cr pp LD LL. Symbols and Abbreviations period of biological rhythm period of zeitgeber phase of biological rhythm phase of zeitgeber phase relationship between zeitgeber and biological rhythm length of daily activity length of daily rest (a+ p ==) amplitude of biological rhythm (mean to maximum or mean to minimum) amplitude of zoitgeber cycle circadian time, a time scale covering one full circadian period. ‘The zero point is usually defined as lights-on when the circa- dian rhythm is entrained by a light-dark cycle, but is defined arbitrarily when the rhythm is free-running continuous darkness light-dark cycle, The respective durations of light and dark (in hours) may also be indicated, for example LD 14:10, indicating that the cycle is 14 hours of light and 10 hours of darkness, continuous illumination range of biological rhythm (maximum to minimum) range of zeitgeber cycle zeitgeber time, a time scale covering one full zeitgeber period, ‘The zero point is defined arbitrarily. 1 A Physiological System Measuring Time ‘The expression “as sure as night follows day” reflects the stability of, certain cycles in our environment. The earth, spinning on its axis ap- proximately once every 24 hours, submits plants and animals to highly predictable daily rhythms of light and temperature (Fig. 1.1). The availability of food and the activity of predators are in turn affected by these periodic variations. It is not surprising, therefore, to discover that the behavior and metabolism of most organisms follow a 24-hour schedule. The most obvious explanation for such 24-hour rhythms is that plants and animals passively respond to the cycles in thei ment. However, when an organism is isolated from all em time cues—when light, food, temperature, and sound are kept constant around the clock—the majority of its rhythms persist with an inde- pendent period. This “free-running” period is usually close to but not exactly 24 hours. It is little wonder that living systems should generate periodic oscil- lations in a wide variety of physiological variables. Engineers know that complex control systems tend to oscillate in their performance; indeed, much of their job is to minimize such oscillations when they interfere with the function of the machine. The remarkable develop- ment, however, is that evolution has selected the frequency of certain oscillations in biological systems so that they can serve as an organ- ism’s internal clocks.2. | The Clocks That Time Us ONE ROTATION ON axis me mage NZ = raw, = Fig. 11 The earth’s yearly revolution about the sun and its daily rotation fn its axis determine the light-dark patterns to which we are exposed. Seasonal changes occur because the earth’s axis of rotation is tilted with, respect to its plane of revolution. The north pole is tilted toward the sun from March to September, so the northern hemisphere rec sunlight per day than the southern hemisphere, Then from Sep mber to A Physiological System Measuring Time | 3 ‘The physiological system responsible for measuring time and synchronizing an organism's internal processes with the daily events in its environment is known as the circadian timing system. The word circadian (Latin: circo=about; dies=day) was coined by Franz Halberg in 1959 to describe the approximately 24-hour cycles that are endoge- nously generated by an organism. Although virtually all plants and an- {mals have circadian timing systems, this book will focus on mammals, because there is consistency in the physiological strategies of this class and the most direct parallels to clinical medicine can be drawn. How- ever, from time to time we will refer to other organisms that can help to explain mammalian mechanisms. In addition to circadian processes, a very wide range of biological rhythms, with periods of less than a second to more than a year, has been demonstrated in mammals, as Figure 12 illustrates. Some rhythms are normal products of mammalian physiology, while others become apparent only in disease states. Many of the observed period- icities correspond to periodicities in the environment, such as the solar year. Circadian events are the focus of this book, but we will consider the interrelationships between the circadian timing system and other biological rhythms, such as the estrous cycle and circannual rhythms. March the southern hemisphere receives more sunlight per day than the northern hemisphere because the north pole is tilted away from the sun. In midsummer at the north pole there is continuous light, and in midwin- ter there