Chapter 3 Circadian Rhythms Contents Page GENERAL PROPERTIES OF CIRCADIAN RHYTHMS . 37 THE CELLULAR CLOCK . .. 38 THE PACEMAKER IN THE BRAIN . ...........40 HUMAN CIRCADIAN RHYTHMS . 41 The Body Circadian . 42 The Timing of Sleep . .. 45 Human Performance . 47 DISRUPTION OF CIRCADIAN RHYTHMS . ,...49 Aging and the Body Clock . .. 49 Sleep Disorders . 51 Chronobiology and Mood Disorders . .. 51 CONTROLLING CIRCADIAN RHYTHMS IN HUMANS . 53 Light . .. 53 Melatonin . 55 Benzodiazepines . .. 56 Other Chemical Substances and Diet . 57 Activity . ,. 57 SUMMARY AND CONCLUSIONS . .+....*. 58 CHAPTER PREFERENCES . 58 Boxes Box Page 3-A. Circadian Rhythms and Drugs . ● . 43 3-B. Cycles That Last From Minutes To Days . .44 3-C. Napping . 46 3-D. Jet Lag . 48 Figures Figure Page 3-1. Circadian Rhythm . 37 3-2. Synchronized and Free-Running Circadian Rhythms . 38 3-3. Phase Response Curve. -. 39 3-4. Gene Expression in the Pacemaker . 40 3-5. The Transplanted Pacemaker . ....*.,. 41 3-6. Human Circadian Rhythms . .42 3-7. Human Circadian Rhythms in the Absence of Time Cues . 46 3-8. Sleepiness During the Day . .47 3-9. Circadian Rhythms of Alertness . 49 3-10. Aging and the Pacemaker . .*.....* . 50 3-11. Levels of Light . 52 3-12. Resetting the Human Pacemaker With Light. ....*.., . .54 3-13. Bright Light and Air Travel . ....,.*, . 55 3-14. Melatonin Rhythms and Light . .. 56 Table Table Page 3-1. Differences Between Rapid Eye Movement (REM) Sleep and Slow Wave Sleep (SWS) . 45 Chapter 3 Circadian Rhythms Many biological functions wax and wane in An entraining agent can actually reset, or cycles that repeat each day, month, or year. Such phase shift, the internal clock (12). Depending on patterns do not reflect simply an organism’s passive when an organism is exposed to such an agent, response to environmental changes, such as daily circadian rhythms may be advanced, delayed, or not cycles of light and darkness. Rather, they reflect the shifted at all. This variable shifting of the internal organism’s biological rhythms, that is, its ability to clock is illustrated in a phase response curve (PRC) keep track of time and to direct changes in function (figure 3-3). PRCs were first derived by exposing accordingly. Biological rhythms that repeat ap- organisms housed in constant darkness to short proximately every 24 hours are called circadian pulses of light (40,65,125). The organisms were rhythms (from the Latin circa, for around, and dies, isolated from all external time cues. When light for day) (61) (figure 3-l). pulses were delivered during the portion of the organism’s internal cycle that normally occurs Human functions, ranging from the production of during the day (therefore called subjective day), they certain hormones to sleep and wakefulness, demon- had little effect on circadian rhythms. In contrast, strate circadian rhythms. This chapter summarizes when light pulses were delivered late during the the basic properties of circadian rhythms and ad- organism’s nighttime, circadian rhythms were ad- dresses the following questions: vanced. Light pulses delivered early during sub- How are circadian rhythms generated? jective night delayed circadian rhythms. How are they influenced by the environment? What specific human functions display cir- Several factors make it difficult to identify time cadian rhythms? cues that can reset the internal clock. First, there is What implications do these rhythms have for no way to examine the function of the circadian health and performance? pacemaker directly. The pacemaker’s activity can How can circadian rhythms be manipulated? only be evaluated through the circadian rhythms it drives, but unfortunately such functions are subject GENERAL PROPERTIES OF to other influences. Environmental stimuli may alter CIRCADIAN RHYTHMS a particular circadian rhythm without disturbing the Circadian rhythms display several important char- acteristics. First, circadian rhythms are generated by an internal clock, or pacemaker (9,124). Figure 3-l—Circadian Rhythm Therefore, even in the absence of cues indicating the Amplitude time or length of day, circadian rhythms persist. The 5 Maximum precise length of a cycle varies somewhat among Cycle length individuals and species. Although organisms gener- K 4 .