Circadian clocks in zebrafish

Organs that see the light: circadian clocks in zebrafish

It's not just the clock on your wall that ticks!

Have you ever wondered why you feel lively and full of energy during the day but all of your energy fades away as the day passes by and you become tired and sleepy? The answer to that question is the presence of what is known as the circadian rhythm in human bodies as well as in other organisms. This internal circadian clock is self generated and independent of any external factors. However some external factors such as sun-light and food which are collectively known as zeitgebers can change the 24-hour cycle rhythm. The circadian clock is in fact very closely synchronised with the environments day-night cycle and extended periods of light or darkness will disturb the rhythm of the cycle causing it to become shorter or longer than the usual 24-hour cycle.

When you wake up its not just you who begins a new day, the circadian cycle begins a new cycle and is reset when the eyes open again and daylight is detected. The retina of the eye has an outer layer containing photoresponsive ganglion cells which are responsible for transmitting visual information received from photoreceptors to different parts of the brain. These ganglion cells contain specialised pigments called melanopsin. Melanopsin is able to detect sunlight and generate action potential which is then transmitted through a pathway known as the retinohypothelamic tract towards the hypothalamus in the brain. More accurately the specific destination is the suprachiasmatic nucleus (SCN) which is located in the hypothalamus. The SCN is the site of circadian control of homeostatic functions and it is commonly known as the ‘master clock'. The importance of the master clock has been shown through studies where the removal of the SCN from animals abolished their circadian sleep-wake cycle. One of the key functions of the SCN is the stimulation of the pineal gland which in response secretes a sleep promoting hormone known as melatonin. The melatonin secretion is all but absent during daylight, however when light from the surrounding environment decreases melatonin secretion is stimulated by the SCN. This is known as the dim-light melatonin onset (DLMO). In fact melatonin secretion is at its peak between 2am-4am. Melatonin works by breaking down hormones which essentially keep you up and give you energy. It also reduces brain activity and withdraws hormones and oxygen from muscle tissues to reduce physical activity and help you fall fast asleep. This is one way in which environmental factors impact the body's circadian rhythm.

The SCN regulates other factors which affect the circadian rhythm of the body. The SCN stimulates the secretion of the so called ‘stress hormone' cortisol by the adrenal glands during the day while its level drops as daylight decreases and reaches its minimum during the evening which helps you go to sleep. Cortisol is one of the primary hormones which kicks you out of bed and gets you going. Other hormones include adrenaline and serotonin which increase motor activity and cerebral activity respectively. When daylight fades away serotonin is also transformed into melatonin which is an efficient way to reduce serotonin levels and at the same time produce required melatonin.

Having just read about the ‘master clock' and its numerous influences on our circadian rhythm, you wouldn't think that any other circadian clock was present in our body. However research done by Dr Whitmore of University College of London (UCL) has found that not only circadian clocks are present in tissues outside the brain, but in some cases they even act completely independently from the master clock. After the identification of the CLOCK gene which encodes circadian clock proteins, to Dr Whitmore's surprise he found that the CLOCK gene was not just expressed in SCN. The CLOCK gene was also present in peripheral tissues and not only was this gene expressed but its expression oscillated in a rhythmic fashion similar to that in the SCN. This finding provided proof that circadian clocks apart from the SCN are present and they are now known as peripheral oscillators. Using zebrafish as a model organism Dr.Whitmore and his colleagues were able to detect these peripheral oscillators in various tissue and organs. In fact they were able to detect expression of the CLOCK gene in zebrafish embryonic cells which can explain the widespread presence of circadian clocks in zebrafish. These peripheral oscillators are able coordinate with local dark-light cycle without requiring signals from the master clock. These results were a surprise as vertebrates were previously thought to depend on the signal transmission from the retina and the SCN to synchronise circadian clocks to light-dark cycle. This is the case in mammals as their peripheral clocks are under the control of the SCN as they are not light sensitive and do not directly respond to environments light-dark cycle. They may however use other zeitgebers such as feeding patterns to set circadian rhythm. So next time you decide to skip a meal and get hungry at the same time that you would usually eat it's because your disturbing a circadian rhythm in your body!

Scientists are set to continue their search for more clocks, their functions and physiology. After the detection of a master clock in the shape of the SCN which controls the circadian day-night rhythm in humans and other organisms, there is now strong interest in peripheral circadian clocks. Studies have shown that zebrafish peripheral circadian clocks are independent of the master clock and can synchronise their cyclic rhythm directly from sunlight. So however many clocks you might have on your wall, you've got plenty more inside you!

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