Chapter 15 - The circadian system: From clocks to physiology

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Abstract

The circadian system, composed of the central autonomous clock, the suprachiasmatic nucleus (SCN), and systems of the body that follow the signals of the SCN, continuously change the homeostatic set points of the body over the day–night cycle. Changes in the body's physiological state that do not agree with the time of the day feedback to the hypothalamus, and provide input to the SCN to adjust the condition, thus reaching another set point required by the changed conditions. This allows the adjustment of the set points to another level when environmental conditions change, which is thought to promote adaptation and survival.

In fasting, the body temperature drops to a lower level only at the beginning of the sleep phase. Stressful conditions raise blood pressure relatively more during the active period than during the rest phase. Extensive, mostly reciprocal SCN interactions, with hypothalamic networks, induce these physiological adjustments by hormonal and autonomic control of the body's organs. More importantly, in addition to SCN's hormonal and autonomic influences, SCN induced behavior, such as rhythmic food intake, induces the oscillation of many genes in all tissues, including the so-called clock genes, which have an essential role as a transcriptional driving force for numerous cellular processes.

Consequently, the light–dark cycle, the rhythm of the SCN, and the resulting rhythm in behavior need to be perfectly synchronized, especially where it involves synchronizing food intake with the activity phase. If these rhythms are not synchronous for extended periods of times, such as during shift work, light exposure at night, or frequent night eating, disease may develop. As such, our circadian system is a perfect illustration of how hypothalamic-driven processes depend on and interact with each other and need to be in seamless synchrony with the body's physiology.

Introduction

Light on earth is essential for life; it is necessary to produce energy, e.g., by photosynthesis or the generation of warmth. Therefore, the development of life under the eternal light–dark cycle induced by the rotation of the earth has promoted the development of biological systems that can use light input as a synchronizing cue to organize activity, inactivity, and energy consumption. These light susceptible systems allowed organisms to be active during a specific phase of the light–dark period and help anticipate the sun's rising and setting, coupling it to the moment of energy consumption and rest. This arrangement of light input, connected to behavior or directly to locomotor systems, has allowed organisms to determine the most favorable moment to be active, to forage for food, and to avoid predators. A simple example of this is the swimming behavior of a marine zooplankton; these tiny shrimp-like creatures need to feed near the surface of the sea, where most food is available. However, when the sun is shining, the UV light of the sun will damage it. Therefore, the animal's movement is inhibited by light, resulting in the sinking of the animal to lower levels where light is less or absent. The mechanism of this light-induced inhibition of activity is as follows: In the absence of light, the animal starts producing melatonin (also our “dark” hormone), which initiates muscle contraction driving the animal up until the animal gets exposed to light. This stops the production of melatonin, followed by the arrest of muscle contraction, inducing the animal to sink into the deeper regions where darkness prevails, and the whole cycle starts again (Tosches et al., 2014).

Later in evolution, light could no longer penetrate whole complex organisms. Consequently, specific mechanisms, i.e., clock genes, developed, allowing organisms to still anticipate the sunset and sunrise. Consequently, now all organisms can anticipate the moment when they need to become active and eat, and when they need to sleep. This predictive capacity was so crucial for survival that evolutionary pressure has resulted in the development of an entire circadian system, composed of cellular and molecular mechanisms that enable the organism to arrange its activity according to the light–dark cycle, even when those changes in light are absent.

This rhythmic anticipatory process is made possible by the presence of clock genes that through the interaction of their transcriptional–translational feedback loops have a periodicity of ~ 24 h. Ultimately, their protein products can steer functional cyclic processes within the cell with a cycle of 24 h (Beytebiere et al., 2019). The rhythmicity of these clock genes depends on two things: the moment of energy use by and energy availability for the organs; clock genes prepare cells for the moments when the energy enters, or is needed. This becomes clear by the observation that besides being modulated by the light–dark cycle, a significant part of the clock genes is driven by metabolic cues (Dibner and Schibler, 2015).

The circadian system's importance for many fundamental functions in the body was recognized by awarding the Nobel Prize in Physiology and Medicine to three investigators (Jeffrey C. Hall, Michael Rosbash, and Michael W. Young) who were crucial for the discovery of the molecular mechanism of the circadian clock. As the committee indicated in the justification of their Prize in Physiology and Medicine: “Chronic misalignment between our lifestyle and the rhythm dictated by our inner timekeeper is associated with increased risk for various diseases.” Therefore, in the present review, most attention will be given to the importance of timing for our physiology and health in general and less to the more detailed molecular mechanisms.

