Funding for this site is provided by readers like you.
Sleep and dreams
The Sleep/ Dream/ Wake Cycle

Help Regulation of the Mammalian Circadian Clock by Cryptochrome At last: Just three cell types detect light in the eye Cryptochrome: the second photoactive pigment in the eye and its role in circadian photoreception
Les mécanismes moléculaires de l’horloge circadienne Circadian Rhythms Les noyaux suprachiasmatiques : une horloge circadienne composée Light-Independent Role of CRY1 and CRY2 in the Mammalian Circadian Clock
More Evidence Mammals, Fruit Flies Share Make-up On Function Of Biological Clocks Two Brandeis Scientists Shed Light On The First Photoreceptor Known To Set Circadian Rhythms Shedding Light on Circadian Rhythms Discovery: Experiments Confirm Novel Eye Pigment Controls Circadian Rhythm
Researchers Identify Unique Circadian Rhythm Photoreceptor There's more to vision than meets the eye : Researchers identify key protein in the eye's nonvisual system Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice De la vision aux rythmes biologiques : quand la lumière est un signal
Environmental stimulus perception and control of circadian clocks Missing link found between circadian clock and metabolism Researchers better understand biological clock
Steven Reppert Nicolas Cermakian
Original modules
Tool Module : Cybernetics Cybernetics
  History Module: How Biological Clock Genes Were First Discovered in Fruit Flies   How Biological Clock Genes Were First Discovered in Fruit Flies
Tool Module : Optics   Optics

In addition to the biological clock, the brain contains another time-dedicated component that works more like a stopwatch. Instead of providing an absolute time reference the way a clock does, this “mental stopwatch”lets you estimate how much time has elapsed since a given event. For example, suppose a traffic light changes from green to yellow as you are approaching an intersection in your car. When you actually reach the intersection, your decision whether to drive through it or not depends on how much time has elapsed since the light turned yellow.

This mental stopwatch that lets you monitor the passing of time appears to involve the cortex, the thalamus, and another structure that seems to play a central role in this process: the striatum of the basal ganglia.

Outil : Le " chronomètre mental "

The first gene identified as being involved in the circadian cycle of a living organism was the period gene, in the fruit fly, in 1971 (follow the History Module link to the left). The second was the clock gene, identified in mice in 1997. Since then, scientists have learned a great deal about the molecular mechanisms of the biological clocks of various species.

One of the first things scientists learned was that all of these mechanisms are based on negative feedback loops (follow the Tool module link to the left), in which proteins in the cell’s cytoplasm enter its nucleus, where they inhibit their own production. In mammals, for example, the period (per) and cryptochrome (cry) genes are activated by a complex of the proteins CLOCK and BMAL1. The DNA of these genes is then transcribed into messenger RNA, which is translated into the proteins PER and CRY in the cytoplasm. These proteins then form complexes (PER/CRY and PER/PER) that enter the cell nucleus and interact with the CLOCK/BMAL1 complex so as to inhibit the transcription process and hence the production of PER and CRY.

We also now know that several of the genes involved in the biological clock are well preserved in evolutionary terms and occur in many species. Also, several types of a given gene sometimes occur in the same species, such as the three types of period gene (per1, per2, and per3) and the two types of cryptochrome gene (cry1 and cry2) in the neurons of the suprachiasmatic nuclei in humans.

Adapted from: Whitmore, D. et al.: A Clockwork Organ. Biological Chemistry 381, 793-800 (2000)

Lastly, we know that this complex feedback loop is subject to the influence of the ambient light, which causes it to be synchronized with the cycle of day and night. When a light stimulus alters a photosensitive molecule (see box below), the production of PER 1 and PER 2 in the SCNs increases, which in turn induces changes in the progression of the loop.

But knowing the main internal mechanisms of the biological clock solves only half the problem, because this clock co-ordinates many functions, such as sleep, body temperature, and the secretion of various hormones. The other half of the problem, which is the subject of a large share of the chronobiological research going on today, is the output: in other words, how does the body’s biological clock speak to all these other systems?

