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Updates on the sleep-wake cycle

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 REVIEW ARTICLE

Updates on the sleep-wake cycle

Atualizações sobre o ciclo vigília-sono
Rosa Hasan1,2, Flávio Alóe1†

Abstract e, portanto, são responsáveis pelo início e pela manutenção do sono

In this review, the authors highlight the main findings on the neural
mechanisms of the sleep-wake cycle, emphasizing the importance of
hypothalamic control of the sleep and wake cycle. The anterior, poste-
rior, and lateral hypothalamic regions are the three divisions involved
in this anatomical-functional control. The galaninergic and inhibitory
GABAergic systems of the ventrolateral preoptic nucleus of the ante-
rior hypothalamus and the neurons producing melanin concentrating
hormone of the lateral hypothalamus are responsible for the inhibition
of the waking system and they are, therefore, responsible for the ini-
tiation and maintenance of non-rapid-eye-movement and rapid-eye-
movement sleep. The neurons of the suprachiasmatic nucleus of the
anterior hypothalamus are responsible for the circadian rhythm of the
sleep-wake cycle. The histaminergic nuclei of the posterior hypothala-
mus and hypocretinergic ones of the lateral hypothalamus are active
during wakefulness, stimulating the aminergic system of the brain-
stem and inhibiting both the ventrolateral preoptic nucleus and also
the melanin concentrating hormone systems and, thus, establishing a
stable waking state. The inhibition-stimulation interaction between
the posterior and lateral hypothalamic system of wakefulness and the
GABAergic sleep system of the anterior hypothalamus is the base
model of the reciprocal interaction, which results in the stability of
the wake or sleep states. Changes in these nuclei or pathways result in
the instability of the sleep-wake cycle and in sleep disorders.
Keywords: sleep-wake transition disorders; ventromedial hypotha-
lamic nucleus; gamma-aminobutyric acid; melatonin/metabolism;
GABA modulators; hypothalamic hormones; sleep/physiology; sleep,
REM/physiology; histamine.
Resumo
Nesta revisão, os autores ressaltam os principais achados sobre os me-
canismos neurais do ciclo sono-vigília, ressaltando a importância do
controle hipotalâmico do ciclo sono e vigília. As regiões hipotalâmicas
anterior, posterior e lateral constituem as três divisões envolvidas no
controle anatomofuncional. Os sistemas GABAérgico inibitório e ga-
laninérgico do núcleo pré-óptico ventrolateral do hipotálamo anterior
e os neurônios produtores do hormônio concentrador de melanina do
hipotálamo lateral são responsáveis pela inibição do sistema de vigília
não REM e do sono REM. Os neurônios dos núcleos supraquiasmáti-
cos do hipotálamo anterior são responsáveis pelo ritmo circadiano do
ciclo sono e vigília. Os núcleos histaminérgicos do hipotálamo poste-
rior e os hipocretinérgicos do hipotálamo lateral apresentam-se ativos
durante a vigília, estimulando o sistema aminérgico do tronco cere-
bral ao mesmo tempo que inibe o núcleo pré-óptico ventrolateral e o
sistema hormônio concentrador de melanina, promovendo assim um
estado de vigília estável. A interação de inibição-estimulação, entre o
sistema hipotalâmico posterior e o lateral de vigíla e o sistema de sono
GABAérgico do hipotálamo anterior, é a base do modelo da interação
recíproca, que resulta na establidade dos estados de vigília ou sono.
Alterações desses núcleos ou vias resultam em instablidade do ciclo
sono-vigília e em distúrbios do sono
Palavras-chave: transtornos da transição sono-vigília; núcleo hipo-
talâmico ventromedial; ácido gama-aminobutírico; melatonina/me-
tabolismo; moduladores GABAérgicos; hormônios hipotalâmicos;
sono/fisiologia; sono REM/fisiologia; histamina.
INTRODUCTION
Sleep is a complex behavioral state and it is one of the great
mysteries of modern neuroscience1. Currently, the control
of the sleep-wake cycle is attributed to the hypothalamic
system and its functional interactions2. The main elements
of the neurobiology of normal sleep in humans, based on
experimental models, are going to be described in the fol-
lowing sections.
NORMAL SLEEP
Sleep is a behavioral state represented by only a temporary
change in the level of mobility, movement and, especially,
awareness, and sleep differs from a coma and deep anesthesia
due to its prompt and complete reversibility3. Sleep is not
a passive, homogeneous event with reduced central nervous
system (CNS) activity, but an odd amalgam of physiologi-

