Theme Region: Hypothalamic Suprachiasmatic Nucleus (SCN).
A long line of experiments, involving lesions, transplants, circadian in situ expression of clock genes, in vitro recordings from the nucleus etc, show that the SCN is the circadian clock in mammals. One compelling experiment involves the transplantation of a mutant SCN from a hamster with a short period circadian rhythm into the hypothalamus of a normal hamster. The resulting shortening of the circadian rhythm in he normal hamster illustrates a number of points:- genetic control of the rhythm, the key role played by the SCN in circadian rhythms, dominance of a short period rhythm over a longer period.

In vitro SCN preparations allow the  circadian rhythm of neurons to be studied directly for a few days (Martha Gillette).. Expression of a wide range of neurotransmitter receptors is on a circadian schedule within the SCN. Individual neurons each have their own rhythms, which are usually shorter than 24 hrs, with the collective effect somehow producing the circadian rhythm. Melatonin applied to these neurons will shift the phase of the oscillation in nanomolar concentrations, a record for pharmacology that was treated with great skepticism. Much current work is focused on the location and action of the diverse melatonin receptor proteins.

Bistable Oscillation:
It has been conjectured for some time that the two sides of the SCN might act somewhat independently as ìmorningî and ìeveningî oscillators. Recently an interhemispheric mode of operation of the SCN was revealed in hamsters exposed to continuous light that lends some support to the idea that the two sides can operate independently. In thse hamsters, SCN oscillation is 180 deg out of phase on each side, with each hemisphere taking turns to ìbe awakeî on a 24 hr schedule (de la Iglesia).
This illustrates the principle that paired midline nuclei of the neuraxis  can act as interhemispheric oscillators. Just behind the SCN is another rhythmic nucleus, the retrochiasmatic (RCN) whose period is ~90 min, the same period as the nasal cycle, the cycle of REM sleep and the basic rest activity cycle

Clock Genes: Per, tim, clock, cry:
This area has been enormously facilitated by work on genetics of Drosophila, even though many are reluctant to face the fact that we share so many genes with flies!
Ron Konopka isolated the first circadian clock mutants, of a gene called per (for periodic). The field exploded once this gene was cloned and homologues were found in other species, including humans.
Transcriptional regulation of the circadian clock:
The product of per is the protein per which dimerises with another clock gene product (tim in DrosophilaÖstill being elucidated in humans). The protein dimer can enter the nucleus where it negatively regulates its own genes. This negative transcriptional feedback circuit takes an hour or so, and is therefore not slow enough to account for the 24 hr circadian rhythm. Phosphorylation of per acts to slow down the cycle, and mutants of the per phosphorylase have fast periods (doubletime mutant).
There is also a positive feedback transcriptional loop involving dimerisation of two other circadian proteins (clock and b-mal) that kicks the cycle off again when low PER levels bottom out.
All Cells Express Circadian Genes:
The cloning of per permitted a sophisticated experiment where the green fluorescent protein gene (GFP) was inserted so that GFP expression was linked to per expression. The surprising result of this experiment was that every cell has a 24 hr rhythm, not just some brain cells! Gonads and kidney cells show even greater expression of per than neurons in the circadian pacemaker. Moreover, the rhythms of these peripheral tissues are sensitive to light, which resets the circadian rhythm.
Extraocular photoreception of this kind  in humans is still controversial (a startling experiment reported in Science showed that a hidden light behind the knees could reset the circadian rhythm if applied at 4 AM, but has not been easy to replicate), but note that acupuncturists around the world are now using light on acupuncture points instead of needles.
Independent circadian cycles in peripheral tissues is highly relevant to jet lag, since one can get oneís sleep-wakefulness rhythm adjusted to local time whilst gut and kidneys are still operating on home time. Much remains to be learned about zeitgebers for these tissues. Perhaps intense, whole-body immersion in light on a beach has effects on these peripheral tissues that explain why this is so effective at curing jet lag.
 

Melanopsin in the retina:
In 2002 there was a remarkable breakthrough in circadian clock research with the discovery of melanopsin photopigment in the cell membranes of retinal ganglion cells that project to the SCN.
This small class (~2,000) of ganglion cells, with very large dendritic trees, are themselves sensitive to light stimulation without the need for input from rods and cones, the conventional photoreceptors that had been thought to be responsible for all light-mediated responses.
Melanopsin is a short-wave sensitive pigment, originally isolated from frog skin where it is the messenger for light-induced darkening. The melanopsin-containing ganglion cells prefer high intensities and respond sluggishly, thereby helping to account for the greater effectiveness of bright, short wave light in treating jet lag and seasonal affective disorders.
Implications: Blindness that involves rod and cone photoreceptors but not the ganglion cell layer (e.g. retinitis pigmentosa), will not be accompanied by circadian rhythm problems and dysrhythmias, whereas this will not be true for forms of blindness involving the ganglion cell layer (e.g. optic nerve atrophy) which can be accompanied by insomnias and other abnormalities of circadian rhythms..
Hypothalamic SCN and melatonin:
Melatonin is a small molecule that diffuses rapidly across all cell boundaries to exert a most powerful anti-oxidant and free-radical scavenging action. These properties were discovered by early life, so that the ability to synthesise melatonin is widespread across kingdoms, including plants which may have large concentrations of melatonin in their leaves (Your granny was right about the healthful effects of eating your broccoli, a plate of which may contain the equivalent of quite a few melatonin pills).
Melatonin is produced during sleep by the pineal gland and by the retina, and perhaps other body organs such as the skin (children produce so much melatonin that researchers are looking for other sources in the body).
SCN controls the rhythmic production of melatonin from the pineal via a circuitous pathway that involves the sympathetic outflow from the thoracic spinal cord. For this reason, tetraplegics with a complete cervical transection have a problems with sleep dysrhythmias to add to their difficulties.

