1Michel JOUVETMECHANISMS OF THE WAKING-SLEEP-DREAM CYCLE

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A brief profile of Professor Michel Jouvet

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Born 16 november 1925, at Lons Le Saunier (Jura), France. Maried with Anne Telinge(1974), 4 childrens : Diane, Philippe, Jean-Christophe, Frédéric.
1944-1945 : Volunteer for Maquis in Jura then fighting with Alpine troops on the Alps
in Alsace and northern Italy as a sergeant.
1946 : Medical school in Lyons
1954-1955 : Research in Pr Magoun Laboratory. VA Hospital Long Beach, California(USA)
1956 : MD Thesis : Etude EEG Liaisons Temporaires dans le cerveau
1958 : Assitant Professor of Experimental Medicine – Medical School Lyons.
1965 : Professor and chairman
1964 : Director of Group U 52 (Molecular Neurology) of the National Institute of
Health and Medical Research (INSERM)
Director of associate laboratory (1195) – Neurobiology of sleep waking cycle.
National Center for Scientific Research (CNRS)
1977 : Elected at the French Academy of Sciences. Member of the French InstituteResearch :o Neurophysiology of the sleep waking cycleo Demonstration that paradoxical sleep is not a phase of light sleep, but anotherstate (with waking & sleep)o First description of the death of the brain in man
o Monoaminergic theory of regulation of waking sleepo Research of the function of dreaming
Books :o Le Château des Songes – O. Jacob, 1992 (translated in Japanese)o Le Sommeil et le Rêve – O. Jacob, 1992 (translated in Japanese)o Le Grenier des Rêves (with M. Gessain). Essai – O. Jacob, 1997
o Pourquoi rêvons-nous ? Pourquoi dormons-nous ? Essai – O. Jacob, 2001
o Le voleur des songes – O. Jacob, 2004
Décorations :o Officier de la Légion d’Honneuro Commandeur de l’Ordre National du Mérite
o Commandeur des Palmes Académiqueso Officier de l’Ordre National du Niger
Distinctions :o Prix Bing-Académie Sciences Médicales – Suisse - 1966o Intra Science Award – Los Angeles – 1981
o Grand Prix de la Fondation pour la Recherche Médicale – 1984o Gold Medal of the Center National of the Research Scientific – 1987o Prix Mondial Cino del Duca – 1991o Prix Blaise Pascal – 1992

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3-o Prix Recherche et Médecine – 1992o Prix Pérouse de la Fondation de France – 1994o Prix Science et Défense – 1994o Prix International Fyssen – 1997
Docteur Honoris Causa of Universities of Zurich (Swizerland), Haifa (Israël), Liège(Belgium), Montréal (Canada)
Adresse : La Colombière – Sainte Croix – 01120 Montluel - FRANCE