Study carried out at Instituto de Psiquiatria of Hospital das Clínicas of Faculdade de Medicina at Universidade de São Paulo (FMUSP), São Paulo (SP), Brazil.
1
Instituto de Psiquiatria, Hospital de Clínicas, Universidade de São Paulo (USP), São Paulo (SP), Brazil.
2
Faculdade de Medicina do ABC (FMABC), Santo André (SP), Brazil.
†
In Memorian
Financial support: none.
Conflict of interests: Dra. Rosa Hasan receives grants from Aché and is speaker for Libbs and Dr. Flávio Alóe, when this manuscript was writted, received grants from
Aché, Apsen and Cristália and was speaker for Libbs.
Corresponding author: Rosa Hasan – Instituto de Psiquiatria – Hospital das Clínicas de São Paulo – Rua Ovídio Pires de Campos, 785 – Caixa Postal 3671 – CEP
01060-970 – São Paulo (SP), Brazil – E-mail: rhasan@hcnet.usp.br
Received: February 10, 2010 – Accepted: June 29, 2011
Sleep Sci. 2011;4(2):�����
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 Hasan R, Alóe F
53

cal events with different levels of activity in the central and

K - complex
peripheral nervous system over time3. Channel 1 - Right eye

STAGES OF SLEEP Channel 2 - left eye

There are two distinct states of sleep, based on the electro-
physiological characteristics of the electroencephalogram Channel 3 - central EEG
(EEG), electrooculogram, and electromyogram4: synchro-
nized, or non-rapid-eye-movement (NREM), sleep; desyn-
Channel 4 - occipital EEG
chronized, or rapid-eye-movement (REM), sleep Sleep spindle

Normal sleep consists of an alternation between REM

and NREM. Sleep spindle Theta wave Sleep spindle
Channel 5 - EMG K - complex K - complex

NREM sleep
Synchronized, or NREM, sleep, is characterized by synchro- Figure 1. NREM sleep stage N2. K-complexes and spindles are present
nous brain electrical activity on the EEG, with distinctive in the EEG.
graphic elements4, and it is divided into three stages: N1,
N2 and N34. The stages, N1-N3, progressively represent
the depth of sleep, with a higher arousal threshold. Channel 1 - Right eye

Normal sleep begins with NREM sleep at the N1 stage,

which is a short and transitional stage that moves to the Channel 2 - left eye
N2 stage of sleep when the EEG begins to exhibit waves of
higher amplitude and lower frequency that contain K-com- Channel 3 - central EEG EEG: high voltage and low frequency
plexes and sleep spindles (Figure 1). The N2 stage occupies
about 50% of the night of a healthy young adult5. The N3
Channel 4 - occipital EEG
stage is characterized by the presence of large amplitude and
slow waves (delta waves) in the EEG (Figure 2), and it is also
known as deep sleep, or slow-wave sleep (SWS).
Channel 5 - EMG
During NREM sleep, there is a significant reduction
in the energy consumption, a reduction of the somatic and
CNS metabolism, and a reduction of the autonomic nervous Figure 2. Slow-wave sleep or REM sleep stage N3. Low frequency and
system (ANS) activity. A reduction in neuromuscular tone high voltage EEG.
can also be observed when mental activity reaches its mini-
mum, and there are no dreams. A definition of NREM sleep EEG dessynchronization
would be: “a state of relative brain inactivity in a partially
inactive neuromuscular system”3.

