By Omar Kassem, Winter 2021.

Biological rhythms

     Circadian rhythms are daily biological rhythms driven by an endogenous, self-sustaining, time-keeping biological clock. Biological time-keeping systems act on coordinating oscillations in the internal biological environment with the external environment in a roughly 24-hour cycle. This daily clock allows animals to accommodate and even anticipate daily recurring environmental changes before they occur, including light-dark cycles, food availability, and temperature. Several rhythmic processes have been observed in animals, some are conspicuous behavioral states such as sleep-wake cycles, and others are less clear, like oscillations in metabolic, neurological, and hormonal functions [1]. Circadian rhythms are not a reflection of environmental cycles; rather, they are endogenous rhythms that could be adjusted by environmental cues. The main distinction between those two models is that an endogenous rhythm could exist in constant, non-cycling external conditions such as constant light and free run with a specific periodicity. 

The clock

     A biological timekeeping system that maintains periodicity in the internal environment and adapts to changes in the external environment must consist of at least three main components: input from the environment, a central pacemaker or clock, and output pathways that mediate communication between the central pacemaker and biological processes. A circadian oscillator consists of an autoregulatory network of multiple transcriptional and translational feedback loops, where the clock genes are activated or repressed by the rhythmic cycling of the proteins encoded by them [2,3]. These genes code for proteins that build up in the cell’s nucleus at night and decline during the day, generating cyclic changes in their own abundance and activity with a periodicity of roughly 24 hours. Mutations in the clock genes can change rhythmic behavior in animals and humans [4].

In mammals, a hierarchical system of multiple circadian oscillators exists, where a central pacemaker receives external environmental cues and regulates the rhythmic output by synchronizing peripheral oscillators that exist throughout the organism. This autonomous central pacemaker has unique properties that aren’t observed in peripheral oscillators. The tissue must express a circadian rhythm with a specific period and phase in vitro in constant conditions, without external cues, it must be necessary for exhibiting rhythmic behavior and ablating the pacemaker should abolish rhythmicity, and it must be sufficient to induce circadian rhythms in the absence of peripheral oscillators. Many scientists attempted to locate a tissue that fulfills these criteria in animal models by lesioning glands and brain regions until the suprachiasmatic nucleus (SCN) was established as the central pacemaker. Lesions in the SCN were shown to abolish rhythmicity [5]. Moreover, transplantation of the SCN tissue into rats with complete bilateral suprachiasmatic lesions restored rhythmicity [6]. Finally, circadian rhythmic changes of neuronal activity were observed in isolated SCN tissue [7,8,9]. 

Figure 1

Light entrains the central pacemaker, SCN. The SCN then coordinates the phases of peripheral oscillators.There are also weaker extra-SCN pacemakers, such as food-entrainable oscillator, that are regulated by nonphotic zeitgeber and contribute to coordinating the peripheral oscillators.

Brown, Alexandra J., Julie S. Pendergast, and Shin Yamazaki. 2019. “Peripheral Circadian Oscillators.” The Yale Journal of Biology and Medicine 92, no. 2: 327–35.

Entrainment and regulation

       Since the biological clock aims to synchronize the internal biological environment with the external one, it must be sensitive to external cues. The external cues that can reset the biological clock or change its phase are called zeitgebers. Light is the main zeitgeber that communicates time information to the clock to entrain it (figure 2). Interestingly, some completely blind individuals maintain a normal circadian rhythm. This phenomenon is explained by the fact that light entrainment is not mediated by cones and rod photoreceptors, which are responsible for visual perception. Instead, another photopigment called melanopsin exists in melanopsin-containing retinal ganglion cells (mRGCs), and it is responsive to pulses of light. The mRGCs innervate the SCN and contribute to photoentrainment. When the internal circadian time is out of phase relative to the external time, Light/Dark (LD) cycle, light will be sensed by mRGCs when it is not supposed to, which phase shifts the subjective internal clock to synchronize it. In a sense, this can be understood as an analogy to the internal circadian rhythm existing in a different time zone than the external environment. The response of the circadian clock to the zeitgeber depends both on the strength of the stimulus and on the circadian phase during which it is applied. Light can advance or delay the circadian clock depending on when it is applied, thereby ensuring its synchrony with the solar day. A prominent example of this process is jet lag when you travel into a different time zone and your circadian rhythm becomes out of sync with the external environment. The light zeitgeber then acts on the SCN to entrain it to the new rhythm; maintaining circadian rhythms depends on sensing the pattern of exposure to the stimulus, light in this case, to transduce temporal information rather than sensing qualitative differences in light to build a conceptual spatial map of the environment.

        In addition to light, there are also weaker non-photic zeitgebers that affect the circadian rhythm (figure1). One of the most interesting non-photic zeitgebers is feeding. In fact, many studies have confirmed the existence of a food entrainable oscillator, separate from the SCN that relies on different molecular mechanisms. However, its exact location and mechanism haven’t been determined.

