Circadian Rhythms: Biological Clock of Living Organisms

The suprachiasmatic nucleus (SCN) is called the biological clock of mammals [3]. SCN is located in a tiny cluster of hypothalamic nerve cells that encloses about 20,000 neurons. The foremost function of the SCN is to act as a cardinal circadian pacemaker so as to control the sleep (i.e., rest) and wake (i.e., activity) cycle. The sleep and wake befall in approximately 24 h cycle that grew in consequence of the amendment of solar cycle [4]. The SCN gets info about illumination through the eyes. When light enters into the eye it causes triggering of retina neurons that transform light (i.e., photons) to electrical signals. The retina of the eye comprises two genres of photoreceptors called rods and cones accountable for scotopic vision [5,6].


Editorial
The biological operation of living beings that spectacle an endogenous, entrainable oscillation of roughly 24 h is called circadian rhythm [1]. The term circadian is derived from the Latin words circa represent "around" and dies represent "day". Even though, circadian rhythm is internally engendered they can be moderated by external gestures, for example, temperature and sunlight [2].
The suprachiasmatic nucleus (SCN) is called the biological clock of mammals [3]. SCN is located in a tiny cluster of hypothalamic nerve cells that encloses about 20,000 neurons. The foremost function of the SCN is to act as a cardinal circadian pacemaker so as to control the sleep (i.e., rest) and wake (i.e., activity) cycle. The sleep and wake befall in approximately 24 h cycle that grew in consequence of the amendment of solar cycle [4]. The SCN gets info about illumination through the eyes. When light enters into the eye it causes triggering of retina neurons that transform light (i.e., photons) to electrical signals. The retina of the eye comprises two genres of photoreceptors called rods and cones accountable for scotopic vision [5,6].
The retina also contains particular photosensitive ganglion cells that succor in synchronization of the cardinal circadian clock [7]. A subset of retinal ganglion cells serves as the precursor for the retinohypothalamic tract (i.e., linked in the circadian rhythms of mammals) leading to the SCN [8]. If cells from the SCN are removed and cultured can engender autonomous circadian vacillations of clock gene expression as well as neuronal firing [9]. Studies suggested that each SCN cell acts as a functional clock, typically harmonized with the action of its contiguous cells. In fact, deprived of external time clues, human bodies conserve a sleep-wake rhythm of almost 24 h [10]. Scheer et al. reported that human subjects can at least be entrained to a 23.5 h day length and a 24.65 h Martian sol [11]. In Figure 1, few sorts of the circadian biological clock of the human being represented.
However, the mechanism of the circadian biological clock endured an enigmatic for many years. In the 1970's, Seymour Benzer et al. decided to discover genes that are liable for circadian rhythm in fruit flies [12]. They reported that mutations in an anonymous gene are causative for the interference of the circadian clock of flies. They entitled this gene period (per).
But, how the clock really operates is a big query. In 1984, Jeffrey CH et al. succeeded in isolating the per gene [13,14]. The study of Jeffrey CH and Michael R were able to discover that PER protein that encoded by per gene, accrued in the course of the night and degraded in the course of the day [13]. Consequently, PER protein levels vacillate over a 24 h cycle, in synchrony with the circadian rhythm.
After that, the researchers decided to find in what manner such sort of circadian oscillations could be engendered and sustained. It may in consequence of impeding of per by PER conjectured by Jeffrey CH and Michael R [15]. Later the researchers reasoned that PER could avert its creation and thus control its level in an incessant, cyclic rhythm by a negative feedback loop.
PER protein is a cytoplasmic protein, so how this protein entered in the cell nucleus? The subsequent study of Jeffrey CH and Michael R suggested that PER is formed in the nucleus at night [16]. Then another fact is how did it become here? In 1994, Michael W discovered another gene, timeless (tim) that encoded the protein, TIM [17]. This TIM is also prerequisite for typical circadian rhythm. Later he exposed that TIM and PER, both proteins were capable to arrive in the nucleus to impede per gene action to close the inhibitory feedback loop.
Aforesaid controlling feedback mechanism clarified how this vacillation of the levels of cellular protein appeared. Then queries lingered what regulated the frequency of the vacillations? Michael WY revealed another gene, double-time (dbt) that encoded DBT protein that delayed the accrual of the PER [18]. This proved how a vacillation is accustomed to more strictly stalemate a 24 h cycle.
Numerous studies identified and characterized the function of several clock genes. In mammals, circadian rhythm comprises of a network of genes with numerous positive and negative feedback loops [19]. The family of bHLH-PAS-containing transcription factors, CLOCK and BMAL1 are accountable to exert positive feedback loops. Firstly CLOCK and BMAL1 bind to each other to form a heterodimer that binds with Periods (i.e., Per1, Per2 and Per3) and Cryptochromes (i.e., Cry1 and Cry2) genes [20]. In case of negative feedback loop, PERs and CRYs bind with each other to form heterocomplexes. These generated heterocomplexes translocate back to the nucleus to block the transcription [21].
Except for aforementioned crucial feedback loops, orphan nuclear receptors REV-ERBα and RORα also serve as a regulatory feedback loop. This feedback loop is also controlled by the heterodimer (i.e., CLOCK/BMAL1) of the positive feedback loop [21]. Furthermore, numerous post-translational modifications are also linked to the typical functioning of the circadian rhythm [20]. In fact, a few hours would be ample for a molecular feedback loop to operate a cycle by only transcriptional triggering and subsequent feedback repression [20].
The biological clock is linked in numerous features of the multifarious physiology with insinuations for our health and wellbeing. The discoveries of the molecular mechanisms controlling the circadian rhythm led to the award of the 2017 Nobel Prize in Physiology or Medicine jointly to Jeffrey C Hall, Michael Rosbash and Michael W Young.