REM sleep
REM sleep is not divided into stages, but it is characterized
by EEG desynchronization (Figure 3). The presence of REM
episodes and muscle relaxation, with a significant reduction
Rapid eyes-movement
of neuromuscular tone, characterizes this sleep stage4. There Muscle atonia
is an activation of the autonomic nervous system, which Figure 3. REM sleep, with EEG desynchronization, rapid eye move-
results in changes in the heart and respiratory rates, blood ments, and muscle atonia.
pressure, cardiac output, cerebral blood flow, and penile
erections in men. Dream reports indicate mental activity. A control (visual dreams), and there is a marked metabolic de-
definition of this state would be: “an active brain in a para- activation of the cortical regions related to executive cogni-
lyzed body”3. tive functions3,6.
REM sleep occupies about 25% of total sleep time in
a healthy young adult5. During REM sleep, there is an in- Sleep cycle
crease in the regional cerebral metabolism in brain regions The stages of sleep alternate throughout the night, form-
that control behavior, such as in those involved in visual ing the NREM-REM cycles. The distribution of these

Sleep Sci. 2011;4(2):�����

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54
Sleep physiology

stages in a normal night of eight hours of sleep shows a

greater amount of SWS in the first half of the night, with a NREM-REM cicle
NREM-REM cicle
V
predominance of REM sleep in the second one (Figure 4)5. REM
The normal sleep onset latency is less than 30 minutes, and N1
normal REM sleep onset latency is from 70 to 120 minutes
after sleep onset5. Sleep efficiency is calculated as the total N2
sleep time divided by the total recording time in the poly- N1stage: 3 to 5%
somnography (PSG)5. N3 N2 stage: 45 to 55%
N3 stage: 25%
REM sleep: 25%
FUNCTIONS OF SLEEP Sleep eficiency > 85%
What is the real function of sleep in humans and mammals?
There is evidence that sleep plays a role in saving energy and Figure 4. Hypnogram of healthy and young adult. The percentages of
in the reversal of metabolic changes in the CNS and somatic each sleep stage are presented.
hormone secretion7. Animal studies have shown that sleep
Chart 1. Functions of sleep7.
deprivation causes death in mice more quickly than the ca- Energy conservation;
loric deprivation does7. Regulation of brain and body temperature;
There are several hypotheses regarding the function of Immune system regulation;
Neuroendocrine system regulation;
REM sleep, with the most accepted theories being associ- Neural plasticity (learning and declarative memory);
ated with procedural learning tasks, memory consolidation, Cognitive development;
Affective regulation.
synthesis of new information, and organization of informa-
tion in networks of associations6,7. Despite the existence of
evidence for those theories, there is not a unique hypothesis
unifying the several mentioned theories7.
Sleep has had an important role in neuronal plasticity
and in the consolidation of episodic memory and learning6-8.
Therefore, sleep would have a role in the preservation of the
individual and species evolution (Chart 1).

MECHANISMS OF SLEEP-WAKE CYCLE

Anatomical regions associated with wakefulness
Wakefulness is the result of a joint action of the ascending
reticular formation (RF) (glutamatergic neurons) in combi-
nation with the aminergic nuclei (serotonin, noradrenaline,
Figure 5. Reticular formation and ascending reticular system (ARAS).
dopamine, and histamine), having cholinergic receptors lo-
cated in the pons, bulbs, and basal forebrain, and in the pos-
terior and lateral hypothalamic nuclei (histamine and hypo-
cretin, respectively)2,3,6-10, as can be seen in Figures 5 and 6.

RF
The RF is a neuroanatomical structure that extends from
Thalamus
the brainstem (medulla oblongata) throughout the midbrain
VLPO Raphe nuclei
and hypothalamus, and it reaches the thalamus10 (Figure 5). (seretonin)
The RF segment at the height of the brainstem receives an Magnocellular
extensive network of general somatic afferents (touch, tem- basal forebrain
(acetylcholine)
perature pain, and body position), and special somatic and Perifornical area
(hypocretin)
visceral excitatory projections significantly contribute to Tuberomammillary nucleus
wakefulness. The RF has the autonomy to maintain wake- (histamine)
Ventral tegmental area
fulness and consciousness10. It is also capable of maintaining and Substantia nigra (dopamine)
Locus coeruleus
alertness with a minimum of external stimuli, showing that Pedunculopontine and Laterodorsal (norepinephrine)
tegmental nuclei
the existence of a traffic reduction of excitatory impulses for (acetylcholine)
the onset of sleep or for the reduction of wakefulness is not Figure 6. Hypocretinergic, aminergic, and cholinergic systems of the ARAS3.