 It is well established that the fetal circadian pacemaker is entrained prenatally through maternal-fetal communication. This process depends on the activity of maternal SCN, as ablation of the mother’s SCN during gestation disrupts the normal phase of the pups’ rhythms. The loss of fetal circadian rhythm is rescued through rhythmic humoral injections that efficiently entrain fetal pacemaker, which essentially is bypassing the clock and hijacking the output signaling pathways to achieve the result [10,11,12].

Figure 2

SCN receives light information from the retina. This photic entrainment corrects the phase of the pacemaker to synchronize it with environmental time. The SCN then synchronizes peripheral clocks in organs and maintains circadian rhythmicity across the body. Nonphotic zeitgebers such as food can also contribute to adjusting the phase of peripheral oscillators. Activity rhythms can also feed back on the SCN and adjust its phase.

Schibler, Ueli, and Paolo Sassone-Corsi. “A Web of Circadian Pacemakers.” Cell 111, no. 7 (December 27, 2002): 919–22. https://doi.org/10.1016/S0092-8674(02)01225-4.

Sleep-wake cycle + Dealing with shift work and late classes (misalignment)

        One of the most important outputs of the circadian clock is the sleep-wake cycle. Timing of sleep is determined by two factors: sleep pressure—the need to sleep, and it’s dependent on how tired we are and how long we have been awake—and the circadian clock. The distinction between these two factors becomes very clear in instances like jet lag, where the circadian rhythm is out of phase relative to the environment, so it induces sleep and wakefulness at the wrong time. Sleep timing and duration are highly sensitive to the internal and external state of the animal, and one of the most important output pathways of the circadian clock that regulate sleep patterns is melatonin, a known sleep inducing molecule. The circadian clock determines a window during which the pineal gland will secrete melatonin if it is dark—hence the name “hormone of darkness.”[13] A direct consequence of this is that a misalignment between the SCN and external time will lead to a situation where the melatonin secretion window might come during the day, which will prevent melatonin secretion.

        Our 24-hour society demands a lot from the circadian system and significantly strains it. Nontraditional schedules require employees and students to be awake during nighttime hours when their biological clock program is inactive. Such disruption in the circadian system could cause chronic misalignment of the circadian rhythm with the sleep/wake cycle and misalignment of food intake and metabolism with the light/dark cycle. Exposure to light during a night shift can reset the circadian phase and suppress melatonin release in humans, which also suggests that the common exposure to artificial light at night may affect circadian function [14,15,16]. Evidence indicates that shift work is associated with deteriorated neurobehavioral performance[17,18,19,20, 21,22,23], as well as a wide variety of serious physiological and psychological disorders, including cardiovascular disease, metabolic syndrome, obesity, immune dysfunction, increased risk for cancer, and reproductive complications [24,25,26,27]. Another set of experiments set out to explore the effects of disruptions in circadian rhythms on the academic performance of students [28]. A lack of daily sleep stability in sleep duration was found to be correlated with lowered academic performance in men and women. For women, having later sleep timing correlated with worse academic performance. Furthermore, increased social jet lag, misalignments between endogenous circadian rhythms and the built environment due to imposed societal schedules, strongly correlate with a decrease in academic performance [29]. The same study investigated the relationship between class time and average student performance and showed that all chronotypes, morning larks and night owls, exhibited significant academic improvement across the day, with the average evening class points being at least 0.27 points higher than the average morning grade points. These findings provide significant insights into the potential benefits students could gain from taking advantage of their own biological rhythms and chronotypes. It’s also important to note that chronobiology literature might provide legitimate reasons for adjusting school start timing. Specifically, a 30 minutes delay in school start time was associated with significant improvements in measures of adolescent alertness, mood, and health [30]. Finally, chronobiology gestures at expected struggles that students face and the need for academic flexibility in the current situation where many students are functioning on a significant time difference from their class times

      Many experiments were conducted to study the efficacy of multiple conditions and patterns in treating night shift workers. Controlled exposure to bright light at night and complete darkness during the day to simulate the natural light/dark cycle were found to be effective in resetting the circadian rhythms of night-shift workers, partially due to the enhanced melatonin released during their scheduled daytime sleep time [31,32,33]. This circadian rhythm realignment improved performance during night shift hours and increased the duration of sleep during the daytime hours by nearly 2 hours per day. In addition to evening bright light exposure and mimicking dark conditions before sleep, practices such as having a consistent sleep schedule, napping before night shift or class, evening melatonin ingestion, restricting eating to daytime, and exercising are recommended for coping with nontraditional schedules[34,35,36]. Although these habits and lifestyle changes help mitigate the impact of disrupted circadian rhythms, it is important to emphasize that maintaining a consistent sleep time at night and minimizing exposure to light around sleeping time are ultimately the optimum ways to minimize potential cognitive, physical, and mental disturbances.

 

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38. Schibler, Ueli, and Paolo Sassone-Corsi. 2002. “A Web of Circadian Pacemakers.” Cell 111, no. 7: 919–22. https://doi.org/10.1016/S0092-8674(02)01225-4.