Circadian Rhythms Overview: A Brief Introduction

A signature of life on our rotating planet are the ‘circadian’ (24h) rhythms of biochemistry, physiology and behavior evident in virtually all living organisms. Circadian rhythms are driven by internal, biological clocks that likely arose early in the evolution of life, to coordinate sensitive biochemical processes with the dramatic daily changes in solar radiation and temperature. Circadian clocks are best known as nature’s alarm clocks, providing an alerting signal in day (or night, for ‘nocturnal’ organisms) and a sleep signal at night, creating the familiar sleep-wake rhythm that structures our daily lives. But nature is ingenious, and in various species circadian clocks have been adapted for a number of other vital, and fascinating functions, such as seasonal rhythmicity (based on the use of circadian clocks to measure daylength), navigation using the sun as a compass (based on the use of circadian clocks to compensate for the movement of the sun across the sky), and memory for meal times (based on the ability to sense and remember the internal circadian time at which food was found at a particular place).

The adaptive functions of circadian clocks require that they remain in synchrony with local environmental time. Thus, at a minimum, the biological system that controls our daily rhythms must consist of at least one internal circadian clock, at least one sensory input to keep the circadian clock synchronized to the environment, and at least one output signal by which the circadian clock can exert temporal control over behavior and physiology. The revolution in molecular genetics that heralded the turn of the last century has yielded extraordinary new insights into how circadian clocks rule our biology. A master circadian clock has been located in the mammalian brain, in a small, formerly mysterious ball of ~10,000 neurons known as the suprachiasmatic nucleus (SCN, named for its location, sitting on top of the optic chiasm in the hypothalamus). The SCN has the distinction of being the first place in the brain that receives information from the eyes, and many of the neurons here are activated by specialized photoreceptors in the retina. Most SCN neurons can be classified as ‘circadian clock cells’, as they contain a fully functional circadian timer, created by intracellular feedback loops involving ‘circadian clock genes’ (at least 12, and counting) and the proteins that they encode. The loops are constructed in such a way that clock protein levels rise and fall with a precise 24h periodicity, regulating transcription of many other genes along the way, thereby creating daily rhythms in cell functions. Remarkably, circadian clock cells are now known to exist throughout the brain and in virtually every other organ and tissue. Metaphorically, the master clock in the SCN is the conductor, and the circadian clocks in the rest of the brain and body are the orchestra, each ‘instrument’ making its own unique contribution to the ‘circadian symphony’.

Four overlapping eras can be recognized in the history of research on circadian rhythms, each addressing unique sets of questions, and setting the agenda for the next era. In the first era, dating to the 17th century, the existence of circadian rhythms in plants and animal behavior and physiology was catalogued and the properties of these rhythms carefully described. By 1960, this work had yielded wide acceptance of the concept of self-sustaining biological ‘clocks’, internal devices that could generate daily rhythms that mirrored the solar day, but that continue to operate even without exposure to environmental stimuli. The next era was devoted to localizing the physical substrates of circadian clocks within several widely used model species, including molluscs (with big neurons amenable to electrophysiological study), fruit flies (excellent for genetic studies) and lab rats and mice (mammals with brains and behavior like us). The ‘black box’ conceptual models (input, clock, output) of the ‘circadian timekeeping system’ were gradually filled in with the names of specific body parts, brain regions and cell types, and the cellular properties of these clocks were probed using electrophysiological and other techniques. The potential role of the SCN as a master clock in mammals was first recognized in 1979, and this role was confirmed with a series of ground breaking studies, culminating in 1995 with the discovery that individual SCN neurons were indeed self-sustaining circadian oscillators. By this time, the genomic era was well underway, and dissection of the molecular genetic basis of mammalian circadian clocks became a realistic objective (an increasingly complex story still in progress). A revolutionary aspect of this work was the recognition that circadian clocks regulate a large percentage of the entire genome, and that this temporal regulation, this ‘day within’, is deeply embedded in the normal functioning of our biological systems. This heralds the next era, in which the role of circadian clocks in health and disease will be more fully specified, and this knowledge translated into novel treatment approaches to a wide range of behavioral (e.g., mood and sleep disorders), physiological (e.g., obesity), and genetic (e.g., cancer) disorders.

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