NIH Public Access: Control of Sleep and Wakefulness

NIH Public Access
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Physiol Rev. Author manuscript; available in PMC 2013 July 01.
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Physiol Rev. 2012 July ; 92(3): 1087–1187. doi:10.1152/physrev.00032.2011.
CONTROL OF SLEEP AND WAKEFULNESS

Ritchie E. Brown, Radhika Basheer, James T. McKenna, Robert E. Strecker, and Robert W.
McCarley
Laboratory of Neuroscience, VA Boston Healthcare System and Harvard Medical School,
Brockton, Massachusetts
Abstract
This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness
promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple
interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain
converge onto common effector systems in the thalamus and cortex. Sleep results from the
inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric
oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-
amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and
frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in
conservation of brain energy and facilitates memory consolidation through the modulation of
synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem
cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic
reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs,
dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a
role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking
and NREM sleep are strongly conserved throughout evolution, underscoring their enormous
importance for brain function. Sleep disruption interferes with the normal restorative functions of
NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes
in emotional reactivity, and cognitive impairments in attention, memory, and decision making.
I. INTRODUCTION
The purpose of sleep is one of the great unsolved mysteries of biology and has fascinated
people for millennia. Although the function or functions of sleep are still unresolved, great
progress has been made in understanding the brain mechanisms that control sleep and
wakefulness. An understanding of these mechanisms is of paramount importance to our
society. Sleeping tablets are among the most widely prescribed medicines, and disturbances
in sleep are associated with a wide range of medical and psychiatric conditions. Conversely,
an increase in sleep is one important mechanism that the body uses to combat infection and
maintain optimal health. Adequate sleep is also essential for optimal cognitive function; lack
of sleep has been implicated in major industrial disasters as well as car and workplace
accidents. In this unusually comprehensive review we summarize current knowledge
regarding the brain mechanisms which control wakefulness, non-rapid-eye-movement
(NREM) sleep, and rapid-eye-movement (REM) sleep.
Address for reprint requests and other correspondence: R. W. McCarley, Laboratory of Neuroscience, Dept. of Psychiatry, VA Boston
Healthcare System & Harvard Medical School, VA Medical Center Brockton, Research 116A, 940 Belmont St., Brockton, MA 02301
(Robert_McCarley@hms.harvard.edu).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
Brown et al. Page 2
A. Characteristics of Sleep-Wake States

Sleep is defined in the sleep laboratory, in both humans and animals, by recording the
electrical field activity of large groups of cortical neurons and muscle cells. Thus scalp
electrodes record the electroencephalogram (EEG), electrodes placed on or in skeletal

muscles record the electromyogram (EMG), whereas electrodes placed over or near the
muscles responsible for horizontal eye movement record the electro-oculogram (EOG).
Deep brain electrodes are used to record the activity of individual brain areas or individual
neurons. These so-called polysomnographic recordings are used to define the states of
wakefulness and sleep as follows (FIGURE 1): wakefulness is defined by low-voltage fast
EEG activity (LVFA) and high muscle tone, NREM sleep is characterized by high-
amplitude low-frequency EEG and decreased muscle tone, whereas REM sleep has LVFA
coupled with a complete loss of muscle tone (REM muscle atonia) and characteristic rapid
eye movements which contrast with the slow rolling eye movements observed during
NREM. Further characteristics of these three states and the brain circuitry which generates
them are discussed in sections II–IV. A summary of studies involving inactivation of
different parts of the brain controlling sleep and wake is provided in TABLE 1. The location
of these brain regions is shown in FIGURE 2.
B. Control of Sleep Timing and Intensity

The timing, depth, and duration of sleep are controlled by the interaction of time of day
(circadian control, process C) and by the duration of prior wakefulness (homeostatic control,
process S) as proposed in the two-process model of Borbely (122). The cellular mechanisms
in the suprachiasmatic nucleus (SCN) which generate circadian rhythms are not covered
herein, since they have been reviewed extensively elsewhere (1263). The output pathways
from the SCN that control the circadian timing of NREM and REM sleep are covered in
sections III and IV. Homeostatic control of sleep is also covered in these sections.
C. Effects of Sleep Loss on Cognition

An important function ascribed to sleep is offline processing of information encountered
during the day and consolidation of memory. Conversely, loss of sleep, either voluntarily or
due to an underlying medical disorder, is associated with substantial impairments in
cognitive function. The mechanisms underlying these impairments are discussed in Section
V.
D. Sleep Ontogeny
Sleep is the predominant behavioral state in developing animals (645, 1070), and REM sleep
is proportionally more abundant in young mammals (1070). As such, sleep, in particular
REM sleep, has been suggested to play an important role in the elaboration of neuronal
circuitry during development (1070). The circuitry controlling sleep and wakefulness
appears to mature early in development (606), although cycling between states is more
frequent in younger animals (111, 645). EEG signs of sleep and wakefulness do not become
“adultlike” until the later full development of the cortex (110, 377, 585, 1144). In fact, in
humans, the development of fast EEG synchrony typical of wakefulness continues through
adolescence, reflecting the prolonged maturation of the cortex in higher primates (1318).
E. Sleep Phylogeny
A form of NREM sleep appears to be present in most animals investigated to date (185,
1478), which is one of the arguments in favor of sleep performing a vital function (1174). A
distinct REM sleep state only appears in mammals, although a primitive form is evident in
reptiles and birds (1175). Sleep physiology is adapted to the particular features of different
animals. For example, dolphins and other cetaceans exhibit unihemispheric sleep (1174).