-o Mean ate circadian rhythms internally, they are ordinarily G3 c— i’flGr - exposed to daily cycles in the environment, such as li2 light and darkness. The internal clock that drives Minimum circadian rhythms is synchronized, or entrained, i to daily time cues in the environment (figure 3-2). Animal research has shown that only a few such cues, such as light-dark cycles, are effective entrain- 12 24 ing agents (12). In fact, the light-dark cycle is the Time (hours) principal entraining agent in most species, and recent research suggests that it is very powerful in Circadian rhythms have a single cycle length of approximately 24 hours. The amplitude, a measure of the degree of variation within synchronizing human circadian rhythms. The sleep- a cycle, is the difference between the maximum value and the wake schedule and social cues may also be impor- mean. tant entraining agents in humans. SOURCE: Office of Technology Assessment, 1991. .- 38 . Biological Rhythms: Implications for the Worker pacemaker at all. For example, going to sleep causes evaluating potential entraining agents in humans a temporary lowering of body temperature, without have been devised (see later discussion). shifting the circadian cycle. Second, a function that exhibits a circadian rhythm may be controlled by both the circadian pacemaker and other systems in THE CELLULAR CLOCK the body. For example, the timing and quality of sleep are controlled by circadian rhythms and other Circadian rhythms exist even in single cells. In factors. Finally, classical techniques used to evalu- fact, studies have shown that a wide range of cell ate the pacemaker in animals and to generate a PRC functions exhibit circadian rhythms (159). Pre- involve complete isolation from all time cues (e.g., cisely how cells generate circadian rhythms is not constant darkness) for several days, a difficult known, but protein synthesis is critical to the process approach in human studies. Alternative methods for (50,168). Figure 3-2-Synchronized and Free-Running Circadian Rhythms Midnight 6 am Noon 6 pm Midnight Day 1 1 Imposed light-dark 1 schedule; rhythm entrained. 1 1 5 1 I I r I I I 1 I 10 I I I 1 Self-selected light-dark cycle; I 1 rhythm free-runs. I I I 1 15 I I 1 ~ Timing of peak cortisol secretion Plot of human sleep and maximum cortisol secretion when synchronized to the environment and when free of environmental input. SOURCE: Adapted from G.S. Richardson and J.B. Martin, “Circadian Rhythms in Neuroendocrinology and Immunology: Influence of Aging,” Progress in NeuroEndocrinlmmunology 1:18-20, 1988. Chapter 3-Circadian Rhythms ● 39 Specific genes code for circadian rhythms. chromosome, called the per gene, has been identi- Genetic control of circadian rhythms has been fied, cloned, and characterized (15,25,64,202). examined most extensively in the fruit fly (Droso- phila melanogaster), an organism that has played a Other genetic mutations influencing circadian key role in the study of genes and inheritance rhythms have been identified in the fruit fly (71), and (63,76,142). Initially, painstaking studies were con- genes other than the per gene have been found to ducted, using chemicals that cause genetic muta- control circadian rhythms in other species. The frq tions to alter circadian rhythms (77). It was found gene, for example, controls circadian rhythms in that mutations on the X chromosome disrupted the bread mold (Neurospora crassa) (52,63). A genetic fruit fly’s circadian rhythms by accelerating, slow- mutation altering circadian rhythms in hamsters has ing, or eliminating them. A specific gene on the X been identified (13 1). In these experiments, a mutant Figure 3-3-Phase Response Curve Day /4 B c D E -4 -3 -2 Light -1 pulse E 0 ■ ■ , \ 1 \ 1 \ \ \ \ \ 2 \ \ \ \ \ \ \ 3 \ \ \ \ \ \ 4 \ \I \ \ 5 \ i~ [ o\ -l\ -3\ +4 \ +2 ; \ \ \ \ \ \ / \ \ \ I \ \ \ \ I \ \ \ \ \ \ \ \ I +4 \ \ Advance \ \ \ D 1’ +2 \ i \ \ \ A Phase 0– E shift A -2- B Delay -4– c Subjective day Subjective night I Circadian time (hours) Experiments demonstrate that exposure to light at different points in a single circadian cycle variably shifts the internal pacemaker (A-E). The pulse of light given in mid-subjective day (A) has no effect, whereas the light pulses in late subjective day and early subjective night (B and C) delay circadian rhythms. Light pulses in late subjective night and early subjective day (D and E) advance circadian rhythms. In the lower panel, the direction and amount of phase shifts are plotted against the time of light pulses to obtain a phase response curve. SOURCE: M.C. Moore-Ede, F.M. Sulzman, and C.A. Fuller, The Chxks That Time Us (Cambridge, MA: Harvard University Press, 1982). 40 . Biological Rhythms: Implications for the Worker Figure 3-4-Gene Expression in the Pacemaker Dark m Light 200 phl 50 pM Photographs from the pacemaker (the suprachiasmatic nucleus) of hamsters housed in darkness (A and B) or following a pulse of light (C and D). The silver grains indicate the activation of the c-fos gene. Data show that exposure to light that would reset circadian rhythms stimulates the c-fos gene. SOURCE: J.M..