Sleep Sci. 2011;4(2):�����

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enough, but it is necessary that there is an active inhibition
of the RF by other neural systems (GABAergic and MCH
systems)2.
The RF activity is maximal during wakefulness, whereas
its activity is substantially reduced by the GABAergic in-
hibitory system of the nucleus of the anterior hypothalamus
during NREM and REM. The RF is an active region during
wakefulness (“wake-on”) and inactive during sleep3,9.
Ascending reticular activating system
The ascending reticular activating system (ARAS) is a func-
tional concept, not an anatomical structure, which clus-
ters neural systems with different neurotransmitters2,3,6-10.
These systems are located in the brainstem reticular forma-
tion, with its glutamatergic interneurons, thalamocortical
system, nuclei noradrenergic, serotonergic, dopaminergic,
pontine and basal forebrain cholinergic and histaminergic
hypothalamic systems (Figures 5 and 6)2,3,8-10.
The ARAS is responsible for wakefulness and desyn-
chronization of the cortical and cognitive alerts10. Redun-
dancy and inter-relationships among these ARAS compo-
nent systems represent an evolutionary adaptation for the
maintenance, optimization, and specificity of wakefulness
for the adaptation and survival of the individual and some
species8-10.
Monoaminergic systems
The ascending reticular activating monoaminergic system
consists primarily of the dorsal raphe nucleus (DRN – se-
rotonergic) and locus coeruleus (LC – noradrenergic) of the
brainstem, medial forebrain, and meso cortical-limbic dop-
aminergic system, which connect the ventral periaqueductal
gray dopaminergic matter, called vPAG area, to the lateral
hypothalamus and the tuberomammillary nucleus (histamin-
ergic TMN) of the posterior hypothalamus (Figure 6). These
systems belong to the ARAS project diffusely to the cortex
and thalamic reticular nuclei (Figure 5)8,10. The aminergic
activity during wakefulness stimulates the thalamocortical
circuits, but it is reduced during NREM sleep and absent
during REM sleep. Aminergic neurons are called “REM-
off”3,6,8,9. The aminergic system projects to the anterior hy-
pothalamus to inhibit GABAergic cells of the ventrolateral
pre-optic (VLPO) nuclei of the anterior hypothalamus3,8,9.
Cholinergic pontine-mesencephalic system
There are two cholinergic pontine-mesencephalic nuclei,
the laterodorsal nucleus (LDN) and the pedunculopontine
nucleus (PPN), and a cholinergic nuclei located in the basal
forebrain (Figure 6). This cholinergic system makes excit-
atory connections with the RF, the limbic system (amygda-
la), and the direct cortical projections8,9. These cholinergic
Hasan R, Alóe F
55
projections are fundamental to the various manifestations of
REM sleep. For example, there is an EEG desynchronization
and a significant reduction of neuromuscular tone during
REM sleep, with the latter being a typical manifestation of
REM8.
The neuromuscular tone control during REM sleep in-
volves the area anatomically adjacent to the PPN and LDN,
which is called the sublocus coeruleus nucleus. These cholin-
ergic neurons project to the anterior bulbar region through
the reticulospinal tract, which causes the glycinergic and
GABAergic inhibitory synapses in the brainstem motoneu-
rons and spinal anterior horn to induce post-synaptic inhibi-
tion of motor neurons and, thus, a significant reduction of
the characteristic neuromuscular tone of REM sleep. Lesions