Brown et al. Page 3
The distribution of the durations of sleep bouts in mammals is exponential with time scales
that vary across species from mice to humans that are proportional to body mass and
metabolic rate, indicating a connection with energy metabolism (742, 1174; discussed more
fully in sect. III). Whereas most early animal studies of sleep used cats, dogs, and rats as
experimental subjects, more recently there has been an explosion of interest in using more
genetically tractable organisms to identify and study the genes and proteins involved in
controlling sleep (1478). This work is reviewed in section VI. Interestingly, this work
suggests that even organisms such as the fly Drosophila melanogaster (492, 1159) and the
worm Caenorhabditis elegans (1042) have a “rest state” with similarities to mammalian
sleep. Furthermore, several homologs of genes controlling rest in these species play a role in
the control of mammalian sleep (230).
F. Sleep Disorders
Polysomnographic recordings are used not only in experimental studies but also in clinical
sleep laboratories to identify sleep disorders such as sleep apnea and narcolepsy which
involve a dissociation and fragmentation of waking, NREM, and REM (780). Disorders of
sleep and the brain mechanisms that underlie them are discussed in section VII.
II. WAKEFULNESS
A. Electrographic Signs of Wakefulness
Synchronized electrical activity in large numbers of cortical neurons provides the basis for
observable extracellular field potential changes in the EEG. Summed synaptic currents from
the apical dendrites of pyramidal neurons are the main contributors to these EEG waves,
although intrinsic membrane properties and neuronal firing also contribute (178). Faster
frequency EEG rhythms (LVFA) typical of wakefulness and REM sleep are of low
amplitude and involve synchronized activity in small, functionally interrelated areas. Lower
frequency rhythms such as the theta rhythm occur over more widespread areas and
synchronize faster, locally generated fast rhythms (beta/gamma). These EEG rhythms are
thought to provide a temporal framework for higher-order brain functions such as attention,
memory formation, and conscious awareness by binding together the firing of neurons
within cortical areas and by synchronizing cortical and subcortical sites (178, 1238). During
quiet or drowsy wakefulness, the slower EEG frequencies become more prevalent. Alpha
rhythms appear in posterior cortical recordings whilst theta rhythms increase in frontal
cortical regions.
1. Gamma/beta rhythms (15–120 Hz)—Low-amplitude gamma (30–120 Hz) and beta

(15–30 Hz) frequency rhythms are a prominent feature of the EEG during quiet waking
(baseline or spontaneous gamma; FIGURE 1) and are enhanced in particular cortical areas
following presentation of sensory stimuli (evoked or steady-state gamma). Gamma rhythms
often occur concurrently with theta rhythms during active waking and during REM sleep
(187, 739, 880), particularly following phasic REM periods with PGO wave activity (26).
Gamma rhythms also occur during the brief upstate of the slow oscillation during NREM
sleep (see sect. III) (1219). In some studies, gamma rhythms have been subdivided into two
frequency bands: low gamma (30–70 Hz) and high gamma (7–120 Hz), which arise in
different cortical layers and have different pharmacological modulation properties (35, 950).
We here primarily discuss low gamma. Gamma rhythms are generated by cortical networks
of fast-spiking [especially parvalbumin (PV)-Pos] interneurons targeting the cell bodies of
glutamatergic neurons (FIGURE 3). Rhythmic inhibition and disinhibition of the pyramidal
neurons are responsible for the observed field potentials with rate being set by the decay
time of the inhibitory synaptic currents. In turn, the interneurons are driven by excitatory
input from the pyramidal neurons. Synchrony is enhanced by electrical synapses mediated

Brown et al. Page 4
by gap junctions between interneuronal networks and between the axons of pyramidal
neurons as well as by interneuron-interneuron chemical synapses (1405).
Gamma rhythms are generated locally in the neocortex but are modulated by subcortical
inputs. The ability to elicit gamma rhythms in isolated brain slices in vitro (163, 366, 1407),
together with current-source density and cross-correlational analysis in vivo (26, 1218),
suggests that gamma rhythms are generated locally in the cortex. However, their dependence
on behavioral state and stimulus presentation indicates that their occurrence is also
dependent on subcortical inputs. In fact, gamma rhythms are enhanced by stimulation of the
mesencephalic reticular formation, the origin of the ascending reticular activating system
(502, 903). Further information on the subcortical control of gamma rhythms is provided in
section IIC.
Fast-spiking interneurons containing PV generate gamma rhythms. Evidence supports the

conclusion that beta and gamma rhythms are generated by GABAergic interneurons, in
particular fast-spiking, PV GABAergic interneurons which synapse on the cell bodies and
axon initial segments of pyramidal neurons. 1) In vivo, fast spiking interneurons discharge at
gamma frequency and their firing is phase-locked to the extracellularly recorded oscillation
(133, 1026, 1311). 2) In vitro, gamma and beta rhythms are completely blocked by GABAA
receptor antagonists (366, 1407), and gamma frequency is inversely correlated with the
decay time constant of inhibitory synaptic currents (1406). 3) Optogenetic stimulation of PV
neocortical interneurons in vivo (via genetic introduction of bacterial light-activated ion