Why not continuous melatonin?
I am always asked, when pointing out the remarkable free-radical-scavenging and protective qualities of melatonin, why is it produced only at night, instead of all the time, when it would seem to do twice as much good?
The answer, if I had a good one, would probably explain ìwhy do we sleep?î as well, an old chestnut with no real consensus yet. The key issue here concerns the normal role of oxidation, which is used for a large variety of functions and which is probably also used in signaling, since there are now reports of G-protein systems that are specifically sensitive to free radical production. NO and CO are both active products of oxidation that are used as signals by the nervous system, for example. For these reasons, it may not be possible, or at least efficient, to make ìrunning repairsî on some vital systems. Instead, these systems that intimately involve oxidative processes, may be shut down for repair of oxidative damage during a less active phase of the circadian cycle instead of being disrupted by the continuous interference with key functions that would result from continuous production of melatonin. Most of you who have experienced jet lag, when high daytime concentrations of melatonin make one feel groggy and mislay vital personal effects like passports, will have some insight into this.
Oscillators and Zeitgebers: The science of jetlag
The most important principle here is also the hardest to grasp in practice:

The effect of a zeitgeber depends crucially on the phase of the cycle when it is applied.

For example, a bright light applied to your own circadian system during your subjective nighttime (e.g. during the early hours of the morning) will advance the clock so that you will wake up earlier.

On the other hand, a bright light applied during subjective day (e.g. late in the afternoon) will tend to retard the clock so that you will wake up later.

Zeitgebers include physical activity, bright short wave light (sunlight on a beach or over water is great), melatonin, drugs like benzodiazepines.

If you are jetlagged in a place where there is no sun, then melatonin or sleeping pills can be used to get you to sleep at local nighttime. They will have the added benefit of shifting the phase of your clock.

These phase specific effects are the most difficult to keep in mind if one is intending to shift oneís clock on an international trip to bring it in line with local time. I try to do this myself if the trip away is of sufficient duration. Note, however, that many international travelers solve the problem by keeping on home time for the brief period that they are away. This solution is easier if the foreign hosts will accommodate the schedule of the guest instead of expecting conformity to theirs, something not always possible for mere mortals who may be traveling for a job interview and need to be awake when their SCN is telling the pineal that it is sleep time.
 
 

The mystery of sleep: Rip van Winkle revisited: Sleep, oxidative damage and ageing.
The following explanation for sleep is my own idiosyncratic one, but it accounts for many of the facts and paradoxes of sleep.
1. Sleep time is proportional to metabolic rate: This is a precise linear relationship in mammals, with large, low-metabolism animals like elephants sleeping very little, while tiny highly-metabolic mammals like mice and shrews sleeping a lot (despite their need to keep active to support their high metabolism with food intake).
2. In birds, sleep time is also proportional to metabolic rate, but the overall sleep time is reduced with respect to mammals despite the fact that birds have higher metabolic rates than mammals of the same size.
3. Birds have mitochondria that are 10X more efficient that mammalian mitochondria at producing reactive oxygen species (ROS).
One can put this all together by proposing that sleep is repair of oxidative damage. In mammals 3% of oxygen molecules passing down the electron transport chain get converted to ROS. If sleep repairs the damage done by ROS (which oxidize lipid, protein and nucleic acid molecules), it is apparent that you would have more repairs to do if you had a high metabolic rate, or if you were a mammal with less efficient mitochondria than a bird. This account also links sleep to ageing , since this is thought to be the accumulated effects of oxidative damage (cf. Rip van Winkle, Beauty sleep etc).
Melatonin is a very effective scavenger of ROS (especially OH-), another feature of sleep that fits the oxidative damage idea.
Why not repair oxidative damage on the run? Clearly the effects of oxidative damage would need to be repaired in the brain, where errors would otherwise accumulate to the point of malfunction. The question nevertheless becomes, why not do running repairs? Why shut down the nervous system during sleep when repairs could be undertaken while the brain keeps running. Some possible answers:-
1. Some errors involving unique events, like a one-trial event in declarative memory, could not be discovered while the brain is running normally, but only if it were shut down and given test inputs (?dreams). Procedural memories, by contrast, could be repaired on the run by directly observing the effects of the errors on normal function and applying a correction.
2. Oxidation is a vital part of some neuronal functions, especially in monoaminergic neurons, so that the intrinsically anti-oxidative nature of repair might be inimical to normal function, necessitating a shut down for repairs.

Restorative action of sleep fits with one's intuitive feel about its action and can partly be explained by the actions of melatonin. Melatonin receptors are so widespread that the actions of melatonin are complex (quite apart from its direct anti-oxidant, -OH-scavenging action). For example, melatonin has a very powerful up-regulatory effect on cellular immunity. This helps explain why excessive exposure to sunlight, which suppresses melatonin secretion the following night, can lead to an outbreak of a resident virus, such as herpes simplex. The other side of this coin is that one can abort an incipient herpes blister (at the tingling stage) if one's goes to sleep with an big dose of melatonin.
 
 

You can read more about the representation of time in your own brain at www.uq.edu.au/nuq/jack/PL293.html. The topic of subjective time dilation (or contraction) is the topic of a TV special on SBS at 8:30 PM Friday 28 April. I am not sure whether this show on time will deal with my "Two Clocks Experiment" that helps to explain dilation when one is in the grip of intense emotion and call to action (such as when a vehicle is about to collide with you). These lecture topics will not be examinable.
Those interested in the electrical stimulation of Parkinson's patients' brains, with dramatic mood changes, can see my website on bipolar disorder:_ http://www.uq.edu.au/nuq/jack/Bipolar Disorder.html