SLEEP-WAKE SYSTEM FUNCTIONING

 
We invite you to watch the following video that will explain the Sleepwake system in pictures (15-minute video).
 
Vidéo sur le système Veille-Sommeil
 
You will find below a synthetic explanation, but less detailed than the video.
 
 
In man, the pineal gland, or epiphysis, is a small endocrine gland of approximately 8mm, located in median position at the back of the upper part of the thalamus.
 
For 8 hours, throughout the year and as soon as we go to sleep, the pineal gland simultaneously secretes three hormones:

 

Melatonin (MLT),


the neuroprotective hormone
,

the primary role of which is to eliminate the oxygenated free radicals that destroy the neurons and all living cells;

6-methoxy-harmalan (6-MH),


the daytime, wakefulness and consciousness hormone,

which keeps the body in wake mode during the activity period;

and Valentonine (VLT),


the night and sleep hormone
,

which keeps the body in sleep mode during the rest period.

 

The suprachiasmatic nucleus, located on the path of the optic nerve (retinohypothalamic projection) is the body’s biological clock. It controls the body’s rhythm, in 24-hour sections, adapting it to its lifestyle and environment, based on information on the ambient light perceived by the retinal cells.

For someone who is accustomed to going to bed at 10pm, the Suprachiasmatic Nucleus will trigger, via neural pathways, the secretion of the 3 hormones by the pineal gland from 10pm.

Figure 1 - The secretion of the 3 hormones by the pineal gland, from 10pm to 6am, is triggered by the suprachiasmatic nucleus.

 

In the pineal gland, the three hormones are biosynthesised, from serotonin, in 3 successive acetylation stages, catalysed by the same enzyme, N-acetyltransferase (NAT).

Figure 2 - Biosynthesis of the 3 hormones in the pineal gland from serotonin, from 10pm to 6am.

 

Given their serial biosynthesis, these three hormones are produced and secreted by the pineal gland in the same proportions, which means that any quantitative variation, either too little or too much, in the pineal secretion will affect the three hormones in the same way. This has two consequences:

  • The three hormones must be jointly administered for all neurological disorders due to the hypofunction of the pineal gland, to avoid any imbalance of the Sleep-Wake system and maintain the harmonious regulation of the body.
  • Melatonin is a secretion marker of the three hormones; measuring its concentration in blood plasma in the middle of the night provides information on the status of the Sleep-Wake system in patients.

 

As we studied the secretion of melatonin in young and old healthy subjects, we observed significant variations in melatonin secretions, with a factor of 13 between extreme pineal secretions. We are therefore not all equal when it comes to the secretion of the 3 hormones by the pineal gland, for which melatonin is a marker.

 

Figure 3 - Changes in the plasma concentrations of the 3 pineal hormones over 24 hours
 

In man and all mammals with nocturnal sleep, such as the dog, the pharmacokinetic properties of Valentonin and 6-methoxyharmalan are perfectly adapted to maintaining the body in sleep mode from 10pm to 6am, then in wake mode from 6am to 10pm. The concentrations of Valentonin in the body are higher than those of 6-methoxyharmalan during sleep; conversely, during the period of activity, 6-methoxyharmalan becomes prevalent in the body.

The three pineal hormones protect our body and control its functioning.

The level of wakefulness is determined by the functioning of 5-HT2C serotoninergic neurons, the cell bodies of which are located in the brain stem. The impulse is transmitted to these neurons by serotonin, an endogenous agonist of the 5-HT2C receptors.

Between 10pm and 6am, during its prevalence period, Valentonin amplifies the response of the 5-HT2C receptors to serotonin, following a specific allosteric deformation which makes them more sensitive to serotonin; this causes a decrease in wakefulness, leading to sleep.

 

Figure 4 - The sleep barrier delimits the states of waking and sleep

 

The sleep state, with loss of consciousness, appears when wakefulness falls below a certain level, which can be described as the “sleep barrier”.

In normal subjects, during the nocturnal rest period, from 10pm to 6am, the sleep state is achieved if the Valentonin concentrations in the 5-HT2C serotonin receptors are sufficient to maintain the level of wakefulness below the sleep barrier.

In depressed subjects, the stress that causes the depression raises the level of wakefulness. The Sleep-Wake system must be reinforced to lower the level of wakefulness below the sleep barrier.

The psychostimulant properties of 6-methoxyharmalan, similar to those of LSD, are due to its antagonism of the 5-HT2C receptors, which causes an increase in wakefulness.

Every 24 hours, our body alternates between 2 very different states:

 

SLEEP MODE, FROM 10PM TO 6AM

  • Melatonin reduces the amount of oxygenated free radicals and protects neurons as well as all the cells in the body, against their destructive actions. These free radicals are produced by normal aerobic respiration, which is how we release energy.

These oxygenated compounds with a single electron (•) include: superoxide radical anion O2•-, hydroxyl radical HO, hydrogen peroxide radical HO2, peroxide radical ROO and alkoxyl radical RO, nitrogen monoxide NO, and peroxynitrite ONOO

They are extremely reactive and cause the progressive deterioration of living cells. When the secretion of melatonin is insufficient, the destruction of neurons by the oxygenated free radicals causes neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease.

 

  • Valentonin, prevalent in the body during this period, induces the following actions:
    • a decrease in wakefulness, leading to sleep;
    • lowered blood pressure and heart rate;
    • and muscle relaxation.

 

These actions result from the specific activation of the serotoninergic, noradrenergic and dopaminergic receptors.

Valentonin provides physiological sleep, restorative for the body, characterised by the predominance of deep slow-wave sleep and REM sleep, necessary for the memory.

Conversely, benzodiazepines such as Diazepam (Valium®), Lorazepam (Temesta®) and related drugs such as Zolpidem (Stilnox®) or Zopiclone (Imovane®), provide anaesthetic, non-restorative sleep, with amnesia-inducing effects due to the absence of REM sleep.

 

WAKE MODE, FROM 6AM TO 10P

As soon as the endocrine function of the pineal gland shuts down at 6am, after 8 hours’ secretion, 6-methoxyharmalan concentrations in the body become prevalent in a few minutes. The previous actions are reversed, with increases in:

  • vigilance which causes and maintains wakefulness until 10pm;
  • blood pressure and heart rate;
  • and muscle contraction.

These actions result from the specific antagonism of the serotoninergic, noradrenergic and dopaminergic receptors.

Dysfunctions of the Sleep-Wake system help explain the mechanisms of neurological disorders.

The neurological disorders caused by the insufficient pineal secretion of the three hormones are the most frequent.