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The brain structures and neurotransmitters that command and regulate the cycle of waking
slow wave sleep and paradoxical sleep (during which most dreams occur) have beendelimitated during the past three decades.
In this review, I shall successively summarize the organization of the network of cells groupwhich collaborate to induce and maintain waking. Then, I shall describe the hypothalamic
preoptic system which induces slow wave sleep according to a circadian “clock”. Finally, thethree systems which constitute paradoxical sleep (PS) will be summarized.
Since most of the impetus to discover waking and sleep systems were started by a very gifted.
Neurologist it is fair to write his name at the beginning of this review.
I. Von Economo, the Encephalis lethargica and the waking system :In 1916, Constantin Von Economo, a Viennese Neurologist, began to receive numerous
patients who were suffering from what has been named “Encephalis lethargica” or“sleeping sickness”. Most of these patients sleep for 20-24h, waking only to eat and drink
but many died. Von Economo found a lesion at the junction of the brainstem and forebrain
in their brain.(Figure 1). Then, Von Economo thought that there should be an arousal
system ascending from the brainstem that kept the forebrain awake.
During the following years, it became possible to register the electrical activity of thebrain with electroencephalogram (EEG) and it was demonstrated that waking wascharacterized by a low voltage fast cortical activity (Arousal reaction) and sleep was
responsible for cortical spindles and slow wave. Using this technique in cats, in 1950,
H.W. Magoun and G. Moruzzi, and their colleagues demonstrated that the cortical fast
EEG was suppressed by destroying (by coagulation) the brainstem reticular formation (2).
Then the concept of an ascending mesencephalic reticular activating system was adopted
by most neurophysiologists at this time.
However, new methods appeared which permitted to destroy only cell bodies (injection ofKaïnic or Ibotemic acids into the reticular formation) whereas coagulation destroyed also
ascending fibers. With this new technique Denoyer and al (3), in Lyons, demonstrated thatthe total destruction of the cells of the mesencephalic reticular formation did not impair
either behavioral waking or EEG arousal. For this reason, the suppression of waking after
coagulation of the mesencephalic reticular formation could have been provoked by theinterruption of ascending fibers coming from other systems located below.
II. The waking system (4)Thanks to the development of new neuro-anatomical methods (histofluorescence,
immunohistochemistry) it has been possible to map out new neural systems which releasedifferent neurotransmitters.

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5Since these systems are organized as a network, it is quite difficult to understand theintimate organization of the systems which collaborate for inducing and maintaining
waking.
However the following data may show how it has been possible to demonstrate the active
participation of some systems in the executive mechanisms of waking.
The noradrenergic system :The principal part of the system is located in the pons, at the level of the locus coeruleus
whose unitary activity increases during waking and decreases during sleep. The specificlesioning of the locus coeruleus with selective poison induces a temporary diminution of
waking. Neuropharmacological experiments have also demonstrated that amphetamine
increased waking whereas the inhibition of catecholamins synthesis (dopaminenoradrenaline) suppresses the amphetaminic waking. The effect of amphetamine upon
dopaminergic systems is probably responsible for tolerance and dependence. A new drug,
the Modafinil, which also acts upon catecholamine does not induce tolerance nor
dependence and it is believed that it acts post-synaptically on central alpha adrenergic
receptors.
The extensive network of waking
The tonic activation of cortical neurons is the result of both the direct activation of thetelediencephalon and the inhibition of the pacemakers responsible for the spindles andslow wave characteristic of slow wave sleep.
Three groups of neurons which project to the cortex are sufficient (but not necessary) for
cortical desynchronization.
1. The posterior hypothalamic system
This system contains the only histaminergic group located in the nucleus tuberomammillaire (4).
2. The diffuse thalamic system
The intralaminar thalamic neurons project to every part of the cortex. Their transmittersare excitatory amino acids (aspartate – glutamate).
3. The basal telencephalic system
It is composed of neurons which synthetize acetylcholine and/or GABA which projectboth to the cortex and thalamic nuclei. This system may be altered by degenerative
process in Alzheimer disease.
These 3 systems are activated by brainstem ascending neurons :Nakayama Foundation for Human Science
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1. The mesopontine cholinergic nuclei project upon the thalamus where acetylcholine(ACH) acts according 2 ways : hyperpolarisation thru muscarinic inhibition ofreticular neurons (which belong to the sleep system) and a nicotinic activation ofcortical and thalamic neurons.
2. The mesencephalic reticular formation : neurons containing aspartate and glutamine
project massively upon thalamic neurons. Together with mesopontine cholinergic
neurons, the mesencephalic reticular formation is only a part of the waking system but
no more the only waking system as it was believed at the beginning.
3. The magnocellular reticular bulbar nucleus, cholinergic projects to the mesencephalicreticular formation, the cholinergic mesopontine and basal telencephalon. They
constitute the so called reticulo-hypothalamo-cortical pathway. The stimulation of themagnocellular bulbar nucleus induces a long lasting arousal.
Besides the noradrenergic locus coeruleus, the nuclei of the raphe contain serotoninand project to the hypothalamus and the cortex. Their neurons are active during
waking, but their lesion provoke a long lasting insomnia (this contradiction will be
explained in the next chapters).t
Besides these ascending waking systems which are responsible for cortical arousal(then for consciousness and memory) there are 2 other systems which modulate
motricity and sympathic tone. The first one is the dopaminergic nigro-striatal system
whose lesion is responsible for Parkinson disease.
The second system is situated in the medulla and commands the sympathic system
which contains adrenalin and a peptide (NPY). This system is responsible for theadaptation of vegetative reactions during waking.
In summary, the regulation of waking is a complex phenomenon which activates
several different structures. None of these systems, isolated, is necessary for waking.
Thus the necessary and sufficient condition for the induction and the maintain of
waking is the reunion of sufficient condition which are responsible for waking.
III. Von Economo “Schlaf Zentrum” and the structures and mechanisms responsible forslow wave sleep
Passive or active sleep ?
During the 1950-60, the discovery of the mesencephalic reticular formation as a
“waking system” did open the hypothesis of an active sleep system which would
inhibit it. The so called “principe of economy” led some scientists to postulate some“ad hoc” process of “passive deactivation”. However, the discovery of paradoxical
sleep whose mechanisms are active, and the demonstration that lesion of the raphesystem was followed by insomnia could only be explained by an active sleep system.