channels) can elicit gamma rhythms, whereas optogenetic inhibition reduces gamma (193,
1194). 4) Wavelet analysis of local field potentials in the CA3 region of the hippocampus
combined with simultaneous intracellular recordings from pyramidal neurons during
cholinergically induced gamma rhythms revealed that perisomatic inhibitory currents
generated the majority of the field potential (955). 5) In human visual cortex, GABA
concentration measured by magnetic resonance spectroscopy predicts peak gamma
frequency and orientation discrimination performance (331, 906). 6) Gene linkage analysis
indicates significant linkage between the beta frequencies of the human EEG and GABAA
receptor genes (1015).
PV knockout mice have enhanced gamma oscillations (1379), suggesting PV itself may not
be required, although developmental compensation may have taken place. Alterations in PV
neurons may be responsible for dysfunctional gamma rhythms in schizophrenia and other
disorders that are associated with cognitive abnormalities (1319, 1428).
A) Beta Oscillations: Beta frequency EEG oscillations (15–30 Hz) are thought to represent
one or more of the following: 1) a slow gamma oscillation, 2) a subharmonic of ongoing
gamma whereby inhibitory neurons fire at gamma frequencies but some excitatory neurons
remain refractory for longer periods so that they only fire on a proportion of the gamma
cycles, or 3) a rhythm with its own distinct underlying properties (653). Computational
modeling suggests that beta rhythms are more effective than gamma rhythms in
synchronizing activity between spatially distant brain loci (653).
2. Alpha rhythms (8–14 Hz)—The two most well-known alpha rhythms in humans are
the occipital alpha rhythm which dominates the EEG during relaxed wakefulness (FIGURE
1) and the Rolandic mu rhythm observed over somatosensory cortex in the absence of
movement (536). Occipital α rhythms were one of the first described EEG rhythms (7, 92).
They are commonly observed during relaxed wakefulness in parietal and occipital cortex
areas including primary visual cortex and are suppressed by eye opening and visual stimuli
(961). Alpha rhythms may play an important role in internally directed thought processes

Brown et al. Page 5
since they are strengthened during tasks requiring mental arithmetic and visual imagery
(1052).
A) Thalamocortical Mechanisms Generating Alpha Rhythms: The mechanisms

underlying the generation of alpha rhythms were little understood until recently (536). Alpha
rhythms result from an interaction of thalamic and neocortical circuitry, together with a
moderate level of brain stem cholinergic input. At the level of the visual cortex, alpha waves
are due to a dipole located at the level of the cell bodies of pyramidal neurons in layer V and
basal dendrites of pyramidal neurons in layers IV where thalamic input terminates (747,
748). At the level of the thalamus, the firing of two groups of thalamocortical relay neurons
in the lateral geniculate nucleus are suppressed at either the positive or negative peak of the
alpha rhythm through phasic inhibition. For the occipital alpha rhythm, local lateral
geniculate GABAergic interneurons excited by high-threshold bursting thalamocortical
neurons are important in periodically silencing thalamocortical neurons, whereas for the mu
rhythm the GABAergic reticular nucleus may fulfill this role.
In vitro work in the cat thalamus suggests that alpha rhythms require stimulation of
muscarinic cholinergic receptors (mimicking brain stem input) or stimulation of
metabotropic glutamate receptor stimulation (mimicking cortical input). Stimulation of these
receptors leads to depolarization and the generation of an after depolarizing potential (ADP)
in the gap junction-coupled network of high-threshold bursting thalamocortical neurons
(537, 751, 752), leading to synchronized firing. Concerning these two mechanisms, in vivo
microdialysis experiments suggest that the brain stem muscarinic input is more important
(752). Interestingly, the number of spikes in a burst and the interburst frequency (2–14 Hz)
are dependent on the level of muscarinic receptor activation so that the transition from alpha
to the slower theta frequency waves in early (light) sleep or drowsy wakefulness may reflect
a gradual withdrawal of brain stem cholinergic input (536, 537).
3. Theta rhythms (4–8 Hz)—Theta-rhythms occur prominently during waking associated

with movement in rodents, during tasks requiring attention/ memory in humans, and during
REM sleep in all mammals (FIGURE 1). They provide a temporal code for pyramidal/
granule cell firing important for spatial navigation and episodic memory formation and
facilitate synaptic plasticity (178, 587, 1362). In rodents and other lower mammals, very
regular theta rhythms, also called rhythmic slow activity, have been studied most closely in
the hippocampus and related temporal lobe structures, which in these species are located
close to the dorsal surface of the brain (FIGURE 2) and strongly influence the EEG signal
during movement and REM sleep. In humans, where the temporal lobe is located ventrally,
theta rhythms are recorded and studied mainly in frontal and midline cortices that are part of
the default network. Interestingly, in both animals and humans, theta-band activity increases
strongly in frontal-midline areas during the course of sleep deprivation and is correlated with
sleep drive (365, 1386). However, this theta activity is less regular than that generated by the
hippocampus and may result from different mechanisms. Here, the mechanisms underlying
hippocampal theta are discussed first followed by mechanisms that may be involved in
human frontal-midline theta.
The medial septum drives hippocampal theta. A major afferent input to the hippocampus
arises in the rostral basal forebrain (medial septum, vertical limb of the diagonal band; MS/
vDB, FIGURE 2) via the fimbria-fornix. Withdrawal of this input by lesions,
pharmacological inactivation or transection completely abolishes hippocampal theta rhythm
(30, 106, 445, 1090). MS/vDB neurons fire rhythmically in phase with theta rhythm (997,
998). Thus the MS/vDB is thought to be a pacemaker for hippocampal theta (FIGURE 4).
Selective lesion of MS/vDB cholinergic neurons reduce the amplitude but do not change the
frequency of hippocampal theta (697). In contrast, kainic acid lesion of the MS/vDB, which

