The waking brain: an update.

Abstract

Wakefulness and consciousness depend on perturbation of the cortical soliloquy. Ascending activation of the cerebral cortex is characteristic for both waking and paradoxical (REM) sleep. These evolutionary conserved activating systems build a network in the brainstem, midbrain, and diencephalon that contains the neurotransmitters and neuromodulators glutamate, histamine, acetylcholine, the catecholamines, serotonin, and some neuropeptides orchestrating the different behavioral states. Inhibition of these waking systems by GABAergic neurons allows sleep. Over the past decades, a prominent role became evident for the histaminergic and the orexinergic neurons as a hypothalamic waking center.

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REVIEW
The waking brain: an update
Jian-Sheng Lin•Christelle Anaclet•
Olga A. Sergeeva•Helmut L. Haas
Received: 21 November 2010/Revised: 25 December 2010/Accepted: 13 January 2011/Published online: 13 February 2011
? The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract
perturbation of the cortical soliloquy. Ascending activation
of the cerebral cortex is characteristic for both waking and
paradoxical (REM) sleep. These evolutionary conserved
activating systems build a network in the brainstem, mid-
brain, and diencephalon that contains the neurotransmitters
and neuromodulators glutamate, histamine, acetylcholine,
the catecholamines, serotonin, and some neuropeptides
orchestrating the different behavioral states. Inhibition of
these waking systems by GABAergic neurons allows sleep.
Over the past decades, a prominent role became evident for
the histaminergic and the orexinergic neurons as a hypo-
thalamic waking center.
Wakefulness and consciousness depend on
Keywords
Histamine ? Orexin
Wake ? Sleep ? Cortical activation ?
Activation of the cerebral cortex
The cerebral cortex is active day and night, but we are not
always aware of its activity. During slow wave sleep, the
electroencephalogram (EEG) is dominated by high-voltage
d-waves (0.5–3 Hz) indicating a high degree of cortical
inactivation or synchronization. Consciousness depends on
external perturbation that causes a radical change in the
cortical mode of function visible in the EEG as cortical
activation or desynchronization, with low voltage and fast
frequency (mainly b and c, 20 and 60 Hz). This is achieved
by ascending afferents leading to cortical activation during
waking or paradoxical sleep (synonym REM sleep). Both
of these behavioral states are conscious though in different
ways.
Moruzzi and Magoun [1] demonstrated cortical arousal
in the cat by stimulating and lesioning the brain stem
reticular formation and formulated the concept of the
ascending reticular activating system (ARAS), that reaches
the cortex through the non-specific thalamus, the medial
and intralaminar nuclei, as well as through extrathalamic
pathways. During the following decades, stimulations,
lesions, and brain transsections in combination with elec-
trophysiological recordings (from EEG to single cells)
have been used to determine the structures involved in the
regulation of sleep and waking. Acute preparations of high
brainstem transsection [2] or isolated forebrain display
continuous slow synchronous high-amplitude activity,
similar to that seen during deep slow wave sleep. These
studies led to the conclusion that the cerebral cortex does
not possess an intrinsic mechanism for its own activation
and have identified four brain regions that can activate the
cortex: (1) the thalamus, medial and intralaminar nuclei;
(2) the basal forebrain (substantia innominata and adjacent
areas); (3) the monoaminergic nuclei of the brainstem; (4)
the posterior hypothalamus.
The hypothalamus, though long suspected to play a role
in sleep-waking regulation, has been relatively neglected in
the past and will be treated with preference here in the
network formed by the four regions listed above. The
thalamus, basal forebrain, and brainstem have been
extensively reviewed in this context [3–11].
J.-S. Lin ? C. Anaclet
INSERM-U628, Integrative Physiology of Brain Arousal
Systems, Claude Bernard University, 69373 Lyon, France
O. A. Sergeeva ? H. L. Haas (&)
Department of Neurophysiology, Heinrich-Heine-University
Du ¨sseldorf, POB 101007, 40001 Du ¨sseldorf, Germany
e-mail: haas@uni-duesseldorf.de
Cell. Mol. Life Sci. (2011) 68:2499–2512
DOI 10.1007/s00018-011-0631-8
Cellular and Molecular Life Sciences
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The ascending reticular activating system
The ARAS-concept [1] (Fig. 1) has been supported and
complemented, especially at the cellular and electrophysi-
ological levels, mainly by Steriade and co-workers [5, 6, 9,
12]. The excitatory inputs to the thalamus and other sub-
cortical relay structures include cholinergic neurons of the
mesopontine tegmentum, aminergic neurons in the brain-
stem and hypothalamus, and glutamatergic neurons located
in the large brainstem reticular core [4, 8, 13, 14]. The
reticulothalamocortical pathway is not the only system
involved, however, as cortical EEG desynchronization can
reappear following extensive destruction of the mesence-
phalic reticular formation [15] or its thalamic relay [16–18]
indicating the existence of extrathalamic systems, capable
of activating the cortex, that have drawn more attention
recently: the magnocellular substantia innominata, the
adjacent basal forebrain and the cholinergic and GABA-
ergic corticopetal neurons [6–8], as well as the posterior
hypothalamus with the histamine and orexin systems [19,
20].
