hour cyclicity in electrical activity. A series of elegant studies in which the SCN from mutant animals was transplanted into SCN-lesioned wild-type animals, and vice versa, resulted in the host animals exhibiting the circadian characteristics of the donor animals, further evidence of the role of the SCN as the circadian pacemaker. Since that time, further studies have demonstrated that the near-24-hour pattern of electrical activity is a property of individual SCN neurons.

In the 1990s, great progress in understanding the molecular and cellular basis for near-24-hour rhythmicity was made. The production of 24-hour rhythms from much shorter biochemical events within the cell results from the interaction of several genes and their protein products. Rising levels of proteins interact and then bind to DNA to halt further protein production. As the levels of these clock component proteins fall, the genes are no longer inhibited, and begin production of these proteins again. In some cases, levels of particular proteins are suppressed by exposure to light, adding another feature to the variation of gene and protein levels between day and night that might be related to the mechanism of photic resetting of the circadian clock. The genes and proteins involved in generating circadian rhythmicity have now been identified for a number of species, and while some details differ from species to species, the general mechanism of transcriptional-translational feedback loops is highly conserved—meaning that the general mechanism of having a transcription-translation feedback loop to produce near-24-hour rhythms is quite similar across a wide array of species, from lower to higher organisms.

The primary source of environmental information to this internal pacemaker is the light-dark cycle, which is transmitted along a mono-synaptic pathway (the retinohypothalamic tract, or RHT) from the retina to the SCN. There are other, non-photic, rhythmic factors from the environment that have been shown to provide information to the circadian pacemaker in some species, including cycles in environmental temperature or food availability. Rhythmic alterations in behavior can also provide timing information to the circadian system in certain situations.

Circadian rhythms are endogenously generated, and not simply a reflection of daily changes in light and darkness, ambient temperature, or patterns of rest and activity. As such, circadian rhythms continue to be expressed when the organism is studied in constant conditions, although the exact period (cycle length) of the rhythm is usually no longer precisely 24 hours, but instead is slightly shorter or longer than 24 hours. The actual cycle length of a circadian rhythm when studied under constant environmental conditions is termed the free-running period. Under normal conditions, these non-24-hour rhythms are synchronized to the 24-hour day by periodic exposure to signals from the environment, a process called entrainment. For most mammals, regular exposure to the light-dark (LD) cycle entrains the circadian timing system to the 24-hour solar day. In order to maintain entrainment, an organism with a slightly shorter than 24-hour circadian period must have its circadian system reset slightly later each day, while an organism with a longer than 24-hour period must have its circadian system reset earlier each day.

The time of a particular event within the circadian cycle is referred to as the phase of that event. For example, the nadir of the endogenous circadian rhythm of core body temperature is often used as a circadian phase marker. The time at which the core body temperature phase occurs can then be compared with respect to the timing of the sleep-wake cycle, can be compared between individuals, or can be compared before and after an intervention. Thus, the term phase refers to a reference point within the near-24-hour rhythm.

Another key feature of the circadian timing system is that it typically has a phase-dependent response to many types of stimuli. This means that the time within the circadian cycle that a stimulus is applied will affect the magnitude and direction of the response to that stimulus. For example, the resetting response of the circadian system of most organisms to light is phase-dependent. A light stimulus applied in the early night will cause a phase delay shift of the animal's circadian rhythms (the timing will be shifted to a later hour), a light stimulus applied in the late night will cause a phase advance shift (to an earlier hour), and a light stimulus applied in the middle of the day will cause a very small change in phase. The phase-dependent response of the circadian system to a stimulus is typically summarized in a phase-response curve (PRC).

Under entrained conditions, the phase of a circadian rhythm has a fixed relationship to the signal from the environment (in most cases, the light-dark cycle) that synchronizes, or entrains, the circadian timing system to the 24-hour day. This phase relationship is termed the phase-angle of entrainment.

Another feature of a circadian rhythm is its amplitude, or the size (magnitude) of the oscillation.