in the region of sublocus coeruleus nucleus cause REM sleep
without atonia8,11.
In contrast to aminergic activity, which is absent dur-
ing REM sleep, cholinergic activity is maximal during REM
sleep and wakefulness, but it is absent during NREM8,9. The
cholinergic cells are called “REM-on”8,9.
Posterior hypothalamus and sleep-wake cycle
Type - 1 and type - 2 hypocretinergic system
The diminished hypocretinergic system, containing about
50,000 neurons, is located in the posterior and lateral re-
gions of the hypothalamus12,13 (Figure 6). Both hypocretin-1
and -2 are excitatory neurotransmitter peptides that are
synthesized exclusively by these hypothalamic cells from a
common substrate, pre-pro-hypocretin12,13. There are two
sub-populations of hypocretinergic receptors in the CNS,
receptors 1 and 2, which are both excitatory G protein-cou-
pled transmembrane receptors that are encoded by chromo-
somes 1 and 6 in humans13,14. Hypocretinergic-1 receptors
activate phospholipase-A and allow the influx of calcium,
whereas the hypocretinergic-2 receptors inhibit adenylate
cyclase12-14.
Hypocretin-1 binds, with high affinity, to the hypo-
cretinergic-1 receptor but also to the hypocretinergic-2
receptors, with an affinity rate from 100 to 1000 times
smaller. Hypocretin-2 binds to hypocretin-1 and -2 recep-
tors. Therefore, the hypocretinergic-1 receptor has a higher
selectivity for hypocretin-112-14.
Hypocretins are exclusively excitatory and regulate the
sleep-wake cycle, energy balance, ANS activity, and neu-
roendocrine activity14. The hypocretins have excitatory pro-
jections to the ARAS and the reticular thalamic nuclei (thal-
amocortical circuits), and direct projections to the cerebral
cortex and limbic system (amygdala complex) (Figure 6)15,16.
The densest projections of hypocretinergic neurons project
to the LC, mammillary nucleus tuber, and DRN15,16. The
hypocretins are also excitatory and project to the cholinergic
Sleep Sci. 2011;4(2):�����
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56
Sleep physiology
nuclei in the pons (pedunculopontine tegmental and latero-
dorsal nucleus) and the basal forebrain cholinergic nucleus
(Figure 6). However, there are no synaptic projections of
hypocretins to the anterior hypothalamus GABAergic re-
gion, the VLPO. In contrast, the VLPO and the melanin
concentrating hormone (MCH) neurotransmitters inhibit
hypocretinergic cells2,3,9.
The hypocretinergic system receives excitatory afferents
from the limbic behavioral system, basal forebrain (cholin-
ergic-adenosine nucleus) and suprachiasmatic nucleus (SCN)
of the anterior hypothalamus9,17. The excitatory efferent from
the limbic system to the hypocretinergic system plays a key
role in the stability of wakefulness during the main period
of activity in important behaviors, such as seeking food or
survival (fight or flight)18. The hypocretinergic system is the
end effector responsible for the occurrence and stability of
the wake state during sleep deprivation. During sleep depri-
vation, the limbic system is responsible for the stimulation
and increased neurotransmission of hypocretin, which sup-
ports the state of wakefulness during sleep deprivation3,6.
The hypocretinergic system shows maximum activity
during wakefulness by stimulating all of the excitatory cir-
cuits responsible for wakefulness, which are absent during
NREM and REM sleep. The hypocretins increase monoam-
inergic tone, which indirectly inhibits the VLPO through