The basal forebrain
Cholinergic neurons of the basal forebrain discharge toni-
cally during both wakefulness and paradoxical sleep [6,
18]. They can excite cortical neurons directly and suppress
the thalamic reticular nucleus oscillation generating the
cortical spindles and drowsiness or light slow wave sleep
[21]. In keeping with this, electrical stimulation of certain
basal forebrain sites elicits cortical acetylcholine release
and cortical desynchronization, while chemical inactivation
or unilateral lesion in the basal forebrain cholinergic zone
decrease cortical fast rhythms and increase slow activity
[18, 22, 23]. Like thalamocortical neurons, basal forebrain
cholinergic neurons can relay excitation (e.g., from gluta-
matergic, noradrenergic, and histaminergic neurons) from
the lower brain reticular structures to the cortex [7, 10, 24].
GABAergic ascending neurons in the basal forebrain also
project to the cortex [7] and might act in synergy with the
cholinergic neurons in cortical activation, likely by
ascending disinhibition, since they largely innervate
inhibitory cortical neurons [25]. Thus, there is little doubt
that the substantia innominata and the adjacent basal
forebrain as a whole, including cholinergic, GABAergic,
and perhaps further, non-identified neurons, play an
important role in cortical activation both during waking
and paradoxical sleep and in the modulation of different
cortical rhythmic activities. However, the basal forebrain is
not indispensable for the long-term maintenance of fast,
low-voltage cortical activity, since, in the cat, extensive
destruction of the basal forebrain, including the adjacent
lateral preoptic areas, does not abolish cortical activation
[26]. Ibotenic acid lesioning of the cholinergic zone within
the basal forebrain results in a transitory reduction in
waking lasting 1–2 days, after which the sleep-wake cycle
returns to the pre-lesioning level [27].
Monoaminergic systems
An intense interest in the diffuse ascending projections
from the brainstem monoaminergic neurons arose in the
1960s from the histochemical demonstration of their
locations and projections [28] and the pharmacological
intervention on monoaminergic transmission in major
psychiatric disorders, schizophrenia, and depression. These
diseases include disturbed sleep-waking regulation. Inhi-
bition of catecholamine synthesis results in decreased
waking and behavioral somnolence. Moreover, psycho-
stimulants, such as amphetamine or cocaine, lead to an
accumulation of catecholamines, causing a waking state
and behavioral excitation.
Noradrenergic and serotonergic (but not most of the
dopaminergic) neurons discharge tonically during waking,
decrease their activity during slow wave sleep, and cease
firing during paradoxical sleep [5, 9, 29–31]. In mice, locus
coeruleus noradrenergic neurons show the earliest activa-
tion at wake onset among the known waking systems (137).
In the cat, lesioning of the ventral tegmental area and
the substantia nigra, containing dopaminergic ascending
Fig. 1 Ascending activation of the cortex. The ascending reticular
activation system (ARAS) reaches the cortex through a ventral
pathway (hypothalamus, basal forebrain), through the aminergic
nuclei (containing catecholamines, acetylcholine, and serotonin) and
a dorsal pathway, the thalamic relay. Switching between paradoxical
sleep (REM-sleep) and slow wave sleep occurs in the reticular
formation, whereas the switch between sleep and waking lies in the
hypothalamus
2500J. Lin et al.
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neurons, induces behavioral unresponsiveness and akine-
sia, but is not associated with loss of cortical activation
[32].
A group of diffusely projecting dopaminergic cells in
the ventral periaqueductal grey matter expresses c-fos
after natural or forced wakefulness and their lesioning
results in increased sleep. These cells may provide the
long-sought ascending dopaminergic
Large lesions of the mediopontine tegmentum, including
the locus coeruleus and the ascending noradrenergic
pathway, impair waking [11], while electrolytic or chem-
ical lesioning confined to the locus coeruleus region [34]
or selective DSP-4 lesioning of locus coeruleus ascending
projections to the cortex [35] does not cause a major
deficit of waking. Ascending dopaminergic neurons, as a
whole, can thus play an important role in waking, notably
locomotion, motivation and cognitive activities, whereas
the brainstem noradrenergic neurons (groups A1–A7,
including neurons in the locus coeruleus) are permissive in
paradoxical sleep, and modulate behavioral and cortical
arousal, as well as qualitative and cognitive aspects of
waking, such as perception [5, 8, 11, 14, 29, 31, 36] or the
expression of immediate early genes [37]. Although dorsal
raphe serotonergic neurons possess widespread ascending
projections to the cortex and discharge tonically during
waking [5, 30], and although serotonin may participate in
cortical activation when associated with acetylcholine
[38], pharmacological depletion of serotonin using para-
chlorophenylalanine or lesioning/inactivation of the dorsal
raphe nucleus results in insomnia [39]. The postsynaptic
action of serotonin on many neuronal targets is dominated
by the strong inhibition through 5-HT 1A receptors, while
the waking amines, such as noradrenaline or histamine
display predominantly excitatory or excitation potentiating
actions [7, 8, 10, 14, 40, 41]. A modulation of the sleep-
wake cycle by serotonin is evident but it seems not
directly and centrally involved in cortical activation and
waking (Fig. 2).
activation [33].