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A. The serotoninergic theory of sleep
The destruction of the raphe system which contains of serotonin (5 hydroxytryptaminor 5HT) is followed by a total insomnia which may last 2 weeks in the cat. The
duration of the insomnia is correlated which the decrease of cerebral 5HT.
On the other hand, the inhibition of the synthesis of 5HT with P. chlorophenylanine(PCPA) which inhibits the tryptophan hydroxylase (the first step of 5HT synthesis) isfollowed by a total insomnia which is also proportional to the decrease of central 5HT.
Moreover, a secondary injection of 5 hydroxytryptophan (5HT) the precursor of 5HT
restores SWS and PS after a latency of about 1 hour.
These experiments effectuated in the 1970 were the basis for a serotoninergic theoryof sleep according to which 5HT would inhibits the waking system (6).
However, it was shown latter that the unitary activity of 5HT neurons were maximal
during waking and almost silent during PS (7) and the development of voltammetry
demonstrated that the release of 5HT was more important during waking than during
sleep (8). Then it was impossible that 5HT liberation would be synchronically
responsible for sleep and the 5HT, theory of sleep was abandoned.
It has revived more recently as the theory that 5HT plays a diachronic role in inducing
sleep :Firstly, the hypnogenic target of 5HT has been discovered. In an insomniac PCPA
treated cat, only local injection of a very small dose of 5HT in the preoptic area (the“Schlafzentrum” of Von Economo) is followed by the return of sleep (9). Then it was
shown that the destruction of the cell bodies of the preoptic area induced a long lasting
insomnia.
Since the waking systems are organized as a network, there should be somes pathway
coming out the preoptic area to inhibit the waking systems in some specialized targets.
The research of these targets was obtained by local injection of Muscimol (a GABA
agonist) for inducing sleep in an otherwise insomniac cat (either after PCPA or bylesion of raphe system). After most part of the encephalon were micro injected, it was
found that there were only 2 hypnogenic targets. One in the posterior hypothalamus
and the other in the periaqueducal grey matter since injections of small dose ofMuscimol only in these areas were followed by long period of SWS (10).
Then, the mechanisms of sleep may be summarized as followed : during waking, 5HT
neurons of the raphe system fire like a clock (1 – 2 Heztz). It is likely that the 5HT
neurons which project also to the main clock of the suprachiasmatic nuclei (see below)
are calculating the duration of waking. The liberation of 5HT in the preoptic area
trigger GABA neurons located in a pathway descending to the posterior hypothalamus
and the periaqueducal grey. Then, the inhibition of the waking network will liberate apace maker system located in the thalamus which is responsible for the corticalspindles and slow wave (which contribute to the unconsciousness of sleep).
There is also another sleep inducing system situated in the medulla at the level of thenucleus of the solitary tract. This system, which receives informations from the“internal milieu” though the vago aortic nerves, projects also to the preoptic area.

