Circadian Rhythms, Light and Sleep

Synopsis

The circadian system in animals and humans, being near but not exactly 24-hours in cycle length, must be reset on a daily basis in order to remain in synchrony with external environmental time. This process of entrainment is achieved in most mammals through regular exposure to light and darkness. In this chapter, we review the results of studies conducted in our laboratory and others over the past 25 years in which the effects of light on the human circadian timing system were investigated. These studies have revealed, how the timing, intensity, duration, and wavelength of light affect the human biological clock. Our most recent studies also demonstrate that there is much yet to learn about the effects of light on the human circadian timing system.

 

Introduction

Circadian rhythms are variations in physiology and behavior that persist with a cycle length close to 24 hours even in the absence of periodic environmental stimuli. It is hypothesized that this system evolved in order to predict and therefore optimally time the behavior and physiology of the organism to the environmental periodicity associated with the earth’s rotation. Because the cycle length, or period, of this endogenous timing system is near, but, in most organisms, not exactly 24 hours, circadian rhythms must be synchronized or entrained to the 24-hour day on a regular basis. In most organisms, this process of entrainment occurs through regular exposure to light and darkness.

Early reports from studies of human circadian rhythms had suggested that humans were unlike other organisms, being relatively insensitive to light and more sensitive to social cues to entrain their circadian systems. However, subsequent studies, and re-analysis of results from those early studies, have found that the human circadian system is like that of other organisms in its organization and its response to light, and is as sensitive to light as other diurnal organisms. In this chapter we review the results of studies conducted in our laboratory and others over the past 25 years in which the effects of light on the human circadian timing system were investigated.

Neuroanatomy of the mammalian circadian system

Studies published in the early 1970’s established the suprachiasmatic nucleus of the hypothalamus as the central circadian pacemaker in mammals (). This pacemaker is comprised of individual cells which, when isolated, can oscillate independently with a near-24-hour period (;). The SCN receives direct input from the retina (), providing a mechanism by which entrainment to light-dark cycles occurs. Recently, a subset of retinal ganglion cells has been described that serve as photoreceptors for circadian and other non-image-forming responses (). These specialized retinal ganglion cells are distributed throughout the retina, project to the SCN, are photosensitive, and contain melanopsin as their photopigment (;). While the photosensitive retinal ganglion cells can mediate circadian responses to light, there is also evidence that rod and cone photoreceptors can play a role in circadian responses to light (;). The relative contribution of different photoreceptors to circadian responses is not yet well understood, and this is an area of intense research currently. It is likely that the intensity, spectral distribution, and temporal pattern of light can all affect the relative contribution of different photoreceptors to circadian responses. The same neuroanatomical features of the circadian system described in mammals are also present in humans ().

Phase-dependent response of the human circadian system to light

Studies of the effects of light on the circadian system of insects, plants, and animals conducted from the late 1950’s through the 1970’s had demonstrated that the timing of a light stimulus has an important influence on the direction and magnitude of response to that stimulus (). Those studies indicated that the circadian system of both nocturnal and diurnal organisms is most sensitive to light during the biological night. Because humans sleep throughout most of their biological night, testing the influence of light on the human circadian system therefore required that in the sleep-wake cycle be shifted in order to deliver the light stimulus at the time of highest expected sensitivity. That manipulation of sleep-wake timing was a concern in the earliest human light studies, because of prior reports suggesting that social cues influenced human circadian rhythms (;).

For those reasons, we therefore conducted one of our earliest studies of the effect of light on the human circadian system on a subject whose circadian temperature rhythm had an unusual phase-relationship to her sleep-wake cycle (). We identified a subject whose sleep-wake cycle timing was fairly normal, but whose circadian core body temperature rhythm was several hours earlier than normal, resulting in much of her biological night occurring prior to the time she went to bed. In the experiment we conducted, the subject was exposed to several hours of light every evening for a week, and the timing of her rhythms of core body temperature and plasma cortisol were assessed before and after that week of evening light exposure. Both rhythms were shifted by approximately 6 hours, and examination of temperature data collected throughout the experiment suggested that the shift had already occurred after only 2 days.

This finding that light could have this rapid and strong effect on the timing of human circadian rhythms led us to conduct a series of studies in normal young adults in which we applied a series of light stimuli over 2–3 days (;;). In those studies carried out in the late 1980’s, we held the intensity, spectral distribution, and duration of the light stimulus constant, but varied the time at which the initial stimulus was applied. To do this, we had to shift the timing of the sleep-wake cycle so as to be able to present light stimuli across the entire 24-hour circadian cycle. In the course of doing these initial experiments, we were attempting to produce a phase response curve (PRC) ().

Our results in some ways were not surprising, but in other ways were. We found that humans, like other organisms, are most sensitive to light stimuli during the biological night, and far less sensitive to light in the middle of the biological day (;). We also found that when humans are exposed to a light stimulus in the late biological day/early biological night, that stimulus produces a phase delay shift (a shift to a later hour), and light stimuli presented in the late biological night/early biological day produce phase advance shifts (shifts to an earlier hour).

What was somewhat unexpected in those studies was the large magnitude (up to 12 hours) of the phase shifts we were able to achieve, and the PRC that was developed from those 3-cycle light stimuli was a type 0 (strong) PRC. A type 0 PRC is characterized by large phase shifts of + 12 hours, with no “cross-over” point between maximal delays and maximal advances (). Type 0 resetting also implied that the phase shift has been produced via changing the amplitude of oscillation of the underlying pacemaker (). When we subsequently conducted additional experiments to test the phase shifts that could be achieved with a 2-cycle stimulus, we found that in some studies we could markedly reduce the amplitude of the core body temperature and cortisol rhythms (). This finding suggested that the amplitude of the underlying pacemaker was affected by the stimulus, lending additional support to the idea that the phase shifts to the strong 3-cycle stimulus were type 0 ().

Since describing that PRC to a strong light stimulus, we and others have conducted PRCs to single light pulse stimuli (;;;). In the late 1990’s, we constructed a human PRC study to a single 6.7-hour light stimulus (). Results from those studies indicated a type 1 PRC, with a shape and magnitude consistent with type 1 PRCs from other organisms. Type 1 PRCs are characterized by a lower amplitude than type 0 with smaller maximal phase shifts, as well as by a cross-over point between maximal delays and advances. In the human PRC to the 6.7-hour stimulus, the maximal phase shifts were 2–3 hours. There was a phase delay region in the late biological day/early biological night, a phase advance region in the early biological day, small phase shifts during the middle of the biological day, and a transition point towards the end of the biological night [see Figure 1, reproduced from ()].

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