The posterior hypothalamus is a waking center
The posterior hypothalamus is a heterogeneous structure
made up of different neuronal populations containing
diverse neurotransmitters (histamine, dopamine, glutamate,
GABA) and neuropeptides [orexins, melanin concentrating
hormone (MCH), galanin, enkephalins, substance P, thy-
reotropin releasing hormone (TRH)]. This region has
extensive reciprocal anatomical connections with many
brain regions, notably those involved in sleep-wake control
such as the cortex, thalamus, preoptic-anterior hypothala-
musandotherforebrain
cholinergic, and monoaminergic nuclei [42–45].
structures, thebrainstem
The posterior hypothalamus has only recently been
recognized as a major waking center in spite of early
indications (Fig. 2). After the influenza epidemic of 1918,
von Economo identified hypothalamic lesions in the ante-
rior or in the posterior hypothalamus correlating with
insomnia and hypersomnia (encephalitis lethargica [46]).
Subsequent studies in cats, monkeys, and rats have con-
firmedthat electrolyticlesioning
hypothalamus causes somnolence, hypersomnia, or coma
[4]. Nauta defined a waking center in the posterior hypo-
thalamus and a sleep center in the preoptic/anterior
hypothalamus on the basis of lesion studies in the rat. He
suggested a reciprocal interaction between these two
hypothalamic centers in the alternation of sleep and
wakefulness [47]. The posterior hypothalamus as a waking
center is also supported by the fact that electrical stimu-
lation of this region in the normal [48] or mesencephalic
transsectioned [22] cat causes EEG desynchronization.
This role of the posterior hypothalamus has recently
received increasing interest with the identification of
widespread hypothalamo-cortical projection systems [49–
51] and electrophysiological studies revealing several types
of neurons, discharging with neocortical activation [42,
52–54], suggesting a source for driving cortical arousal.
oftheposterior
Fig. 2 The waking brain. Schematic localization of the brain’s
waking systems and their inhibition. NA (noradrenaline, locus
coeruleus); ACh (acetylcholine, pedunculo-pontine nucleus, PPN;
lateral dorsal tegmentum, LDT; basal forebrain, BF); DA (dopamine,
periaquaeductal grey, PAG), 5-HT (serotonin, dorsal raphe, DR); HA
(histamine, tuberomamillary nucleus, TMN), OX (orexins, periven-
tricular nucleus, PVN); POA: preoptic area, GABAergic neurons
which inhibit all the waking systems, black lines indicate inhibitory
pathways
The waking brain2501
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Sakai et al. [55] have identified three types of tonic unitary
activity in the cat: type-I neurons, discharging during
waking and paradoxical sleep, and type-II neurons with a
significantly higher discharge rate during paradoxical sleep
than during waking and slow wave sleep. Both patterns are
encountered diffusely in the posterior hypothalamus.
Type-III neurons displaying paradoxical sleep-off or
waking-specific discharge have been identified in the tu-
beromamillary nucleus and the ventrolateral area of the
posterior hypothalamus. Thus, the posterior hypothalamus,
like the thalamus and the basal forebrain, represents a
major component of the ascending activating system.
As electrical lesions [4] destroy not only cellular somata
but also fibers en passage, more recent studies [15, 56] have
used chemical agents such as excitatory amino acids (kainic
or ibotenic acid) to induce selective cell death following
over-excitation of neurons. Cellular destruction, under
anesthesia, of large areas in the cat posterior hypothalamus
including the most caudal part and the hypothalamo-
mesencephalic junction produces hypersomnia including
both paradoxical sleep and slow wave sleep lasting
1–2 days, accompanied by narcoleptic episodes, i.e., direct
onsets of paradoxical sleep from waking (sleep onset
REM); while lesions restricted to the rostral part of the
posterior hypothalamus, sparing the hypothalamo-mesen-
cephalic junction produce a significant decrease in waking
and an increase in slow wave sleep lasting for 1–3 weeks.
Muscimol (GABAA-receptor agonist) injections can
acutely inactivate different hypothalamic loci and deliver
functional information on their role in sleep-wake states. In
normal freely moving animals, muscimol microinjection
into the preoptic/anterior hypothalamus or the hypotha-
lamo-mesencephalic junction provokes increased waking
and hyperactivity. In sharp contrast, the same injection in
the rostral and middle parts of the posterior hypothalamus
induces a pronounced and long-lasting increase in deep
slow wave sleep, accompanied by a reduction in, or sup-
pression of, paradoxical sleep. When the injection is
performed in the caudal part, the increase in deep slow
wave sleep is followed by an increase either in waking or
paradoxical sleep, depending upon the exact injection site.
In the latter case, paradoxical sleep can even occur directly
from waking as narcolepsy (sleep onset REM) [57].
The rostral and middle parts of the posterior hypothal-
amus, so far the sole brain region associated with such a
pronounced hypersomnia after inactivation by muscimol,
are therefore the main hypothalamic waking territory.