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The executive system of slow wave sleep (figure 4)
The GABAergic neurons of the reticular nucleus of the thalamus are responsible forthe spindles. Slow wave are produced at the cortical level since neo decortication
suppresses this activity. They are the result of the summation of hyperpolarisation of
the pyramidal cells of the V layer which are induced by GABA inter neurons. Such arhythmic activity does not permit the cortex to elaborate cognitive processes which
necessitate a fast cortical activity as during waking or dreaming.
Structures and mechanisms of paradoxical sleep (4) (11)
I have given the name of “paradoxical” sleep (PS) to this state which behavior looks
like sleep, but which is paradoxically characterized by a fast cortical activity similar to
the arousal reaction of waking (11). The term rapid eye movements (REM) sleep is not
appropriate since the owl (which does not move its eyes) or the mole (which has noeye) present normal PS but of course have no REM sleep !
PS which occurs only in warm blooded animals (birds and mammals) is characterized
by both behavioral and central components : i.e. : a total atonia of the neck muscle,
rapid eye movements, a specific central activity of large spikes which can be recorded
from the pons, the lateral geniculate nuclei and the occipital cortex. The so called PGO
activity, and a fast cortical activity (figure 6).
As early as 1960, it was shown that the pontine reticular formation is necessary andsufficient for PS to occur. Indeed, on the one hand, as shown in figure 5, the total
removal of the cerebral structures in front of the pons does not suppress PS since theso called “pontine cat” still presents periodical PS episodes with rapid lateral eye
movements and total atonia of the mucle (11). On the other hand, destruction of thedorso lateral pons suppresses PS without interfering with waking and slow wave sleep.
Again, with the development of new techniques, it has been possible to map out themain systems which enter into plays during PS.
The muscular atonia during PS and the “oneiric behavior” (14)The striking muscular atonia which occurs during PS is the result of an activation of agroup of neurons located in the region of the locus coeruleus α(alpha) and peri α andthe magnocelllar bulbar nucleus. These bulbar neurons descend in the spinal cord andrelease the neurotransmitter glycine which inhibits the spinal motoneurons. The
pontine locus coeruleus neurons have cholinergic receptors, this is why the injection of
Carbachol (a cholinergic drug) may trigger immediately postural atonia and PS. The
suppression of postural atonia (either by lesion in the cat) a by degenerative diseases
in man suppresses the inhibition of PS (12). There are no disturbances of waking or
slow wave sleep, PS still occurs without atonia. Then the cat stand up and display
different behaviors (attack-play-toilet) but it does not react to visual stiumuli and still
display a myosis and retraction of the nictitating membranes as during sleep. Oneiric
behaviors have also been observed in human subjects (mostly males between 50-60
years). There are often aggressive behaviors and the dreamer may attack his wife in