The circadian system with all its components can drive rhythmicity, synchronization, and anticipation. For the sake of clarity and to focus on the importance of human physiology, we will only pay attention to the circadian system in mammals. In mammals, the circadian system consists of a central biological clock, the suprachiasmatic nucleus (SCN), and other brain and body structures that follow its signals. The location of the SCN in the central nervous system, at the base of the hypothalamus, is fundamental for the circadian system's functioning. This strategic location allows the SCN to integrate light dark information and interact with a wide variety of hypothalamic nuclei, thus influencing all aspects of body homeostasis by synchronizing behavior, via autonomic and hormonal outputs, with the functionality of the organs (Fig. 15.1).

There is another functional advantage of the location of the SCN. As its name indicates, it is located above the optic chiasm, receiving direct light input from the retina, allowing synchronization of its neuronal activity with the light–dark cycle, and imposing this synchrony to target structures (Jones et al., 2018). The importance of the circadian system for the homeostasis of the organism is illustrated by the development of the SCN as a central autonomous clock, that is able to synchronize physiology, in particular hormone secretion and behavior, even in conditions without a clear light–dark cycle (Kalsbeek et al., 1996; Buijs and Kalsbeek, 2001; Perreau-Lenz et al., 2003, Perreau-Lenz et al., 2004).

Section snippets

Clock Genes: The Driving Force Behind the Rhythm in the SCN and of the Metabolism in Peripheral Cells

As explained previously, clock genes and the specifically timed expression pattern of their clock gene proteins are essential for the organization of circadian rhythms and SCN neuronal activity. Although clock genes are also expressed in other neurons, these neurons do not have an endogenous rhythm. The specific organization of SCN neurons and their glia cells (Herzog et al., 2017; Jones et al., 2018; Brancaccio et al., 2019) makes the SCN a unique brain region with autonomous rhythm capacity.

Circadian Rhythms in Physiology: Continuously Changing Homeostasis

Already some years ago, Nicholas Mrosovsky coined the term rheostasis for naturally occurring, e.g., seasonal and daily time-induced changes in homeostasis (Mrosovsky, 1990). It is clear now that homeostasis is continuously changing under the influence of the SCN. However, how can the SCN in interaction with other brain areas drive the temporal organization of our homeostasis? For instance, glucose levels that are fine in the morning are an indication of hyperglycemia if the same levels appear

Rhythmic Secretion ofHormones: A Reflection of SCN Activity

Through its connections with other hypothalamic nuclei, the SCN has vast possibilities to influence the secretion of multiple hormones produced by hypothalamic neurons. Other hormone rhythms, such as blood insulin or vasopressin rhythm, are generated by behavior modulated by the SCN, such as food or water intake, or general activity. Many hormones show a precise circadian rhythm directly driven by the SCN. For example, melatonin secretion is induced by neuronal activity of glutamatergic SCN

The SCN Controls the Rhythmic Physiology of All the Organs in the Body

In addition to the variation in hormonal regulations, as discussed previously for melatonin, cortisol, and LH, the SCN also organizes the functionality of our organs mainly by setting, via the autonomic nervous system, a level of response, activity, and rest associated with the time of the day. Our basal heart rate, for example, is lower at night than during the day, even under the same activity conditions (Scheer et al., 2004). The direct influence of the SCN on the activity of our organs is

Disturbances in SCN Activity Trigger Pathologies

Considering, as shown previously, that the biological clock plays an essential role in determining the set points of several aspects of our physiology, any long-term disturbance in the activity of the SCN may have severe repercussions for our health. For instance, it has been shown that older people and people with Alzheimer's disease have a diminished melatonin secretion (Mirmiran et al., 1989; Uchida et al., 1996), indicating a lower activity of the glutamatergic neurons of the SCN. In this

Desynchrony of Behavior With the Light–Dark Cycle: A Deviation in Modern Life Leads to a Wide Variation of Pathologies

The influence of the SCN over physiology is not an immediate matter of life and death, disease, or health. However, every day, it is there setting the thresholds of nearly all systems in a subtle but undeniable way. Consequently, ignoring the signals of our biological clock in a regular way like we do when we do shift work, eat or simply, are in front of a cellular screen at night, makes us prone to develop diseases like obesity, cardiovascular, or immune disorders (Fig. 15.3) (Gangwisch et

Conclusion

The intertwining of most of our body's physiological processes, with daily activity and food intake, has resulted in a high evolutionary pressure on the development of the circadian system. This evolutionary pressure culminated in the development of a central biological clock and additional molecular clock mechanisms in all the cells of the body, allowing synchronization of their function to accommodate the needs of the organs. The function of the central biological clock is to synchronize

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