Brown et al. Page 6
largely spares cholinergic neurons but kills PV GABAergic projection neurons, and likely
other noncholinergic neurons, eliminated hippocampal theta (1463). In vivo, single-unit
recordings from identified PV neurons reported bursts of action potentials at theta frequency
which are synchronized with the ongoing hippocampal theta activity (125, 1182). Within the
burst, action potential firing rates are at gamma frequencies, providing an explanation of the
phase-locking of gamma rhythms to theta rhythms. Two populations of PV MS/vDB
neurons fired anti-phasically, i.e., one population fired at the peak of hippocampal theta,
whereas the other fired at the trough (125). In contrast to the GABAergic neurons, slow-
firing cholinergic neurons fired only single action potentials in synchrony with theta rhythm
(1182). Together these data suggest that PV GABAergic MS neurons are crucial pacemakers
for hippocampal theta, whereas cholinergic neurons modulate the amplitude. MS/vDB PV
projection neurons selectively innervate the PV hippocampal interneurons (basket and
chandelier neurons) responsible for controlling firing of principal neurons (385). Thus
hippocampal theta rhythm is (at least partially) generated by rhythmic inhibition and
disinhibition of hippocampal pyramidal and dentate granule cells (176). In addition,
rhythmic input from the entorhinal cortex plays a large role in the observed variation in
extracellular potential (176).
A) Brain Stem Control of Theta Rhythm: The ascending pathways from the brain stem
which generate theta rhythm are still an active area of investigation (1365). Precise mapping
studies by Vertes and colleagues (1356, 1365) revealed that the most effective brain stem
stimulation sites for theta generation are located within the nucleus pontis oralis (PnO)
region of the brain stem reticular formation (FIGURE 2). Extracellular single- unit
recordings in the PnO of freely moving rats identified cells that fire in association with states
when theta rhythm is present. However, these cells did not fire rhythmically, but fired
tonically at high rates (60–100 Hz) (935, 1355). Thus these neurons are unlikely to be
involved in coding the frequency of hippocampal theta rhythm.
Tonic brain stem input is converted into rhythmic firing in the supramammillary nucleus
(FIGURE 4). Although it was originally assumed that tonic firing in the reticular formation
is translated into rhythmic firing in the MS/vDB, anatomical tracing studies revealed that
few neurons in the reticular formation project directly to the MS/vDB (1357, 1359). Thus at
least one additional nucleus is likely interposed between these two areas. Anatomical tracing
and physiological mapping studies using the local anesthetic procaine suggested that MS/
vDB projecting, glutamatergic neurons containing the calcium-binding protein calretinin in
the supramammillary nucleus (SuM; FIGURE 2) may fulfill this role (638, 710, 1360, 1366)
(FIGURE 4). Single-unit SuM recordings in urethane-anesthetized animals reported single
spike or rhythmic burst firing phase locked with hippocampal theta (105, 637, 639, 649).
Rhythmic SuM firing is not due to descending inputs from the septum or hippocampus since
it was not altered by inactivation of the MS/vDB with the local anesthetic procaine (639).
However, SuM procaine injection blocked the ability of PnO stimulation to elicit theta
(638). Thus it was proposed that the SuM translates tonic firing of the reticular input into
phasic bursting at the frequency of hippocampal theta (636). However, in contrast to
experiments in urethane-anesthetized animals, in freely moving animals procaine causes
only a small reduction in the frequency of hippocampal theta (845, 1286), suggesting that
additional pathways are involved. The precoeruleus region of the pons (758), located just
rostral to the locus coeruleus, provides the major brain stem glutamatergic input to the MS/
vDB. In addition, the nucleus incertus of the medulla (933) projects to the MS/vDB and
SuM regions. Although these areas have been implicated in brain stem theta generation,
rhythmically firing neurons have not been recorded in these regions. Thus they may relay
the activity of the reticular formation (especially PnO) to the MS/vDB and SuM. In contrast,
the GABAergic ventral tegmental nucleus of Gudden, located just ventral to the dorsal
raphe, contains intrinsically bursting neurons (155) which fire rhythmically at theta

Brown et al. Page 7
frequencies during waking and REM sleep and may generate theta rhythmicity in the limbic
Papez circuit through their interconnections with the medial mammillary body (81, 648).
B) Theta Rhythms in Humans: In humans, where the hippocampal formation and temporal
formation are located ventrally, theta oscillations are most commonly recorded just anterior
to the Fz electrode site over frontal and midline cortices (prefrontal and anterior cingulate)
(862). Mechanisms that may be responsible for generating this frontal-midline theta (FM-
theta) are as follows: 1) FM-theta may be generated through direct or indirect projections
from the hippocampal formation, synchronizing information flow between hippocampus and
neocortex (1184). However, FM-theta is not always coherent with hippocampal theta (862).
2) FM-theta may represent a slow alpha-rhythm generated by thalamocortical loops during
drowsiness (see preceding section). 3) FM-theta may be generated by pacemaker
GABAergic (PV-Pos), cholinergic, and glutamatergic projections from the caudal basal
forebrain (BF). GABAergic PV-Pos and cholinergic neurons in the caudal BF show similar
firing patterns (321, 481, 698) and projections to interneurons and pyramidal neurons in the
neocortex (386) as their counterparts in the rostral BF which project to the hippocampus.
Furthermore, the firing of ensembles of noncholinergic BF neurons are correlated with
prefrontal cortex field potentials (729). Further research is required to determine the
contribution of these three mechanisms to FM-theta. They are not mutually exclusive, and
any of them may contribute under different conditions.
B. Brain Stem Reticular and Basal Forebrain Activating Systems

