All species on Earth, from microscopic fruit flies to humans, have internal clocks that regulate their daily rhythms. On the basis of a 24-hour circadian cycle, the circadian clock allows organisms to undergo periodic changes in behavior and physiology. Our biological clock, for example, prompts our brain to release melatonin, a sleep-inducing hormone, at night.
The Nobel Prize in Physiology or Medicine was awarded in 2017 for the discovery of the molecular mechanism of the circadian clock. Our circadian cycles are not controlled by a single centralized clock, according to what we know. Instead, it works as part of a hierarchical network with “master pacemaker” and “slave oscillator” components.
Light, for example, is one of the input signals that the master pacemaker receives from the environment. The slave oscillator, which governs numerous outputs like as sleep, eating, and metabolism, is subsequently driven by the master. Despite their diverse functions, pacemaker neurons are known to share basic chemical pathways that are found in all living things.
Fruit flies, for example, have been researched extensively for interlocked systems with multiple transcriptional-translational feedback loops (TTFLs) made up of core clock proteins.
However, we still have a lot to learn about our own biological clocks. Because of the hierarchically ordered arrangement of master and slave clock neurons, it is commonly assumed that they share the same molecular clockwork.
Simultaneously, the various functions they play in regulating biological rhythms raise the question of whether they operate under different molecular clockwork.
When the circadian clock loses its robustness and flexibility, the circadian rhythms sleep disorders can occur. As this study identifies the molecular mechanism that generates robustness and flexibility of the circadian clock, it can facilitate the identification of the cause of and treatment strategy for the circadian rhythm sleep disorders.
Chief investigator Kim
Researchers from the Institute for Basic Science (IBS) and Ajou University, led by Prof. KIM Jae Kyoung and KIM Eun Young, employed a combination of mathematical and experimental methodologies to answer this question using fruit flies. The researchers discovered that the master and slave clocks use different chemical mechanisms.
A circadian rhythm-related protein called PER is generated and destroyed at variable rates in both master and slave neurons of fruit flies depending on the time of day.
The scientists previously discovered that in wild-type and Clk-Δ mutant Drosophila, the master clock neuron (sLNvs) and the slave clock neuron (DN1ps) exhibit distinct PER profiles. This suggested a possible difference in molecular clockworks between the master and slave clock neurons.
However, due to the molecular clockwork’s complexity, pinpointing the source of such variances proved difficult. As a result, the scientists devised a mathematical model for the master and slave clocks’ molecular clockworks.
Then, using computer simulations, all possible chemical changes between the master and slave clock neurons were rigorously explored.
The model anticipated that the master clock neurons produce PER more efficiently and then destroy it more quickly than the slave clock neurons. Following up with animal trials, this prediction was confirmed.
So, why do master clock neurons and slave clock neurons have such dissimilar chemical properties? The research team employed a combination of mathematical model modeling and experiments to answer this topic.
It was discovered that the master clock neurons’ quicker rate of PER synthesis permits them to generate synchronized rhythms with a high amplitude. To provide clear signals to slave clock neurons, a strong rhythm with a high amplitude must be generated.
Strong rhythms, on the other hand, are often unfavorable when it comes to responding to environmental changes. Natural causes such as differences in daylight hours between the summer and winter seasons, as well as more extreme artificial examples such as jet lag after foreign travel, are among them.
The master clock neurons have a unique characteristic that allows them to undergo phase dispersion when the regular light-dark cycle is disturbed, substantially lowering the level of PER.
The master clock neurons will be able to adjust to the new diurnal cycle with ease. Our master pacemaker’s plasticity explains how, after only a short period of jet lag, we can easily adjust to new time zones after foreign travels.
It is believed that the findings of this study will have practical relevance in the treatment of numerous illnesses that impact our circadian rhythm in the future.
Chief investigator Kim notes, “When the circadian clock loses its robustness and flexibility, the circadian rhythms sleep disorders can occur. As this study identifies the molecular mechanism that generates robustness and flexibility of the circadian clock, it can facilitate the identification of the cause of and treatment strategy for the circadian rhythm sleep disorders.”