the aminergic system, preventing the onset of sleep19,20.
Hypocretinergic activity is minimal or absent during sleep,
and during sleep loss, there are extensive GABAergic in-
hibitory projections from the VLPO to the hypocretinergic
system, making the hypocretinergic system activity mini-
mal or absent during sleep (Figure 7)19.
Anterior hypothalamus
The anterior hypothalamus VLPO galaninergic and GABAer-
gic inhibitory neurons are only activated during NREM and
REM sleep9,19. The VLPO is related to SWS and REM sleep,
and the VLPO cells directly project to the DRN, LC, pen-
duculopontine tegmental and dorsolateral pontine cholin-
ergic nuclei, and to the hypocretinergic system, it inhibits
these wakefulness-promoting excitatory nuclei (Figure 7)19.
Inhibitory activity derived from the VLPO to the amin-
ergic and the hypocretinergic systems allows the appearance
of NREM and REM sleep due to the inhibition of the hypo-
cretinergic and aminergic cells8,9. The VLPO receives inhib-
itory synapses from the DRN and the LC, but it does not
receive inhibitory synapses from the hypocretinergic system.
In addition, the VLPO receives inhibitory synapses from the
limbic system nuclei (infralimbic cortex and amygdala cen-
tral nucleus), which explains the persistence of wakefulness
during stressful situations, and the suprachiasmatic nuclei
explains the VLPO circadian rhythm8,9.
Sleep Sci. 2011;4(2):�����
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Hypocretin
VLPO
TMN LDT/PPT
Raphe
LC
VLPO: ventrolateral preoptic nucleus; LDT: laterodorsal tegmental
cholinergic nuclei; PPT: pedunculopontine tegmental nucleus; TMN:
tuberomammillary nucleus of the posterior hypothalamus; DRN: dorsal
raphe nucleus; LC: locus coeruleus3.
Figure 7. VLPO inhibitory projections. VLPO axons (GABAergic and
galaninergic) project to the wake-promoting monoaminergic neurons.
Therefore, the VLPO and hypocretinergic-aminergic
system show a reciprocal functional relationship of mutual
inhibition between both systems20. When the VLPO is acti-
vated during sleep, it inhibits the hypocretinergic-aminergic
system cells. Similarly, when hypocretin-aminergic neurons
are activated during wakefulness, they inhibit the VLPO.
This model assumes that reciprocity of sleep or wakefulness
would remain stable, while a component of the balance re-
mained sufficiently activated9,20.
The suspension of the basal forebrain excitatory stimuli
(adenosine accumulation) combined with the inhibition
that was originated from the VLPO in the aminergic and
hypocretinergic system are responsible for the initiation and
maintenance of NREM sleep19,21.
MCH
The MCH was originally described in the salmon pituitary,
and it is found in all studied mammals and vertebrates22.
The MCH molecule is similar to somatomedin. Neurons re-
sponsible for MCH neurotransmission (about 6,000 MCH
cells in mice against 3,000 hypocretin cells) are morpho-
logically similar to hypocretinergic cells, with a fusiform or
multipolar shape, containing two to five dendrites22. The
MCH neurons and hypocretinergic cells are co-localized in
the lateral hypothalamus region. The MCH neuronal projec-
tions in the brains of primates are also similar to the projec-
tions of hypocretinergic cells.
MCH neurotransmission exerts inhibitory effects on hypo-
cretinergic neurons, and the MCH and hypocretinergic sys-
tems have different functions and biochemical substrates and
a reciprocal neurofunctional relationship. The MCH system is