Under physiological conditions, this region must be inac-
tivated to allow the appearance and maintenance of sleep
likely by the local release of GABA that inhibits the wake
on neurons. A selective increase in GABA during slow
wave sleep is indeed seen in the cat posterior hypothalamus
[58].
Further support for the central role of the posterior
hypothalamus in the maintenance of waking comes from a
number of observations in insomniac cats: insomnia caused
by inhibiting the synthesis of serotonin by para-chlor-
ophenylalanine is reversed by muscimol injection in the
TM and adjacent areas with restoration of slow wave sleep
and paradoxical sleep with short latency [57]. Similarly,
lesioning of the preoptic and anterior hypothalamus results
in long-lasting insomnia and hyperthermia, both effects
being reversed by muscimol microinjection into the TM
and adjacent areas with restoration of both slow wave sleep
and paradoxical sleep [59].
During the long-lasting and total waking state following
the enhancementofdopaminergic
amphetamine, slow wave sleep (but not paradoxical sleep)
is restored at short latency by microinjection of muscimol
into the TM area. The wake-promoting drug modafinil,
which causes long-lasting quiet waking without behavioral
activation, acts through dopamine D2 receptors in the
ventral tegmental area [60] and other arousal systems but
not in TM histamine neurons. This waking state is reversed
by local injection of muscimol [19, 61, 62]. The histamine
neurons display an unusually low sensitivity to D1 and
D2R agonists but are highly sensitive to L-Dopa, which
they can take up and convert to dopamine [63].
Thus, inactivation of the posterior hypothalamus induces
hypersomnia in normal cats and restores sleep in various
models of insomnia, suggesting a key role of this region in
the maintenance of cortical activation and the waking state.
Posterior hypothalamic neurons are likely in a state of
hyperactivity during insomnia and offer themselves as
targets for medication. Nelson et al. [64] reproduced the
muscimol microinjection and also injected gabazine in the
rat posterior hypothalamus TMN which antagonized pro-
pofol anesthesia and loss of the righting reflex. They
attribute a key role to this region for the action of GABA-
ergic anesthetics. The posterior hypothalamus also controls
sympathetic and behavioral functions, such as thermo-
regulation, cardiovascular and respiratory regulation,
locomotion, emotional reactions, and feeding behaviors [4,
65–68]. It therefore seems likely that, during waking,
cortical EEG activity and the concomitant behavioral signs
of arousal are coordinated at the level of the posterior
hypothalamus, thus organizing an integral functional acti-
vation of the brain.
transmissionby
Neuronal substrates involved in arousal in the posterior
hypothalamus
The posterior hypothalamus contains different categories
of neurons: those involved in the control of cortical acti-
vation and waking display arborizing projections, allowing
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the modulation of large brain areas. The dopaminergic A11
group has massive hypothalamic projections and sends
fibers to the mesopontine tegmentum [69], which plays an
important role in the cortical activation during waking and
paradoxical sleep [5, 9, 21, 70]. Muscimol microinjection
in the dorsolateral and perifornical regions, which, in the
cat, contain both type-I and type-II tonic neurons [55]
induces, with a certain latency, continuous deep slow wave
sleep accompanied by suppression of paradoxical sleep
[57]. These populations, including orexin and MCH neu-
rons, send out widespread ascending and descending
projections [51].
Experimental data obtained from our laboratories as
well as the results from other groups suggest a major role
of the histaminergic neurons located in the tuberomamil-
lary nucleus and ventrolateral part of the posterior
hypothalamus in waking. The sedation caused by classical
antihistamines (H1-receptor antagonists) has long been
known as an undesirable side-effect in the treatment of
allergy [71]. Only after histamine was recognized as a
transmitter in the brain [72–77] a block of histaminergic
transmission was made responsible for the drowsiness
caused by antihistamines [78] and many drugs used in
the treatment of neuropsychiatric diseases that bind to the
H1-receptors.
The histaminergic system in brain
Histamine is synthesized from histidine by histidine-
decarboxylase; its levels in the brain measured by micro-
dialysis display a circadian rhythmicity in accordance with
the firing of histamine neurons during waking [79].
Extracellular histamine levels in the preoptic/anterior
hypothalamus follow the oscillations of different sleep
stages (wakefulness[non-REM sleep[REM sleep).
Sleep deprivation does not affect histamine levels, sug-
gesting the relay of circadian rather than homoeostatic
sleep drive [80]. Philippu and Prast [81] have demonstrated
a direct correlation between histamine levels in the hypo-
thalamus and behavioral state by electroencephalography.
Synthesis and release of histamine are controlled by feed-
back through H3-autoreceptors located on somata and
axonal varicosities [82]. Inactivation of histamine in the
extracellular space of the CNS is achieved solely by
methylation through neuronal histamine N-methyltrans-
ferase [83].
The tuberomamillary nucleus contains ca. 3,000 neurons
in the rat and about 64,000 in man, and is the only source
of neuronal histamine in the adult vertebrate brain and
histamine is its main transmitter. Further transmitters (or
their synthetic enzymes) expressed within tuberomamillary
nucleus neurons include GABA, galanin, enkephalins,
TRH, and substance P. Histamine neurons have widespread
projections to the whole brain.