is continuous darkness. In contrast, at the equator there is no seasonal change: there are always 12 hours of light and 12 hours of dark- ness. In the regions between the equator and the poles the duration of the light period continuously changes during the year. ‘As the earth rotates in an easterly direction (lower panel). the earth's shadow and the time of dawn and dusk move in a westerly direction across the earth's surface. The earth's shadow moves most quickly at the equator and most slowly at the poles, simply because the earth's circum- ference is greater at the equator so that the shadow has a greater distance to travel. ‘The true period of rotation of the earth is not 24.0 hours, but 28 hours and 56 minutes. But because the earth is revolving about the sun in the ‘same direction that itis rotating, it must turn for an extra 4 minutes each day to complete a rotation. (Copyright 1982 by Moore-Ede, Sulzman, and Fuller.)4 | The Clocks That Time Us FREQUENCY ©. BIOLOGICAL PERIODICITY (eyctes/sec) Ose ees see carDIAc Gsec. RESPIRATORY | | Fo0min, SLEEP-sTAGE Fe¢hr. SLEEP-wakE }cIRCADIAN Fee doy wenstauaL F365 doy HIBERNATION. cIRCANNUAL Fig. 1.2 Organisms display a wide spectrum of frequencies in their shythmic processes. The left side shows the various frequencies, and the right side shows the periods (that is, 1/frequency) of selected examples. High-frequency events include the electrical activity of the brain (EEG: lectroencephalogram), heart beat (cardiac), rate of breathing (respira tory), and sleep-stage (rate of progression through different levels of sleep). These cycles are often referred to as ultradian rhythms (processes hhaving periods much less than 24 hours). Circadian ehythms are often ar- biteatily defined as having periodicities between 20 and 28 hours. Two ‘examples of low-frequency cycles are the menstrual cycle of women and the seasonal (circannual) cycle of hibernation. Such long-period rhythms are referred to as infradian rhythms. (Copyright 1982 by Moore-Ede, Sulaman, and Fuller.) We will also discuss the many analogous features of the various bio- logical timekeeping systems, because these provide a useful theoretical base for looking at biological clocks in all their apparent diversity. A Physiological System Measuring Time | 5 Historical Milestones ‘Twenty-four-hour rhythms in the activities of plants and animals ‘must have been recognized from the earliest times. The tendency for some organisms to sleep at night and some during the day would have been obvious to man in his earliest contemplations of the temporal order of nature. Written records going back to the marches of Alexander the Great in the fourth century 6.c. document the daily movements of leaves and flower petals. Androsthenes reported that the tamarind tree (Tamarindus indicus), known at that time primarily for its laxative fruit, opened its leaves during the day and closed them at night (Bretal, 1903). However, in these early writings there is no sign that these diurnal rhythms were interpreted as anything other than passive responses to a cyclic environment, ENDOGENOUS ORIGIN OF CIRCADIAN RHYTHMS ‘The apparently quite reasonable assumption that biological rhythms were a direct consequence of @ periodic environment remained un- tested until Jean Jacques d'Ortous de Mairan, an astronomer by train- ing, conducted a critical experiment in 1729. In a brief communication to L’Academie Royale des Sciences of Paris (Fig, 1.3), transmitted by M. Marchant, it was reported how de Mairan had studied the leaf movements of a “sensitive” heliotrope plant (probably Mimosa pu- dica). This plant opens its leaves and pedicels during the day and folds them at night, When de Mairan moved this plant to a place where sunlight could not reach it, he found that the plant still opened its leaves during the day and folded them for the entire night (Fig. 1.4). Thus, the persistence of circadian rhythms in the absence of environ- ‘mental time cues was first demonstrated. De Mairan recognized that these rhythms were related to the sleep- ing patterns of bedridden patients, which persist on a circadian sched- ule even when the patients are unaware of day and night. He also sug- gested that other plants be examined for the same phenomenon and that the role of environmental temperature as a synchronizer be tested. De Mairan proposed that another interesting experiment would be to reverse light and dark and examine the response of the plant but he concluded that his everyday chores did not permit him to pursue