The work of a handful of researchers in the first half of the 20th century allowed the
development of current ideas of how LVFA typical of wakefulness and REM sleep is
generated. Frederic Bremer (136) found that transection of the brain of cats at the
midcollicular level (“cerveau isole” preparation) led to “sleeplike” behavior and slow waves
in the cortex. In contrast, transection at the junction of the brain stem and spinal cord
(“encephale isole” preparation) did not alter the normal cyclic alternation of sleep-wake
states and demonstrated that sensory input from the spinal cord was not necessary for
wakefulness to occur. Later work by Giuseppe Moruzzi and Horace Magoun showed that
electrical stimulation of the midbrain reticular formation in anesthetized cats caused the
appearance of an “activated” EEG similar to that seen during waking (898). Together these
findings led to the important concept of the “ascending reticular activating system (ARAS),”
a network (reticulum) of nerve fibers ascending from the brain stem, which through multiple
intermediary sites causes activation of the forebrain during waking and REM sleep
(FIGURE 5). The activity of brain stem reticular neurons, the origin of both of these
pathways, reliably predicts the onset of changes in behavioral state (818, 1228, 1232, 1236).
The ARAS consists of dorsal and ventral pathways (FIGURE 5). Axonal tracing studies
coupled with histochemical or immunohistochemical visualization of particular
neurotransmitter systems revealed the anatomical pathways transferring brain stem activity
to the cerebral cortex (573, 1228). Single-unit recordings and indirect measures of neuronal
activity (using immunohistochemical detection of the immediate early gene product Fos)
defined the neurons in these areas whose activity is correlated with wakefulness or sleep
(575, 1228). Two main pathways have been identified (FIGURE 5).
1. The dorsal pathway of the ARAS (Figure 5)—This comprises midbrain, pontine,
and medullary reticular formation glutamate neurons (261, 916, 1227, 1235) and cholinergic
neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) (473, 1235)
which innervate the midline and intralaminar (nonspecific) thalamocortical projection
system (paraventricular, parataenial, intermediodorsal, centrolateral, paracentral,
centromedial, rhomboid, reuniens, centromedian and parafascicular thalamic nuclei). These

Brown et al. Page 8
thalamic nuclei project to widespread and overlapping neocortical areas (559, 578, 750, 970,
1203), although each nucleus has some selectivity in their density of projections to their
neocortical targets (1327). Stimulation of the nonspecific nuclei yields widespread cortical
responses and elicits fast cortical rhythms (478, 559, 891), while electrical stimulation in
sensory relay nuclei elicits short responses in local areas of sensory cortex. In addition to
thalamic projections, the brain stem cholinergic (LDT/PPT) neurons also innervate the
dopaminergic and GABAergic neurons of the midbrain ventral tegmental area of Tsai (260),
which are involved in reward processes and project prominently to the nucleus accumbens
and prefrontal cortex. Surprisingly, experiments in rodents (177, 397) and cats (1370)
showed that very large lesions of the thalamus appear to have very little effect on cortical
activation and the sleep-wake cycle in general, aside from a loss of sleep spindles,
suggesting that the dorsal pathway is not absolutely necessary. However, a complete and
selective ablation of thalamus is hard to achieve with lesion techniques, and it remains
possible that a small thalamic projection remained after these lesions which was sufficient to
maintain function. These findings in animals are also seemingly at variance with human
studies of coma patients (see sect. VII) and imaging studies of sleepwake and anesthesia
which suggest that changes in reticular and thalamic function precede changes in the cortical
EEG (66, 152, 928). At the very least, one can conclude that under normal conditions, the
dorsal pathway is involved in and shapes cortical activation.
2. The ventral pathway of the ARAS (Figure 5)—This comprises fibers of the medial
forebrain bundle which pass through and make contact with neurons in the midbrain,
posterior/lateral hypothalamus, and basal forebrain (BF) on the way to the cortex. The
ascending fibers from the brain stem include glutamatergic (parabrachial), noradrenergic
(locus coeruleus, LC), serotonergic (dorsal and median raphe), and dopaminergic
(periaqueductal gray) neurons. These systems synapse onto glutamatergic, histaminergic,
and orexinergic/ hypocretin neurons in the posterior/lateral hypothalamus (575). All of these
systems converge onto caudal BF cholinergic, GABAergic, and glutamatergic neurons
which project to and activate the neocortex (305, 316, 573, 1148, 1228). A branch of this
system innervates the rostral BF theta rhythm generator.
In contrast to the thalamic lesions discussed above, a recent study showed that large lesions
of the BF, or of the brain stem parabrachial nucleus (PB), which provides the major brain
stem glutamatergic input to the BF, led to a comatose state in rats (397), whereas, as
discussed above, thalamic lesions had little effect. However, it is important to note that in
this study, orexin-saporin was used to lesion the BF and PB, whereas ibotenate was used to
lesion the thalamus; thus the two experiments are not directly comparable. Orexin-saporin is
a relatively new lesioning tool that requires further study. In particular, it is important to
determine if very large lesions, resulting in widespread neuronal death, also affect fibers of
passage.
Direct projections to the cortex and the nonspecific thalamic nuclei also arise from brain
stem noradrenergic and serotonergic neurons as well as the hypothalamic histaminergic and
orexinergic/hypocretin neurons. In section IIC, we discuss the role of the different
components of the ARAS, subdivided according to neurotransmitter phenotype.
3. Default network—One novel finding from human imaging studies is the existence of a
so-called “default network” of functionally interconnected cortical regions that are active
when individuals are left to think to themselves and are not involved in responding to the
external environment (1040). Anatomically, the default network consists of regions along
the anterior and posterior midline, the lateral parietal cortex, prefrontal cortex, and temporal
lobe (33, 1040). Upon presentation of external stimuli requiring a response, the default
network regions show a decrease in activity, in contrast to other cortical areas that show

Brown et al. Page 9
increases or no change. Thus, while animal studies have often considered cortical activation
as being fairly uniform throughout cortical regions, human imaging studies show that this is
not the case. Future studies should distinguish how the ascending systems controlling the
default network differ from those affecting other cortical areas.
C. Neurotransmitter Systems Promoting Wakefulness