Histaminergic neurons present morphological and elec-
trophysiological properties similar to those seen in other
aminergic neuron populations [84]. They fire slow and
regular at a membrane potential of about -50 mV with 1–4
action potentials per second [85]. The action potentials
have a significant contribution from Ca2?channels trig-
gering a strong afterhyperpolarization. The excitatory arm
of the pacemaker cycle includes dendritic Ca2?potentials
and a non-inactivating Na?current. The Ca2?-currents are
likely instrumental for histamine release from dendrites
and axons; they are blocked by H3-autoreceptor activation.
In behaving cats, rats and mice, the firing is more variable
during waking and absent upon drowsiness and during
sleep [52, 55, 86, 87]. This is the most wake-selective firing
pattern identified in the brain to date.
Tuberomamillary neurons are influenced by many
transmitters and other humoral signals. Excitatory and
inhibitory synaptic potentials (EPSPs and IPSPs) evoked
by stimulations of several locations are mediated by glu-
tamate and GABA. Monoaminergic, cholinergic, and
peptidergic fibers innervate the tuberomamillary neurons.
Many peptides function as signaling molecules in the
hypothalamus where they are involved in endocrine and
homoeostatic functions. They can be co-expressed and
differentially released with other neurotransmitters; in
many neurons, however, they represent the main trans-
mitter or hormone.
Aminergic and some peptidergic neurons are mutually
connected, mostly through excitation, occasionally also
inhibition, forming an orchestra that is to a certain extent
self-organizing. The orexin neurons give the signals for
sleep-waking architecture and the histaminergic neurons
are the dominant cell group with respect to cortical arousal
and wake quality. Multifold arborizing histaminergic axons
reach the entire central nervous system through two
ascending and one descending bundle [72, 88–92]. The
highest density of histaminergic fibers is seen in the
hypothalamus. In the posterior part, the fibers often make
close contact to the brain surface. The septal nuclei and
those of the diagonal band receive a very strong
innervation.
Four metabotropic histamine receptor types (H1R–H4R)
have been cloned so far. H1R, H2R, and H3R are expressed
in abundance in the brain. All histamine receptors display
constitutive activity. The sedative effects of antihistamines
(H1-antagonists) have prompted early suggestions of his-
tamine as a waking substance [78]. Neuronal excitation is
achieved by activation of H1R, Gq/11-proteins and phos-
pholipase C, the formation of the two second messengers
DAG and IP3, as well as intracellular Ca2?release, which
can trigger: (1) opening of cation channels, causing
The waking brain2503
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depolarization; (2) activation of an electrogenic Na–Ca-
exchanger (NCX), causing depolarization; (3) formation of
NO and cyclic GMP; (4) opening of Ca2?-dependent
potassium channels, resulting in a hyperpolarization [93].
Blocking a potassium leak conductance through direct
G-protein action can shift the thalamic relay mode towards
an open state and cortical activation [94]; or directly excite
cortical neurons [95]. Activation of a tetrodotoxin insen-
sitive Na-current is proposed for the excitation of
cholinergic septal neurons [96] and a mixed cation channel
for the excitation of dorsal raphe serotonergic neurons [97].
Firing is also increased in the suprachiasmatic nucleus [98]
and cholinergic basal forebrain neurons [24].
The histamine H2 receptors, b-adrenergic receptors,
serotonin 5-HT2 receptors, among others, are coupled to
Gs-protein, adenylyl cyclase and PKA, which phosphory-
lates proteins and activates the transcription factor CREB.
The direct action on neurons is usually excitatory or
excitation potentiating. Through this signaling pathway
these transmitters block a Ca2?-dependent potassium
conductance, which is responsible for long-lasting after-
hyperpolarizations and the accommodation of firing. This
effect modulates the response of target neurons (e.g., in
cerebral cortex and hippocampus): an identical stimulus
can thus elicit a response consisting of few or many action
potentials depending on the aminergic activation. Such a
potentiation of excitation is perfectly suited to raise
attention.
H3 receptors function as autoreceptors on histaminergic
cell somata, dendrites, and axons (varicosities) where they
provide a negative feedback to restrict histamine synthesis
and release. Importantly, as heteroreceptors, they are also
located on many non-histaminergic axons where they
modulate the release of glutamate, GABA, noradrenaline,
and acetylcholine. H3 receptors are coupled to Gq and
high-voltage activated Ca channels, a typical mechanism
for the regulation of transmitter release (Fig. 3). A high
degree of molecular and functional heterogeneity through
different transcriptional and post-transcriptional processing
(splice variants) is prototypic for the H3R [82, 99]. H3R-
related drugs are being developed largely for the treatment
of sleep disorders [100].