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his bed. When awakened, the subject will describe a dream in which he was fighting abear or a lion !
B. The PGO activity (see Fig. 2 – Fig. 6) originates from the pontine tegmentum andperibrachial region. These “PGO on” neurons discharge in burst before and during
PGO activity. This PGO neurons are cholinergic and can be activated by injectionof reserpine. PGO activity is relayed in the lateral geniculate nuclei and may act
upon many thalamic and cortical area (where it can be recorded with microelectrode).There are some evidences, in monozygotoas twins that PGO activity
and the REM of PS have some genetic components. For this reason it has been
speculated that PS (and PGO) may program a so called “individuation” in humansubjects (15).
C. The cortical activation during PS
The fast cortical activity of PS is triggered both by the peribrachial pontine tegmentun
and the bulbar magnocellular nucleus. Some of these neurons are cholinergic andproject to the thalamus and posterior hypothalamic neurons which relay to the cortex.
Circadian regulation of the waking sleep cycle (16)Most human beings are awake during the day and sleep during night. (It is the contrary
for the rat). If a man is kept in isolation in a cave, under a continuous illumination,
without any temporal cues, he will sleep every day at about the same time (usually alittle later every day). This is the proof that there is a clock in the brain which is able
to mesurate about a day (circa – dies). The circadian rhythmicity of the sleep waking
cycle depends upon the supra chiasmatic nuclei (SCN). These two small nuclei locatedabove the optic chiasma are receiving information from the retina. They are the“master clock”. The output of the SNC is directed toward the supraventricular area
and the dorsomedial nucleus of the hypothalamic which is also related to sleep in the
VLPO. There are some new data which also show that the NSC may release aneuropeptide : the varopressin. This peptide, injected in the cerebro-spinal fluid
increases the duration of waking whereas the antagonists of vasopressinergic receptors
decrease it (4).

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TABLE I

NA

DA

H

ACH 5HT

MRF

1

+

+

+

+

+

+

2

+

+

+

+

+

?

3

+

+

+

+

+

+

4

+

+

+

?

0

?

5

+

+

+

+

0

?

6

0

0

0

0

0

0

7

0

0

0

0

+

0

Participation of systems noradrenergic (NA – locus coeruleus)
Dopaminergic (DA nigro striatal system) – Histaminergic (H)Cholinergic (ACH mesopontine) – Serotonergic (5HT – N raphe dorsalis) and themesencephalic reticular formation (MRF) to the process of waking
1 : increase of the unit activity during waking
2 : increase of the liberation of the neurotransmitter during waking
3 : the stimulation of the system with excitatory amino acide may increase waking
4 : the inhibition of the synthesis of the neurotransmitter decreases waking (presynaptic
effect)
5 : the injection of antagonists of some receptors may decrease cortical arousal and/or waking
behavior
6 : the destruction of cell bodies may decrease waking for a long period
7 : the destruction of cell bodies may increase waking.
This table demonstrated, on the one hand, that there is not any special system which obey toconditions 1 to 6, then they should act trough a network, and on the other hand that the 5HT
system has some ambiguous state as an “homeostatic” system.
+ : the condition is realized. 0 : the condition is not realized. ? : it has not yet be possible totest the condition (from reference 4)

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Figure 1
A drawing of the human brainstem, taken from Von Economo’s original work. It illustrates
the site of the lesion (diagonal hatching in green) at the junction of the brain stem andforebrain that caused prolonged sleepiness and the site of the lesion (horizontal hatching inred) in the anterior hypothalamus that caused prolonged insomnia.
O = optic nerve - HY = hypophysis – NO = oculomotor nerve (III) ¼ fourth ventricule

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Figure 2
Polygraphic recording of waking sleep cycle in a cat chronically registered
EMG : electromyogram of the neck muscles
EEG : electrical activity of the parieto occipital cortex
EOG : electrooculogram which record eyes movements
LGN : recording from the lateral geniculate nucleus (to register the PGO activity)
Unit A : recording with microelectrode of the unitary activity of a neuron from the bulbar
magnocellular nucleus. This neuron (SP on) fire only during PS
Unit B : recording of a SP off neuron located 500 mm from unit A
E : waking with fast low voltage activity (arousal reaction) : increased EMG activity
SL : slow wave sleep with high voltage slow wave of cortex and decrease of the EMG. The
unit B is still active as during waking
SP : paradoxical sleep : total suppression of EMG activity, fast cortical activity, note the PGO
activity and the eye movements, Unit A is activated.-Waking (E) comes back with the returnof EMG activity, unit A stops and unit B is again activated.
Time scale : 10 sec.
From JOUVET (1995)