Multiple neurotransmitter systems contribute to the promotion of wakefulness. However,
none of them appears to be absolutely essential. In this section we describe the effects of
inactivation or stimulation of these systems, the mechanisms by which they act, and their
possible function during wakefulness.
1. Acetylcholine—The cholinergic system promotes high-frequency oscillatory activity

typical of wakefulness and REM sleep. The BF cholinergic system has an additional role in
the homeostatic sleep response to prolonged waking (discussed more fully in sect. III). The
important role of brain stem cholinergic neurons in REM sleep control is discussed in
section IV.
Neurons involved in sleep-wake control that release acetylcholine are located in the BF and
in the mesopontine tegmentum (LDT/PPT) of the brain stem (44, 849) (Figs. 2 and 6).
Identified, cortically-projecting cholinergic neurons in the caudal BF (substantia innominata,
horizontal limb of the diagonal band, magnocellular preoptic area, nucleus basalis) fire
fastest during both wakefulness and REM sleep (481, 698), and their firing is correlated with
cortical activation (321, 698, 789). In particular, caudal BF cholinergic neurons fire bursts of
spikes in association with neocortical theta rhythms (698). Rostral BF (MS/ vDB)
cholinergic neurons projecting to the hippocampus also fire in association with hippocampal
theta rhythm but fire only single spikes per cycle (1182). Wake/ REM-on neurons have also
been recorded in cholinergic brain stem areas although, to date, the firing of identified brain
stem cholinergic (LDT/PPT) neurons projecting to the thalamus has not been recorded
across the sleep-wake cycle. In urethane-anesthetized animals, identified brain stem
cholinergic neurons fire in association with cortical activation produced by tail pinch (126).
Consistent with the firing patterns of cortical and thalamic-projecting cholinergic neurons,
acetylcholine levels are highest in these areas during wakefulness and REM sleep (200, 560,
1412). Thus increased activity of both brain stem and BF cholinergic systems is associated
with states when cortical activation and conscious awareness occur (572, 993, 1429).
BF cholinergic neurons projecting to the neocortex promote LVFA. Caudal BF neurons

affect electrographic activity via a direct projection to the cortex (305, 450, 500, 1115, 1148,
1431). Intracellular recordings from cortical neurons in vivo and in vitro have revealed a
plethora of cholinergic effects that lead to increased excitability and a facilitation of fast
EEG rhythms at the expense of slow oscillations typical of NREM sleep (827, 1216).
Prominent muscarinic effects include the following: 1) a depolarization of pyramidal
neurons via block of a leak potassium conductance (M-current) and activation of mixed
cation channels; 2) facilitation of subthreshold oscillations in the beta/gamma range (20–40
Hz), and 3) blockade of slow after hyperpolarizations. Nicotinic actions include presynaptic
facilitation of glutamate release (443) and depolarization of interneurons (20, 579). In vivo,
application of agents which depolarize cholinergic neurons in vitro (22, 334, 375, 619)
increases theta and gamma cortical activity, together with waking and REM sleep. In
particular, the action of neurotensin is noteworthy, since it appears to be selective for
cholinergic neurons (191). Conversely, application of serotonin, which hyperpolarizes BF
cholinergic neurons (618), reduces gamma activity (189).

Brown et al. Page 10
A) Cholinergic Elicitation of Fast Eeg Rhythms in vitro and in vivo: In vitro, application
of cholinergic agonists causes theta and gamma/beta rhythms in isolated hippocampal (366,
534, 1165) or neocortical areas (107, 163, 950) and promote alpha or theta oscillations in
thalamic relay nuclei such as the lateral geniculate nucleus (751, 752). The cholinergic
neuromodulatory system is unique in this regard since only cholinergic or glutamatergic
agonists have been shown to induce oscillatory activity in vitro. Early, in vivo studies in
urethane or ether anaesthetized rats and rabbits established that one form of theta activity
(type I theta, 4–7 Hz) was abolished by systemic administration of the muscarinic antagonist
atropine sulfate (667). Both brain stem (LDT/PPT) cholinergic neurons projecting to the
diencephalon and MS/vDB cholinergic neurons projecting to the hippocampus and
neocortex promote theta activity. Infusion of the cholinergic agonist carbachol into the brain
stem (PnO) or SuM/posterior hypothalamus increases hippocampal theta (635, 944, 1363)
whilst selective lesion of MS/vDB cholinergic neurons reduces the amplitude of
hippocampal theta (697). Muscarinic receptor blockade weakens the coupling between
gamma and theta rhythms (501), suggesting that the enhanced acetylcholine release that
occurs during waking and REM sleep promotes this coupling. Thus acetylcholine promotes
the cortical rhythms typical of wakefulness and REM sleep and the coupling of gamma to
theta rhythms.
B) Brain Stem Cholinergic Projections to the Thalamus: While BF cholinergic neurons

promote cortical activation via a direct projection to the cortex, brain stem cholinergic
neurons do so via their projections to the thalamus, comprising a major component of the
dorsal ARAS pathway (FIGURE 5). Anterograde and retrograde tracing studies coupled
with choline acetyltransferase immunohistochemistry revealed a massive cholinergic
projection to the thalamus (291, 473, 474, 940, 974, 1193, 1235, 1430) which, depending on
the thalamic region studied, make up 25–85% of the projection from all neurons in the
pontine tegmentum. A minor cholinergic projection to the thalamus, especially the reticular
nucleus and anterior nuclei, arises from BF (976).
Similar to BF cholinergic neurons, the firing of brain stem cholinergic neurons correlates
with, and anticipates, cortical activation and deactivation (126, 336, 615, 1221). In vivo,
electrical stimulation of brain stem areas containing cholinergic neurons enhances beta/
gamma frequency firing in thalamocortical neurons and in the EEG (1226). In vitro,
cholinergic agonists depolarize relay neurons via a muscarinic (M1/M3, Gαq G protein)
receptor-mediated block of leak potassium conductance. This depolarization facilitates
single-spike firing at the expense of the rhythmic bursting observed during NREM sleep
(143, 826, 832). Acetylcholine directly depolarizes ventral tegmental area dopaminergic
neurons via nicotinic receptors containing α4-α7 and α2 subunits (646, 1002), and by
activation of muscarinic M1-like (probably M5) receptors (680, 1461), which increases burst
firing (743) and facilitates dopamine release in target regions such as the nucleus accumbens
(373).
In addition to acetylcholine, brain stem cholinergic neurons also release the gaseous
neurotransmitter NO. In vitro, electrical stimulation of LDT produced NO (707), whereas in
vivo studies showed that NO is released in the thalamus (1414) and medial pontine reticular
formation (709) in relation to behavioral state. Administration of NO donors enhances
neuronal activity in the thalamus and neocortex (265), while NOS inhibitors cause inhibition
of thalamic cell activity. NO dampens the oscillatory activity of thalamocortical relay
neurons by altering the voltage dependence of the hyperpolarization activated cation current,
Ih (967).
C) Effects of Cholinergic Lesions: While electrical or pharmacological stimulation of

