is the basis of circadian biology. It implies that organisms contain physiological systems. JOSEPH S. TAKAHASHI ⢠Department of Neurobiology and Physiology, ...
Circadian Rhythmicity Regulation in the Time Domain JOSEPH S. TAKAHASHI and MICHAEL MENAKER
1 Introduction The control of rate and of temporal sequence is a major aspect of biological regulation. Inferences about causality are often made on the basis of experimentally determined temporal sequence with the unstated assumption that the underlying temporal processes are linear. Because many biological processes oscillate (especially those with feedback regulation), the assumption of linearity is likely to be false, and the causal connections based on it will often be wrong. When the underlying temporal organization is oscillatory, then processes can appear to occur after the events that they cause. In cases that involve synchronization of oscillations, the regulatory cycle often "phase lags" the oscillation that it controls (Pittendrigh, 1981 b). This example is meant only to illustrate the importance of understanding temporal frameworks. We know perhaps more about circadian rhythmicity as a temporal framework than about any other, and there are clearly many (Aschoff, 1981). Most organisms living under natural conditions express daily rhythms in their behavior, physiology, and biochemistry. Much of what organisms do is temporally organized with respect to the environmental daynight cycle. In laboratory environments from which periodic fluctuations have been eliminated, activities that are expressed as daily rhythms in the field continue as free-running circadian rhythms with periods close to, but rarely exactly, 24 hr. This simple observation is the basis of circadian biology. It implies that organisms contain physiological systems
JOSEPH S. TAKAHASHI • Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60201 MICHAEL MENAKER • Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403
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capable of continued, self-generated oscillation, and that as a rule the daily rhythms observed in the field result from the synchronizing action of the periodic environment upon the organisms' internal oscillators. Clearly such internal oscillators might constitute a temporal framework on which natural selection could organize any number of biological processes. Because they are normally synchronized to the earth's rotation, these oscillators could also function as biological clocks, enabling the adaptive phasing of biological processes to the external day; further, if their properties were lawfully modulated by day length, they could provide organisms with predictive information about season, effectively becoming internal calendars as well as clocks. In fact, there is ample evidence demonstrating that circadian oscillators perform all three of these roles. Circadian oscillators and the daily rhythms that they control are ubiquitous among living things and extend deeply into the physiology of the organisms possessing them. Weare just beginning to identify some of these oscillators and to understand their interactions with the environment, with each other, and with the processes that they control.
2
Regulation of Circadian Rhythms by Light Cycles
Regulation of circadian rhythms occurs primarily by environmental light cycles and takes the form of entrainment (in exact analogy to the entrainment that can be imposed on physical oscillators) (Pittendrigh, 1981 b). Entrainment has the effect of imposing the period of the light cycle upon the rhythm and of establishing a defined phase relation between the rhythm and the entraining cycle. Figure 1 illustrates the entraining effects of light cycles on the circadian locomotor rhythm of the hamster. In this example, the period of the entraining cycle has been varied, and, within limits, the entrained rhythm assumes the period of the light cycle. Note that the light cycle does not cause the biological oscillation, which persists indefinitely in the absence of any cyclic input, but regulates some aspects of its behavior. When a circadian oscillation is entrained by a light cycle, the two are coupled in the simplest possible way because there is only unidirectional information flow-that is, except in unusual cases, the organism cannot affect the light cycle. Coupling of two or more oscillations provides opportunities for finely grained temporal regulation (scheduling) because the phase relationships among them are easily adjusted. This principle has almost certainly been widely employed in the evolution of an internal temporal framework based on the circadian system (Pittendrigh, 1981 a,c). It is a general rule that nonvisual photoreceptors mediate photic information for entrainment. Since the discovery of extraretinal input to the circadian system of the house sparrow (Menaker, 1968), extensive work has uncovered similar phenomena in virtually every vertebrate group examined except the mammals (Menaker and Underwood, 1976; Underwood and Menaker, 1976; Underwood and Groos, 1982). Nonmammalian vertebrates have multiple photic inputs to their clocks: the retinae, pineal and parapineal structures, the hypothalamus, and probably other brain structures as well may all be involved in circadian photoreception, and there is reason to believe that they are not simply performing redundant roles (McMillan et aI., 1975). Although mammals do not have extraretinal photic input to their clocks (Nelson and Zucker, 1981), the major pathway for entrainment of their circadian rhythms by light cycles is a specialized, nonvisual retinohypothalamic tract which terminates in the suprachiasmatic nucleus (Moore, 1978; Rusak and Boulos, 1981; Pickard et at., 1982).
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TIME (PST) Figure 5. Effects of localized low-temperature pulses on cockroach rhythms. The filled circles show the time of activity onset for each day; the open circles are the projected phase of the rhythms before and after the pulse; lines are linear regressions. Pulses were 6 hr in duration and began at activity onset. In A, the intact optic lobe of an animal in which one optic tract had been cut was cooled (CP) while the neurally isolated optic lobe was maintained at 25°C; in B, the neurally isolated optic lobe was cooled while the intact lobe was maintained at 25°C. Cooling the intact lobe caused a large phase delay (f),.