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Figure 3
The waking system
A : reticulo-hypothalamo-cortical pathway
B : reticulo-thalamo-cortical pathway
1. Bulbar magnocellular nucleus
2. Posterior hypothalamus with the histaminergic tubero mamillary nucleus
3. System of the basal telencephalon, basal nucleus of Meynert (ACH)
4. Intralaminar nuclei of the thalamus (Glutamine) (4a). Reticular nucleus of thethalamus responsible for slow wave sleep. This system could be inhibited during
waking5. Mesencephalic reticular formation it is much greater than on this drawing and mostof the ascending fibers coming from the medulla and the pons are also situated at
this level (this is why a lesion by coagulation would induce a coma and suppresses
cortical fast activity because the interruption of the ascending pathways whichcannot activate more rostral system
6. Complex of the solitary tract which receives vegetative afferences coming from theorganism thru the vagus and sino aortic nerves
7. Rostral raphe (5Ht)
8. Complex of the locus coeruleus (noradrenalin)
9. Mesopontine nuclei (ACH)
From Valatx (1995)

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Figure 4
The two stages for going to sleep
1. Serotoninergic stage (inhibition of waking network)
The dorsal raphe nucleus (7) is active during waking. It sent projection to the preoptic
region (ventral lateral preoptic nucleus – VLP0) (10) and the main clock (suprachiasmatic nucleus : SCN) (11). The liberation of 5HT at this level will induce (after aperiod of time which is “calculated” by the circadian clock of SCN) an “homeostatic”
GABAergic descending system coming from the VLPO which will inhibit the waking
network at the level of the posterior hypothalamus (2) or the periaqueducal grey (8).
System descending from the VLPO inhibits the N. of Meynert (3), the mesencephalicreticular formation (5) and the bulbar waking system (1). The solitary tract (6) is also
activated.
2. Thalamo-cortical stage (liberation of the thalamic pace maker) cortical pace maker
responsible for sleep slow wave (0.5 – 2 Hertz)
1) Interneurons GABAergic
2) Pyramidal cell of the V to cortical layer
3) Nucleus of Meynert
4) Thalamic pacemaker responsible for cortical spindles
4a) Reticular nucleus that surrounds the thalamus. It is GABAergic and will
inhibits the intralaminar nuclei.
From Valatx (1995)

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Figure 5
A. Pontine preparation. All the cerebral structures in front of the pons have been removed
by surgery. This preparation may survive for several weeks provided that the
hypophysis is left, and that the internal temperature is regulated in an incubator
B. During paradoxical sleep, the pontine cate which is in a state of decerebrate rigidity
loss it muscular tonus
C. During “wake” then is an increase of the electromyogram of the neck muscle, a fast
activity in the pons and no eyes movements
D. Paradoxical sleep. Total absence of EMG activity (atonia) some rhythmical activity inthe pons, synchronous to the eyes movements (From Jouvet 11).
This is the proof that paradoxical sleep is triggered from the pons and does not depend
from other supra pontine structures.

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Figure 6
A Schematic representation of three of main network of paradoxical sleep
A. Cortical activation 1) cholinergic neurons of the pons (1) act upon the nicotinic
receptors of the intralaminar nuclei of the thalamus (4) and muscarinic receptors of thereticular nucleus (4A) of the thalamus.
2) magnocellular nucleus of the medulla (7) projects to the posterior hypothalamus (3),the thalamus (4) and the basal nucleus of Meynert (5)B. Phasic PGO activity : the “pontine PGO” on (1a) projects to the thalamus and thelateral geniculate nuclei and the pulvinar (4c). Ocular and facial nuclei receive
afferences (glutamate ?) from the pontine reticular nucleus which seems to be the main
generator of phasic activity
C. Muscular atonia : the principal input is provided by the bulbar magnocellular nucleus(2) which neurons “PGO on” glycinergic project upon the spinal motoneurons and theoculo motor nuclei (VI-VII). An inhibitory control of PS network is located in theperiaqueducal grey matter (8) (from VALATX – 1995)

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BIBLIOGRAPHY

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