Mammalian Circadian Rhythms and the Endogenous Pacemaker

At the turn of the century, any observed oscillation in mammalian physiology or behavior was dismissed as a random fluctuation of little importance. This is largely because physiologists and physicians were grounded in the developing tenet of homeostasis. Homeostasis, a term coined by Dr. Walter B. Cannon, describes the relative constancy of the internal environment or milieu de interior. Although the concept of home-ostasis accounted for the presence of daily variations in physiological systems, circadian rhythmicity per se was not recognized as an important biological characteristic. This changed in 1922, however, when Dr. Carl Richter demonstrated the endogenous nature of circadian activity rhythms in rats and, furthermore, showed that the rats were synchronized by both the light-dark cycle and the time of feeding. Later in the

Phasw Response Curve

Figure 3 Derivation of a phase-response curve (PRC). (A)-(E) show five sample experiments in which a nocturnal animal, free-running in constant darkness, is exposed to a 1-hr light pulse. A free-running activity rhythm with a period of 25.0 hr is seen on days —4 to —1. On day zero, a light pulse is given at mid-subjective day (A), at late subjective day (B), at early subjective night (C), at late subjective night (D), and at early subjective day (E). The light pulses in mid-subjective day and early subjective night (B and C) produce phase delays of the activity rhythm that are complete within one cycle. The light pulses in late subjective night and early subjective day (D and E) produce phase advances with several cycles of transients before reaching a steady-state shift by day 5. Lower panel: Direction and magnitude of phase shifts plotted against the time of light pulses to obtain a PRC. When light pulses are given at frequent intervals throughout the subjective day and night, the waveform for the PRC follows the solid line. In mammals there is normally a gradual transition between maximum phase delay and maximum phase advance, with a point in mid-subjective night (like the one in mid-subjective day, A) where there is no phase shift. [Reproduced by permission from Moore-Ede, M. C., Sulzman, F. M., and Fuller, C. A. (1982). The Clocks That Time Us: Physiology of the Circadian Timing System. Harvard University Press, Cambridge, MA].

Figure 3 Derivation of a phase-response curve (PRC). (A)-(E) show five sample experiments in which a nocturnal animal, free-running in constant darkness, is exposed to a 1-hr light pulse. A free-running activity rhythm with a period of 25.0 hr is seen on days —4 to —1. On day zero, a light pulse is given at mid-subjective day (A), at late subjective day (B), at early subjective night (C), at late subjective night (D), and at early subjective day (E). The light pulses in mid-subjective day and early subjective night (B and C) produce phase delays of the activity rhythm that are complete within one cycle. The light pulses in late subjective night and early subjective day (D and E) produce phase advances with several cycles of transients before reaching a steady-state shift by day 5. Lower panel: Direction and magnitude of phase shifts plotted against the time of light pulses to obtain a PRC. When light pulses are given at frequent intervals throughout the subjective day and night, the waveform for the PRC follows the solid line. In mammals there is normally a gradual transition between maximum phase delay and maximum phase advance, with a point in mid-subjective night (like the one in mid-subjective day, A) where there is no phase shift. [Reproduced by permission from Moore-Ede, M. C., Sulzman, F. M., and Fuller, C. A. (1982). The Clocks That Time Us: Physiology of the Circadian Timing System. Harvard University Press, Cambridge, MA].

twentieth century, the endogenous nature of the human circadian timing system was confirmed, and circadian rhythms were documented in hundreds of physiological, biochemical, and behavioral variables. In fact, it became apparent that it was often more significant to find a physiological variable with no circadian rhythm.

The definition of a circadian rhythm may be straightforward; however, defining a biological clock is a bit more difficult. Any biological structure to be considered a clock must be able to measure the passage of time independent of any periodic input from its environment as well as from timed biological events. In addition, in order to keep time reliably, a clock must have both resolution, an ability to detect the temporal order of two events closely spaced in time, and uniformity, a regularity of period and thus the ability to predict the occurrence of other regularly timed phenomena. Experimentation has revealed that a mammalian clock, which we now know resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, has both relatively high resolution and uniformity. The uniformity of the clock is further augmented by the ability of an organism to "reset" its clock each day using environmental cues.

The location and function of the SCN, as a master pacemaker of the mammalian brain, have been confirmed by an impressive variety of experimental approaches. For example, lesion studies, in which the SCN was ablated, resulted in arrhythmic experimental animals. Neural transplantation of fetal SCN tissue into lesioned animals restored rhythmicity, confirming both the location and function of the circadian pacemaker. Similarly, animals with reciprocal SCN transplants have a circadian period determined by the genotype of the grafted tissue and not that of the host. The SCN also exhibits clear circadian rhythms of gene expression, metabolism, and electrophysiological activity in vitro.

Whereas the evidence supports the role of the SCN as a master circadian pacemaker, additional findings suggest that the circadian timing system is multi-oscillatory. In humans, the primary evidence for multiple pacemakers comes from temporal isolation studies in which some rhythms, such as the sleep-wake rhythm, and other rhythms, such as the body temperature rhythm, sometimes free-run with very different periods. This phenomenon is referred to as internal desynchronization.

The overall organization of the circadian timing system is thought to be hierarchical. That is, the SCN acts as a master oscillator, which in addition to receiving temporal cues from the environment drives a variety of slave oscillators. Some of these slave oscillators are thought to also generate oscillations independently, whereas others, termed passive slaves, do not. A study using fibroblasts in culture demonstrated that nonneural tissue might also possess intrinsic clocks. Serum induction of clock behavior in the fibroblast suggests that the SCN, as the principal oscillator, may simply orchestrate rather than actively drive oscillations in peripheral tissues.

Whereas the number of processes that show circadian fluctuation is large, a few physiological and behavioral rhythms (locomotor activity, body temperature, and melatonin) are commonly used to study the circadian timing system. Furthermore, several neural structures comprise the anatomical circadian timing system. Each will be discussed later in the article.

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