inactive during the daytime and it occasionally can be rapidly
activated during NRE, reaching a maximum during REM
sleep, especially during periods of significant reductions in
neuromuscular tone. The rebound of REM sleep induces c-Fos
expression in the MCH cells, and an intraventricular injection
of MCH increases the amount of REM and, to a lesser extent,
NREM sleep in rats. The MCH system reduces motor activ-
ity, temperature and metabolism and activates the parasympa-
thetic system22. The MCH peptide has hypnotic and anorectic
effects in rats, and the MCH-KO rats are usually hyperactive,
with low weight and hypermetabolism22.
Circadian pacemaker
The SCN is an anatomical structure located in the anterior hy-
pothalamus. It is the main central timer structure (biological
clock) capable of generating its own endogenous rhythm23.
The main stimulus synchronizer of the SCN is sunlight,
which acts as an excitatory stimulus for the SCN activity.
Studies in animals have shown that the initial stage of photo-
synchronization of the SCN is in the retinal ganglion cells,
which are responsible for photo-reception, and the excitatory
transduction of light stimulation from the retinohypotha-
lamic tract to the SCN23,24. The SCN cells transmit rhythmic
information photo-synchronized with adjacent hypothalamic
nuclei responsible for the periodicity of the ANS activity, the
secretion of hormones, the melatonin secretion, the changes of
body temperature, appetite, sleep propensity and the duration
of the sleep-wake cycle23. The SCN signal can also be syn-
chronized by other neural pathways representing nonphotic
stimuli, such as time of meals and physical activity24,25.
The main SCN efferents that are relevant for the sleep-
wake cycle are located in the VLPO and in the hypocretiner-
gic system9. The SCN afferents that project to the VLPO
are inhibitory. Thus, the SCN inhibits the VLPO during
the photo-period and relieves inhibition at the end of the
main photo-period19,23. When the sunlight is gone, the SCN
signal decreases, allowing the onset of NREM sleep8,9. The
functional relationship between the SCN and the hypo-
cretinergic system is excitatory. The reduced SCN activity
at the end of the main photo-period (solar day) is reflected
in the reduction of hypocretin-aminergic activity, which is
critical to the waking state; the reduction of hypocretin-
aminergic activity allows the onset of sleep3,8,9.
The photo-synchronized signal of the SCN cells is sent
to the pineal gland, which is responsible for the secretion
of melatonin24,25. Photo-stimulation inhibits the secretion
of melatonin, which occurs during the night sleep or dark
period, and melatonin exerts a self-inhibitory effect in the
activity of the SCN at the end of the main photo-period, be-
ing one more mechanism in the cascade of events to reduce
hypocretin-aminergic activity to sleep onset9,23.
Hasan R, Alóe F
57
Homeostatic control of sleep
Adenosine is a product of neuronal cellular energetic metab-
olism, which accumulates in the extracellular space in the
synaptic cleft during wakefulness21. Adenosine shows a local
inhibitory effect in the basal forebrain cholinergic nuclei21,
and it accumulates where there is local neuronal metabolic
and electrical activity, such as during the main wakeful-
ness period or during sleep fragmentation or deprivation.
Microdialysis studies in monkeys confirmed that the basal
forebrain regions in the CNS region are where the largest lo-
cal extracellular accumulation of adenosine during wakeful-
ness occurs. Therefore, the basal forebrain is considered the
site of the homeostatic control of the sleep-wake cycle, and
adenosine is the neuromodulator that plays a key role in the
homeostatic control of sleep21.
The local inhibitory action of adenosine occurs in the
basal forebrain cholinergic cells. The basal forebrain sends
excitatory projections to the hypocretinergic system, and
inhibitory ones to the VLPO9,20,21. The activity decrease of
these cholinergic cells disinhibits the VLPO GABAergic
cells and no longer stimulates the hypocretinergic system,
initiating NREM sleep at the end of the wakefulness period,
when the level of adenosine rises8,9,21. The reduction of basal
forebrain cholinergic activity by adenosine accumulation
disinhibits the VLPO, which, combined with the reduction
of the excitatory activity of the SCN, triggers NREM sleep.
This is the double trigger for the sleep onset8,9. The antago-
nistic effects of adenosine-1 receptors by caffeine are respon-
sible for stimulating the inhibiting effects on sleep23.
Sleep-wake switch
The inhibitory bi-directional functional relationship be-
tween the hypocretinergic-aminergic systems and the
VLPO constitutes a mechanism of stability control be-
tween wakefulness and sleep behavioral states (Figure
8)2,3,9. This type of anatomical-functional relationship is
called sleep switch8,20,26.
8
Sleep-wake switch
Norepinephrine
Serotonin
Hypocretin
Locus ceruleus
(norepinephrin) VLPO
Dorsal raphe GABA GABA
nucleus
MCH
(serotonin)
Hypocretins
Inhibition
Stimulation
Figure 8. Sleep-wake switch.
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Sleep physiology