cholinergic neurons is highly effective in stimulating LVFA, lesioning of brain stem or BF

cholinergic neurons does not lead to pronounced changes in 24-h amounts of wakefulness.
Selective lesioning of BF cholinergic neurons using the toxin 192IgG-saporin led to
relatively minor changes in wakefulness (94, 611). However, high-frequency EEG power,
especially gamma-activity, was strongly reduced with extensive lesions of caudal

cholinergic BF neurons (94, 600) but was unchanged with less complete lesions (611, 1398,
1399). More consistently, IgG192-saporin lesions of MS/vDB cholinergic neurons reduced
the amplitude of hippocampal theta rhythm (80, 415, 697, 1463). Lesioning of the
cholinergic neurons reduced the homeostatic response to sleep deprivation, but again this
required an extensive destruction of cholinergic neurons (102, 592, 611). Thus it appears
that there is considerable redundancy in the cholinergic system, and effects are only seen
with extensive lesions.
2. Serotonin—Overall, the evidence suggests that serotonin promotes a quiet waking state
with reduced cortical activation. Serotonin also plays an important role in suppression of
REM sleep (sect. IV) and in the response to stress, which may account for some aspects of
stress-related sleep disorders (sect. VII).
Serotonin neurons are clustered in several nuclei along the midline of the brain stem in the
raphe nuclei (FIGURE 2) (553). Early experiments where serotonin levels were depleted
erroneously suggested that serotonin promotes sleep (581, 899). Recent experiments
examining mice in which serotonin neurons are genetically deleted suggest that insomnia
resulting from disruption of serotonin signaling was due to a disruption of thermoregulation,

leading to an increase in motor activity to generate heat (162). In contrast to the early
depletion experiments, recording of the electrical discharge of serotonin neurons (839, 1308)
and measurements of serotonin release (1020, 1411) revealed that serotonin neurons are
wake-active, suggesting that serotonin is wake-promoting. Neuronal firing decreased during
NREM sleep and ceased during REM sleep. Accordingly, systemic application of
serotonergic receptor agonists increases waking and reduces NREM and REM sleep (884).
Serotonergic suppression of NREM sleep is likely due to a 5-HT1A receptor-mediated
postsynaptic inhibition of sleep-active VLPO neurons (403), whereas the inhibition of REM
sleep involves a postsynaptic inhibition of REM-on brain stem cholinergic neurons (130,
522).
A) Mechanisms by which Serotonin Promotes Wakefulness: Serotonin promotes waking

via depolarization of histaminergic tuberomammillary neurons (344) and BF GABA neurons
projecting to the hippocampus (23) and neocortex (154). Serotonin has complex effects on
the thalamus. A direct depolarization of lateral geniculate neurons and other first-order
thalamic relay neurons via a 5-HT7 receptor- mediated modulation of hyperpolarization-
activated cation conductance was initially reported (205, 206, 829, 1342), an action which
blocks spindle oscillations (696). However, most higher-order relay and nonspecific nuclei
are inhibited by serotonin (877) via a combination of a direct 5-HT1A-mediated postsynaptic
hyperpolarization and an indirect increase in inhibitory input due to depolarization of
GABAergic thalamic reticular nucleus neurons (833). Sensory relay neurons may also be
inhibited by serotonin (1071) through a depolarization of local interneurons (877, 969,
1109). However, serotonin also facilitates glutamate release from thalamocortical terminals
via 5-HT2A receptors (10, 11), the main target of hallucinogenic drugs such as lysergic acid
diethylamine (LSD) which act as partial agonists of this receptor (794). Serotonin blocks the
slow after hyperpolarizations of intralaminar thalamic (430), hippocampal (1302), and
neocortical pyramidal neurons (40, 1475) via activation of receptors coupled to stimulation
of adenylyl cyclase (5–HT4/5-HT7), allowing the faster firing typical of wakefulness.
B) State-Dependent firing of Serotonin Neurons: Most serotonin neurons fire in a slow,

tonic fashion across the sleep-wake cycle (839, 1308). However, a subpopulation also fires

in bursts (471). In contrast to norepinephrine and histamine neurons, most serotonin neurons
recorded in vitro do not fire action potentials spontaneously (1335). Thus afferent input from
other wake-active systems is required to maintain their firing (158, 713, 1095, 1335).
Serotonin neurons are depolarized by norepinephrine, histamine, and orexins via activation
of a long-lasting inward current due to the opening of mixed cation channels (158, 735,
1335), likely of the transient receptor potential family (1151). Unlike the other wake-active
neuromodulatory systems discussed here, serotonin neurons promote a state of quiet or
relaxed waking; single-unit recordings report highest activity during feeding and decreased
firing during active waking (554). Serotonin neurons are also activated by stress (476), and
5-HT1A knockout mice lack the rebound of REM sleep observed following the stress of
immobilization (130).
C) Serotonin Inhibits Theta and Gamma Rhythms: Serotonin acts in opposition to the
cholinergic system (FIGURE 6), inhibiting both BF (618) and brain stem cholinergic
neurons (763, 1280), resulting in a blockade of fast rhythms (especially theta and gamma)
promoted by activation of the cholinergic system. In particular, median raphe (MR)
serotonergic neurons inhibit hippocampal theta rhythm (1365). Electrical or
pharmacological stimulation of the MR abolishes theta rhythm in both anesthetized and
unanesthetized rats (51, 629, 1356, 1451), whereas lesions or pharmacological inactivation
of MR result in continuous theta (630, 1451). An involvement of serotonin in these effects
was suggested by the following findings: 1) treating rats with p-chlorophenylalanine,
resulting in a 60–80% depletion of forebrain serotonin, blocked the effects of MR electrical

