The Circadian Clock: Physiology, Genes, and Disease

Fig. 1. A sample wheel-running record from a mouse. Each horizontal row represents the data from 1 day, with subsequent days plotted below previous days. The height of the black vertical lines in each row is proportional to the amount of wheel-running produced by the mouse in that 6-min bin. The animal is initially housed in a lighting cycle of 12 h light and 12 h dark. Note that the animal’s activity is initiated around the same time every day, just after the lights go out. Next, the animal is put into constant darkness. Note that while the animal maintains a daily pattern of activity, it now wakes up a little earlier each day, and it exhibits a free-running period of about 23.5 h. Finally, on the 12th day of darkness, the animal is exposed to a light pulse late in its subjective night (circle). This produces a phase advance in its activ-

ity onset, which can be visualized by fitting two regression lines to the activity onsets: one line on the days prior to the light pulse to predict the expected activity onset in the absence of a treatment (dark gray line) and another line on the days following the light pulse to determine the actual phase of the clock (white line). By comparing the horizontal distance between the two regression lines on the day after the light pulse, it is possible to quantify the magnitude of the phase shift. (Unpublished lab archive data; a color version is available on the accompanying CD.)

state of the body during sleep, including decreasing body temperature and secretion of melatonin and growth hormone, is distinct from each of the previous examples. Most physiological parameters exhibit daily oscillations. Prominent examples include body temperature, hormone secretions, and blood pressure. Behavioral parameters, such as locomotor activity (Fig. 1), also exhibit daily oscillations. The timing of sleep and wake onset and the timing of meals are also important examples of behaviors that demonstrate daily oscillations, but rhythms in human performance have also been noted. Reaction time is optimal in the late afternoon to early evening (4–8 p.m., and poorest in the early morning (4–8 a.m.) [2]. Search speed, reasoning speed, dexterity, and vigilance all exhibit poorest performance between 5 and 9 a.m., with a secondary trough occasionally observed in the early afternoon [3]. Performance on a memory task can also be influenced by a circadian rhythm [4].

Circadian Rhythms in Visual Function

Visual performance and physiology exhibit circadian rhythms as well. In rats, there is a burst of rod outer segment disk shedding that coincides with the onset of light, but this rhythm persists for a number of days even in rats housed in constant darkness, suggesting that it is controlled by an endogenous clock rather than simply being a response to light exposure [5]. The axial length of the human eye changes by as much as 40 m over the course of the day [6]. Intraocular pressure changes over the course of the day, with pressure high during the night, peaking near the end of the night, and lowest during the evening [7]. While this rhythm is largely affected by posture (higher when the person is