In some cases, this communication might involve a direct interaction between the components of the clock and the gene for a particular hormone. For example, the proteins CLOCK and BMAL1 bind to the E-box element not only on the per gene but also on the gene for vasopressin. Like the production of the protein PER, the production of vasopressin will be interrupted when a sufficient number of PER molecules have entered the cell nucleus and bound to the CLOCK/BMAL1 complex, thus deactivating the production of mRNA not only for PER but for vasopressin as well.

The rate of production of a hormone may therefore fluctuate over a 24-hour cycle because of this kind of close linkage with the components of the body’s biological clock.

Link : Peripheral "Swatch" Watches Are A Powerful Force In Body’s Circadian Rhythms

How is this complex feedback loop influenced by light so as to be synchronized with the day/night cycle? Scientists agree that the first link in the process by which mammals reset their biological clock each day to keep it in phase with this cycle must be a photopigment that converts light energy into neuroelectric impulses. But since about the year 2000, the identity of this photopigment has occasioned much debate. One camp of scientists argues that it is melanopsin, while the other champions cryptochrome. As happens so often in these pitched battles between scientists, both sides can marshall data that seem to prove their case, which is what makes the argument so fascinating.

Cryptochromes were first discovered in plant cells, where the proteins CRY1 and CRY2 trigger growth in response to blue and ultraviolet light (follow the Tool module link to the left).  Subsequently, cryptochrome was shown also to be a key component in the feedback loop of the mammalian biological clock.

In fruit flies, crytpochrome acts as a photosensitive pigment that reinitializes the insect’s biological clock. Thus it is this protein that enables fruit flies to adapt their circadian cycles in experiments that reproduce the effects of jet lag.

Hypothetical Structure of the Protein Cryptochrome

Source: The Zhong Group, Ohio State University

But in mammals, according to some researchers, cryptochrome has permanently lost this photoreceptive function and has become just one component in a molecular clockwork mechanism whose activity no longer depends on light. This view is supported by experiments showing that when flies are deprived of all their opsins and cryptochrome, they can no longer synchronize their circadian cycles, but when mice are deprived of their rods, cones, and cryptochromes, they still retain a residual response to light.


Hypothetical Structure of the Protein Melanopsin in
Djungarian Hamsters

Source: Dr. Alexander Lerchl

These researchers instead identify melanopsin as the photopigment that entrains the mammalian biological clock. Melanopsin is found in a very small percentage (about 1%) of the retinal ganglion cells that innervate the suprachiasmatic nuclei. These same ganglion cells that contain melanopsin also innervate other parts of the brain that are affected by light intensity, such as the brain cells involved in the pupillary response.

When the genes both for opsins in the rods and cones and for melanopsin are “knocked out” (eliminated), mice become completely insensitive to the length of day and night. But if only the melanopsin genes are “knocked out”, then only a modest reduction in the circadian response to light is observed. These observations have formed the basis for a model in which opsins and melanopsin are posited to play necessary and sufficient but redundant roles in circadian photoreception in mammals.

But it’s not that simple, because other observations do support a role for cryptochrome in mammalian photoreception. For example, the pupillary response to blue light is 20 times less sensitive in mice that have no rods, no cones, and no cryptochrome than in mice that have no rods and no cones but do have cryptochrome. Further evidence: when mice are deprived of all sources of Vitamin A, they cannot form retinaldehyde, the essential co-factor for all opsins. But though these mice are blind, and their pupillary response is about 1/10 000 that of normal mice, their ability to transmit light signals from the retina to the suprachiasmatic nuclei seems relatively unimpaired.

Contrary to the results obtained with mice whose genes for opsin have been deactivated and that show no response to light, the experiments with mice that are deprived of Vitamin A paradoxically seem to show that some form of phototransduction persists. Some researchers argue that this residual phototransduction may therefore be attributable to cryptochromes.

To reconcile these apparently contradictory findings, a new model may be needed, in which cryptochromes and melanopsin work together to generate the retinohypothalamic signal. But that will probably have to wait until scientists know more about this subject, and in particular about the cascade of biochemical reactions involving cryptochromes.

  Presentations | Credits | Contact | Copyleft