Histamine and waking
The above data strongly indicate that histaminergic neurons
activate or facilitate large brain areas through postsynaptic
H1- and H2-receptors, thus contributing to cortical activa-
tion. Indeed, treatments that impair histamine-mediated
neurotransmission enhance cortical slow activity and
increase sleep. For instance, the blockade of histamine
synthesis with a-fluoromethylhistidine markedly reduces
histamine levels, decreases waking, and increases slow
wave sleep in the cat [19] and rodents [101–103]. In
contrast, enhancement of histaminergic neurotransmission
by inhibiting histamine degradation promotes waking,
reviewed in [19, 75, 102]. The absence of histamine syn-
thesis in histidine decarboxylase knockout mice impairs the
cortical EEG and has deleterious effects on both sleep and
wake quality, causing permanent somnolence and behav-
ioral deficits. Consequently, mice that lack brain histamine
are unable to remain awake when high vigilance is required,
at lights off, or when they are placed in a new environment
[103] (Fig. 4). Like orexin neurons [104], histamine neu-
rons may also be involved in CO2-mediated arousal; they
are activated by short-term hypoxia [105] and are excited by
mild acidification (Sergeeva, unpublished observations).
Taken together, histaminergic neurons have a key role in
maintaining the brain awake. They promote wakefulness
through their direct widespread projections to the cerebral
cortex and indirectly via their subcortical targets in the
thalamus, basal forebrain, and brainstem [14, 75, 92].
Orexinergic/hypocretinergic neurons
Orexins/hypocretins are two peptides (Ox-A, OxB/HCrt1,
HCrt2) derived from proteolytic cleavage of a precursor
peptide encoded by the prepro-orexin(hypocretin) gene.
The orexin-containing neurons are almost exclusively
located in the perifornical area of the dorsolateral hypo-
thalamus, therefore, just dorsorostral to the histaminergic
tuberomamillary nucleus. Like histamine neurons, they
project all over the brain [106]. They bind to two
Fig. 3 The histamine H3R as an autoreceptor mediating negative
feedback on histamine synthesis and release, and, importantly, as a
heteroreceptor suppressing the release of many other transmitters
from their varicosities. H3R antagonists and partial agonists are
widely developed for several neuropsychiatric indications including
sleep disorders
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G-protein-coupled receptors (OX1/2-R, HCrt1/2-R) [107–
111]. Orexin neurons also contain excitatory glutamate and
inhibitory dynorphin [112]. Orexin receptors are expressed
in numerous targets throughout and even outside the ner-
vous system. The name orexins, indicating a function in
food intake, was first envisaged [113]; however, it soon
became apparent that these peptides fulfil important roles
in the regulation of behavioral state and sleep architecture
[114, 115] and serve many physiological functions [108].
Deficiency of the orexins is the cause of narcolepsy-cata-
plexy whereas their hyperactivity, for instance after sleep
deprivation or metabolic challenges [116, 117], predisposes
to addiction and compulsion (see [118]).
Orexin neurons display a wake-active discharge pattern,
clearly correlated to muscle tone and posture change, with
a significant decrease from active waking to quiet waking
and from quiet waking to slow wave sleep [119–121]. In
the rat, the discharge rate of orexin neurons during active
waking is more than 4.5 times that of quiet waking, indi-
cating that their main activity is to promote behavioral
activation during waking [119, 120]. Cerebrospinal fluid
Ox-A level [122] or c-fos expression in orexin neurons
[123] increase after forced waking or behavioral activation.
Finally, central application of orexins elicits active arousal
and hyperactivity in rats, an effect prevented by SB-334867
[124, 125]. Taken together, we suggest that Ox-neurons
promote locomotion and behavioral arousal and thus con-
tribute to the maintenance of waking by enhancing
locomotion [126].
Orexins are also involved in higher brain functions; they
can facilitate memory performance and synaptic plasticity
[127, 128]. An OX2R-dependent increase of GABAergic
transmission in septo-hippocampal pathways may promote
arousal via hippocampal disinhibition and theta rhythm
[129] and a behavioral-state-dependent large-scale oscil-
latory brain activity associated with heightened synaptic
plasticity and memory processing during REM-sleep,
exploratory behavior, and stress [130]. Long-term poten-
tiation of synaptic transmission (LTP) in the hippocampus
[131], a cellular correlate of learning and memory is
enhanced by orexin infusion into the rat dentate gyrus or
locus coeruleus in vivo, while stimulus-induced LTP of
Schaffer collateral-CA1 synapses in dorsal hippocampal
slices as well as spatial memory in a water maze task is
inhibited by orexins. OX-A induces an endogenous form of
LTP at excitatory Schaffer collateral-CA1 synapses
(LTPOX), relying on co-activation of metabotropic amino
acid and biogenic amine receptors [132].
The respective roles of orexin and histamine-systems
for waking
The histaminergic neurons are currently regarded as a
downstream system driven by the orexin neurons through
their dense axon arborizations in the tuberomamillary
nucleus. However, recent studies show that the behavioral
and sleep-wake phenotypes of histidine-decarboxylase
(HDC, histamine-synthesizing enzyme)-/-mice are dis-
tinct from those of orexin knockout(-/-) mice [126, 133].
