The Body Clock

If you’re wondering how you’re unable to wake up on your own in the morning (even after your alarms ring fifteen times), then you’re in the right place.

How does the body measure time?

The body doesn’t measure time as usual periods of the day, but rather in accordance with the periods for which certain genes produce certain chemicals.

Working through Feedback Loops

• The circadian rhythms work on a feedback system.
• This system has two components – positive and negative.
• The positive component is always there and is the part when a certain process keeps increasing the production of a certain product and tries to exceed the equilibrium.
• This is when the negative limb comes into play. In order to maintain equilibrium and stability, the negative feedback acts to reverse or repress the activity of the positive system thereby approaching a stable state.
• Without a negative system working in accordance with that of positive, every process will work with no rhythmicity as they won’t know when to stop.
• Every tissue has its own rhythm but the core clock is the only one which is absolutely light-dependent, and independent of all other external cues such as temperature (that might affect peripheral rhythms).
• The SCN (Suprachiasmatic Nucleus) is a small part in the hypothalamus which adjusts all the peripheral rhythms to the external light-dark cycles and decides the type of feedback (negative or positive) with which different tissues respond to the daylight conditions.
• Other cues that affect the rhythms of biological tissues (Zeitgebers)
  • Atmospheric
  • Drugs
  • Temperature
  • Social interactions
  • Pharmacological manipulation
  • Exercise
  • Eating/drinking patterns

(Sources: Zeitgebers, Positive and Negative Feedback Loops in Biology, Light effects on circadian rhythm)

How does the core clock synchronize with tissue clocks?

To perform its fundamental function of keeping the peripheral rhythms in sync with a universal light/dark cycle, the master clock has developed mechanisms to avoid entrainment from factors other than light.

How genetic information gets transmitted: Components of the core circadian system

1. Transcription Factors (TFs)

2. E-Box (Enhancer Box)

3. Clock Genes

Transcription Factors (TFs) – Basis of Regulation of Cycles

In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA [Messenger RNA (mRNA) is a large family of RNA molecules that convey genetic information from DNA to the ribosome, where they specify the amino acid sequence of the protein products of gene expression. by binding to a specific DNA sequence – Wikipedia]
The function of TFs is to regulate – turn on and off – genes in order to make sure that they are expressed in the right cell at the right time and in the right amount throughout the life of the cell and the organism.- Wikipedia

The two types of Transcription Factors:
1. Promoters                2. Suppressors

E-Box (Enhancer Box) – Home to TFs

An E-Box provides a platform for various genes to function by helping them to bind with the transcription factors. The genes which get attached to the TFs are expressed and their effect can be observed once the DNA is converted to mRNA (mRNA transports the genetic info to the ribosomes where it is converted to amino acids for the respective gene function).

Clock Genes (functioning within the SCN) – Currency of Rhythms

CLOCK, BMAL1 – Involved in the positive feedback
PER, CRY – Involved in negative feedback

Genetics of Circadian Rhythms

Process of transmission

Gene transcription is an interplay of promotion and suppression. The products of the genes in transcription have an inverse effect on their respective genes preventing further transcription after their enough amounts accumulate.
This inverse effect means that the if the genes involved in negative feedback are transcripted, then their produced products will eventually suppress their transcription any further by promoting the genes from the positive mechanism, or vice-versa.

What’s actually happening in the SCN

1. Increase or decrease in the light signals activates or deactivates the circadian genes.

2. At dusk, when the light reception starts, CLOCK and BMAL1 genes (involved in promoting daytime activities) bind to the promoters which further bind to the RNA polymerase (here, the enzymes responsible for the processing of the genetic information). After processing, the info is transported through mRNAs to the ribosomes for final action on the actual cycle. The final products of the CLOCK and BMAL1 genes which are transported by the mRNAs are called CLOCK and BMAL1 proteins respectively.

3. Since regulation is needed to prevent the cycle from getting out of control, the suppressors get activated. This is when the light received from the environment decreases. At this point, the accumulation of the CLOCK and BMAL1 proteins is at peak and no more of their genes get transcripted because the suppressors start binding with them while preventing them to bind with the promoters.

4. This is when the genes of the negative limb (PER and CRY) start to bind with the idle promoters, sending their products to the ribosomes to repress the activity of the CLOCK and BMAL1 proteins.

5. Referring to the beginning of this article, when the negative feedback mechanism becomes successful in achieving an equilibrium state by eliminating all the activities of the positive limb, it starts to degrade (with the advent of light) and leaves the promoters free to enable binding with the positive limb again.
   This way, the cycle continues.
   The study of gene transcription yet extends to the detection of the periods of peaks and lows of the various proteins and how these detectors transmit this info to the suppressors and promoters to change their binding companion. This is under research and lacks adequate resources.

Molecular components of the mammalian circadian clock
Structure and function of negative feedback loops at the interface of genetic and metabolic networks

Why is the master clock important?

The exact reason is still under research but various experiments depict direct dependence of peripheral circadian rhythms on the master clock. This can be shown by the property of photoperiodic memory.

Photoperiodic Memory

Photoperiodic memory allows the special 20,000 neurons in the SCN to remember the intervals for the availability or absence of light according to which they pass on their commands. Why neurons have this property is still unknown. So, it’s treated as intrinsic for now.

It explains why we don’t adapt to changes in the external photic conditions so quickly. This is because although the neurons can be entrained by light but the rates of entrainment are different. The neurons present in the ventral part of the SCN easily shift to the new schedule while the ones in the dorsal region are not that fast and still maintain their older schedule. That’s why the night shift workers feel sleepy at the normal time in their early days. Also, this is why you get a jet lag. (Reference)

Due to this, your body keeps up with the cycle even in the absence of external cues till the time its photoperiodic memory is retained.

So, single circadian rhythms may be entrained by light on their own but they cannot show effect unless the whole master clock adapts to the change and falls into sync.

How circadian clocks communicate with each other

The open question, for now, is to find out the dependency of the peripheral clocks and the master clock on each other, i.e. ‘Do they always work in synchrony or have separate domains in selective cases?’

Blind people follow the same sleeping pattern

If the blind really had dysfunctional eyes then how would they maintain their sleep/wake cycles? The answer lies in first understanding that there is no such thing as absolute photoreceptor-cell degeneration. This means that even if the visual field of a person is gone, it doesn’t imply that his non-visual light receptors are also destroyed. (Here’s how the body still processes light without vision). The retinal ganglion cells in the eye responsible for the non-visual reception are independent of the functioning of rods and cones and keep working after complete visual disappearance as per recent researches. (Reference)

Circadian Rhythms at the Poles
Arctic Reindeer Goes Off the Circadian Clock