The visceral, special, and somatic sensory afferents ac- Wakefulness

tivate the ARAS and, therefore, they activate the hypo- Acetylcholine
(PPT; LDT)
cretinergic and aminergic systems during wakefulness (Fig-
ures 5 and 9)10. The hypocretinergic system activity during
wakefulness is responsible for the aminergic tonus stability
and activity14. Glutamatergic interneurons, which are lo-
cated between hypocretinergic system neurons, reinforce the
hypocretin neuronal activity in a progressive manner, which Acetylcholine
secondarily reinforces the aminergic system and promotes a (BF)
Histamine
long, stable, and consolidated wakefulness period without (TMN) Norepinephrine
the oscillations or transitions moving the equilibrium of the Dopamina Serotonin
(LC)
balance towards the waking state (Figure 10)10,26. Consoli- (VTA) (raphe) Reticular
Motor neurons formation
dated periods of wakefulness are adaptively important for
LDN: laterodorsal cholinergic nuclei; PPN: pedunculopontine nucleus;
seeking food and preserving the species and individuals7. VTA: ventral tegmental area; RF: reticular formation.
Changes of state from wakefulness to sleep require a strong Figure 9. Nuclei, pathways, and projections responsible for wakefulness.
adjustment of activity in the hypocretinergic-aminergic sys-
tem or VLPO inhibitory system9,20. Wakefulness
The aminergic-hypocretinergic activity is minimal during Reciprocal Interation
NREM sleep, hence, there are extensive GABAergic inhibito-
ry projections from the VLPO to the aminergic-hypocretiner- O
VLPBA
gic system, making the aminergic-hypocretinergic activity A
G H
MC
minimal or absent during sleep (Figure 7)19. The absence of
sunlight at the end of the photo-period disables the SCN and nes
Ami retin
oc
adenosine accumulation, which occurs during the main period Hyp
of wakefulness and inhibits the cholinergic cells in the basal Inhibition
forebrain17,21. These two factors, combined with a reduction of Stimulation
the sensory afferent related to resting posture, the reduction of
ARAS activity and cognitive relaxation (limbic system), meet MCH: melanin-concentrating hormone.
the conditions necessary to suspend the inhibitory influence of Figure 10. Predominance of hypocretinergic-aminergic activity during
the SCN, basal forebrain and limbic system over the VLPO, wakefulness.
thus releasing its inhibitory activity. The VLPO inhibits the
aminergic-hypocretinergic system by shifting the equilibrium NREM SLEEP
of the balance of sleep towards NREM sleep (Figure 11)19,26. Reciprocal Interation
With the progression of NREM sleep, the electric silence of
A
the aminergic-hypocretinergic system, REM-off, disinhibits Hyp mines
ocre
the cholinergic system nuclei, and REM-on generates a sec- tin
ond switch that controls REM sleep2,9,26.
VLP
GAB O
RECIPROCAL INTERACTION MODEL OF REM Inhibition MCHA
AND NREM SLEEP Stimulation
Once the onset of sleep has been reached, another neuronal
interaction mechanism is activated, which explains the al- Figure 11. Predominance of GABAergic activity during NREM sleep.
ternation of NREM and REM sleep8,20. This is achieved by
the interaction between the cholinergic and hypocretinergic- During wakefulness and NREM sleep, the hypocretiner-
monoaminergic nuclei8,9. This working model establishes that gic-aminergic system, REM-off, is tonically activated,
NREM sleep is predominantly GABAergic-aminergic, and whereas the cholinergic tone is higher during wakefulness
that REM sleep is predominantly GABAergic-glutamatergic- than during NREM sleep. The hypocretinergic-aminergic
cholinergic8,20. This model proposes two types of cell groups: system inhibits the cholinergic-glutamatergic system,
REM-sleep-activated cholinergic and glutamatergic cells REM-on, which inhibits REM sleep8. During the latter, the
(“REM-on”)3,6,8,9 and aminergic-hypocretin cells, which are VLPO neurons fire more intensely and progressively, deepen-
inactivated during REM sleep (“REM-off”) (Figure 12)8,9,20. ing sleep. The GABAergic inhibitory activity of the VLPO

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 Hasan R, Alóe F
59

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