While both mouse strains display sleep fragmentation and
increased paradoxical sleep, they present a number of
marked differences:
(1) The paradoxical sleep-increase in HDC-/-mice is
seen during lightness, whereas that in Ox-/-mice occurs
during darkness; (2) Contrary to HDC-/-, Ox-/-mice have
neither waking deficiency around lights-off, nor an abnor-
mal EEG and respond to a new environment with increased
waking; (3) Only Ox-/-, but not HDC-/-mice, display
narcolepsy and deficient waking when faced with a motor
challenge. Wild-type, but not littermate Ox-/-mice, when
Fig. 4 Effects of an environmental change on the cortical EEG and
behavioral states in wild-type (upper) and knockout-mice lacking
histamine synthesis (lower). The environmental change (middle)
consists of transferring the mice from their habitual home cage (A) to
a new cage (B). Upper A wild-type mouse with an intact brain
histaminergic system. This mouse placed in the new environment
remains highly awake, as indicated by the alert behavior and waking
EEG. Lower A knockout mouse without histamine. This mouse falls
asleep a few minutes after being placed in the new environment, as
shown by the sleeping behavior and EEG signs of slow wave sleep.
Histaminergic neurons play a key role in maintaining the brain in an
awake state in the presence of behavioral challenges. Modified from
Parmentier et al. (2002) Journal of Neuroscience 22:7695–7711
The waking brain2505
123

Page 8

placed on a wheel, voluntarily spend their time in turning it,
and as a result, remain highly awake (Fig. 5); this is
accompanied by dense c-fos expression in many areas of
their brains, including Ox-neurons in the dorsolateral
hypothalamus. The waking and motor deficiency of Ox-/-
mice is due to the absence of Ox as intraventricular dosing
of Ox-A restores their waking amount and motor perfor-
mance. SB-334867 (Ox1-receptor antagonist, i.p.) impairs
waking and locomotion of wild-type mice during the test.
Thus, histamine- and orexin-neurons, with their reci-
procal interactions, exert a synergistic and complementary
control over waking, the histaminergic system being
mainly responsible for cortical activation (EEG) and cog-
nitive activities and the orexinergic system being more
involved in the behavioral arousal during waking, includ-
ing muscle tone, posture, locomotion, food intake, and
emotional reactions. Orexin deficiency is in most cases the
direct cause of narcoleptic episodes in humans (DREMs,
direct onsets of REMs from wake or SOREMs, sleep onsets
REMs) and cataplexy [134], whereas decreased histamin-
ergic transmission likely accounts for the somnolence and
excessive daytime sleepiness seen in this disease and other
sleep disorders [103, 126, 135, 136]. The advent of opto-
genetic stimulation has opened new ways to study the
impact of defined neuronal populations on behavior. Carter
et al. [137] reported recently such activation of orexin/
hypocretin neurons causing increased waking and c-Fos
expression in locus coeruleus and the tuberomamillary
nucleus, but this effect was lost after sleep deprivation,
presumably being overwhelmed by homoeostatic mecha-
nisms (see below). Interestingly, the increase in waking
was unchanged in HDC-KO mice lacking histamine: the
histaminergic system is an important, but only one of many
targets of the widely arborizing orexin/hypocretin axons.
There clearly is redundancy within the wake-active sys-
tems. They act together like an orchestra and are able to
compensate for the failure of some of their players. For
instance, 3 weeks after triple saporin-induced lesions of the
cholinergic forebrain, the tuberomamillary nucleus and the
locus coeruleus in the rat, the remaining phenotype is a
wake deficit during the light to dark period [138], similar to
that identified in HDC-KO mice [133]. The acute effects of
Fig. 5 Different behavioral
performance and ability to
maintain waking between wild-
type and orexin knockout mice
when faced with a motor
challenge demonstrated using
simultaneous
electroencephalogram and
elecromyogram monitoring
(upper). When wild-type mice
(middle left) were placed on a
wheel, they voluntarily spent
their time in turning it and, as a
result, remained highly awake.
In contrast, orexin knockout
mice (middle right) usually tried
to adapt a position to stay
immobile, thus falling asleep.
Note the absence of orexin
neurons in the knockout mice
(lower). Modified from Anaclet
et al. (2009) Journal of
Neuroscience 29:14423–14438
2506J. Lin et al.
123

Page 9

such lesions, notably those on the neocortical EEG, remain
to be investigated.
The search for substances increasing alertness led to the
discovery of the wake-promoting action of montirelin (a
non-hydrolyzable TRH analogue, which showed beneficial
action in canine narcolepsy [139]). TMN neurons express
two known TRH receptors, are excited by TRH and mon-
tirelin, and the wake-promoting action of montirelin is
missing in histamine-deficient mice [133]. Thus, the his-
taminergic system represents an attractive target for wake-
promoting medication in narcolepsy [136] and e.g., in
Parkinson’s disease [140], where most arousal centers
undergo degeneration while the histaminergic system
remains intact and an H3-receptor inverse agonist increases
alertness [100, 140]. Interestingly, modafinil exerts only a
minor action in PD [140] in accordance with the degen-
eration of dopaminergic neurons and subsequent down-
regulation of D2R.
Other posterior hypothalamic neurons regulating
sleep-wake alternation
The posterior hypothalamus is a heterogeneous structure
also from a functional point of view. In addition to its well-
recognized role in wake, it has long been suggested that
this region exerts hypothalamic control over the brainstem
paradoxical sleep-generating mechanisms and may play an
important role in cortical activation not only during
wakefulness but also during paradoxical sleep, reviewed in
[3, 11, 55].
In addition to the histaminergic wake-specific and
orexinergic wake-active discharge patterns, neurons firing
selectively and tonically during paradoxical sleep were also
identified in the cat and more recently in the rat posterior
hypothalamus [55, 141]. This pattern is driven, at least in
part, by neurons containing MCH in the rat [141].
Although MCH-containing cells are found in the same area
where orexin cells are located, the perifornical area of the
dorsolateral hypothalamus [49, 142], the fact that they
discharge in a reciprocal manner to orexin or histamine
neurons [141] suggests that they might play a different role
than orexin or histamine neurons in sleep-wake regulation.
However, intracerebroventricular supply of MCH increases
paradoxical sleep supporting a role in promoting this
behavioral state, whereas mice lacking MCH-R1 also show
enhanced paradoxical sleep [143]. Thus, the hypothalamic
mechanisms involved in cortical activation during para-
doxical sleep remain to be clarified, but it seems important
to determine the possible interactions between MCH-con-
taining cells and orexin and histamine neurons to further
understand the hypothalamic control on sleep-wake alter-
nation via the three widespread projecting systems.
Interaction between the waking systems
and sleep-generating mechanisms
The waking systems are inactivated to allow sleep. Sleep-
wake alternation results from an interaction between the
waking systems and the brain’s sleep-generating mecha-
nisms. The best defined brain structure for sleep generation
is the preoptic-anterior hypothalamus, which contains
dense populations of sleep-active neurons discharging at a
high rate during slow wave sleep [26, 144]. A lesion of this
region causes severe insomnia [59]; reviewed in Szymusiak
[145]. Later on, it was proposed that the ventrolateral
[146], median [147] or dorsolateral [148] preoptic area and
adjacent regions generate sleep mainly through GABA-
ergic inhibition of the aminergic and peptidergic (orexins)
waking systems.
Early studies also suggest that waking occurs by direct
or indirect inhibition of the preoptic area by the waking
systems. Microinjection of histamine in this area enhances
waking in the cat [149]. In vitro studies demonstrated
direct and indirect inhibition of sleep-active preoptic neu-
ronsby theascending activating
noradrenaline, serotonin, acetylcholine [150], and hista-
mine [151].
The classical view on the orchestration of sleep-wake
alteration by interactions between sleep-generating and
wake-promoting structures is currently challenged or
modified: sleep-active neurons are also identified in wake-
promoting structures like the tuberomamillary nucleus and
the adjacent posterior hypothalamus whereas wake-specific
neurons are also found in the preoptic and the adjacent
basal forebrain. Moreover, at the transition from wake to
slow wave sleep, sleep-active neurons discharge not before,
but after, cessation of activity of the wake-specific neurons,
indicating that release of the inhibition by wake-promoting
systems plays a major role in sleep generation [144, 152,
153].
neurotransmitters
Circadian and homoeostatic regulation
of sleep and waking
A two-process model of sleep-waking regulation proposes
the factors C (circadian pacemaker) and S (sleep propensity
increasing with the duration of waking, homoeostasis)
[154, 155]. A search for endogenous substances interacting
with this regulation continues for decades, in particular for
promoting sleep [156]. Adenosine has been identified as a
candidate that accumulates in the brain during strong ner-
vous activity, during prolonged waking. It causes sedation
[157] and likely induces sleep [158, 159]. Adenosine A1
receptors are positively coupled to various potassium
channels, negatively to Ca2?-channels and cyclic AMP,
The waking brain2507
123

Page 10

exerting post- and presynaptic inhibition at many sites in
the brain, specifically in the cholinergic basal forebrain
[160]. Interestingly, the histaminergic neuron’s firing is
unaffected by adenosine [161]. Adenosine A2A receptors
are more localized, and they mediate excitation of sleep-
active neurons in the preoptic area. Both these adenosine
receptors are blocked by caffeine, resulting in arousal,
especially at times when endogenous adenosine has accu-
mulated during sleep deprivation [159, 162]. Whereas
adenosine levels correlate with low energy reserve [163],
high levels of the energy-rich adenosine-triphosphate
(ATP) can mediate an increased excitability through clo-
sure of KATP-channels and, after release to the extracellular
space, to direct excitation through ionotropic and metabo-
tropic purine receptors of the P2 type, e.g., in histaminergic
neurons [161].
In summary, multiple waking systems operate together to
ensure the complex vital function wakefulness. The dif-
ferent activating and inhibiting systems form a complex
distributed network. Disturbances of sleep and waking are
frequent, socially and economically relevant. Understand-
ing the regulation and the neural mechanisms opens the way
for successful intervention: recent efforts in drug discovery
concern the waking center in the posterior hypothalamus.
Open Access
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
This article is distributed under the terms of the
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