stimulation (51); 2) continuous theta in raphe lesioned animals could be interrupted by
administration of the serotonin precursor L-5-hydroxytryptophan (1451); and 3) inhibition of
MR serotonin neurons with 5-HT1A agonists generates theta rhythm in urethane-
anesthetized rats (631, 1364). Similarly, serotonin inhibits caudal BF cholinergic neurons
(618) and reduces EEG gamma activity (189).
3. Norepinephrine—Norepinephrine neurons are generally thought of as part of the

central flight-or-fight response, being particularly important in waking associated with
stressful situations. Norepinephrine also plays an important role in the maintenance of
muscle tone during waking and suppression of REM sleep (see sects. IV and VII).
Norepinephrine neurons are located in small clusters throughout the brain stem (194). The
most prominent noradrenergic innervation of the forebrain arises from the LC (FIGURE 2).
It is this nucleus that has been studied most closely with respect to the sleep-wake cycle. LC
neurons fire most rapidly during wakefulness and are activated further by stressful stimuli
(1050), but their firing slows during NREM sleep and ceases prior to and during REM sleep
(511). Norepinephrine strongly excites many neurons of the ARAS (FIGURE 6), mainly via
α1 receptors, including thalamic relay neurons (829), serotonin dorsal raphe (DRN) neurons
(9, 68, 158, 962, 1335), BF cortically-projecting cholinergic (375) and GABAergic neurons
(154). Norepinephrine inhibits neurons in the sleep-active ventrolateral (403) and median
preoptic nuclei (63), as well as REM-on brain stem cholinergic neurons (706, 1280), by
acting on postsynaptic α2 receptors and activating an inwardly rectifying potassium
conductance. β-Receptors inhibit slow calcium-dependent after hyperpolarizations of
cortical pyramidal neurons, allowing the faster firing typical of wakefulness (463) and
blocking the slow oscillations typical of NREM sleep (1220).
Studies utilizing neurotoxic or electrolytic lesions of the LC or norepinephrine system

reported minor changes in the amount of wakefulness (100, 244, 576, 758, 881). However,
depletion of norepinephrine using peripheral administration of the toxin DSP-4 reduced the
expression of ~20% of waking-related gene transcripts, particularly those involved in
synaptic plasticity and cellular stress responses (238, 241, 244). Studies of long-term

potentiation implicate noradrenergic β-receptors in promotion of synaptic plasticity (519,

1202). Thus one important function of norepinephrine released during waking appears to be
the promotion of synaptic plasticity required for memory formation, in particular emotional
memory (1312).
4. Histamine—Histamine neurons were first implicated in wake promotion due to the

sedative side effects of first-generation antihistamines (H1 receptor antagonists) that cross
the blood-brain barrier and affect central histaminergic systems (159, 1402). More recent
studies have clearly shown that histamine neurons in the tuberomammillary nucleus (TMN;
FIGURE 2) are slow firing (<10 Hz) and have a wake-on, NREM-slow and REM-off firing
pattern (564, 1264, 1338). In vitro, histamine neurons are spontaneously active (464, 1242)
due to the activity of a persistent tetrodotoxin-sensitive sodium current (1257). They are
excited directly by orexins (342) and serotonin [via 5-HT2C receptors (344)] and indirectly
by norepinephrine [through inhibition of GABAergic inputs (1243)]. Histamine has
excitatory effects on most nuclei of the ARAS (FIGURE 6; Refs. 159, 465) and,
accordingly, injection of histamine into many nuclei of the ARAS promotes wakefulness
(722). Conversely, histamine inhibits sleep-active projection neurons of the VLPO via
excitation of local inhibitory interneurons, leading to a promotion of wakefulness (736).
Modest decreases/increases in waking have been observed following pharmacological

suppression or activation, respectively, of the histamine system (159, 722). However,
inactivation of the histamine system via lesions (302, 413), knockout of the histamine H1
receptor (528), administration of an irreversible inhibitor of the histamine synthesizing
enzyme histidine decarboxylase (HDC; Refs. 551, 642, 1152) or knockout of HDC (29, 978)
have relatively minor effects on 24-h amounts of waking or cortical activation suggesting
that, similar to the other aminergic systems, the histamine system is not absolutely essential
for wakefulness. Histamine neurons maintain their level of firing during cataplectic attacks
in narcoleptic animals (in contrast to norepinephrine and serotonin neurons) implicating
them in the preservation of consciousness which accompanies the cataplectic state (564). In
addition, increased activation of histamine neurons as measured by Fos activity has been
observed during feeding anticipatory behavior (851, 1323). More fine-grained analysis of
sleep and wakefulness in HDC knockout animals revealed a deficit in wakefulness when
placed in a novel, potentially dangerous environment (29, 978). This is consistent with a role
for histamine in stress- or danger-induced arousal (159).
5. Orexins/hypocretins—Orexins/hypocretins were discovered relatively recently by two

groups who gave them their two names (290, 1101). We will use the term orexins for these
peptide neurotransmitters in this review. Orexins consolidate wakefulness (increase the
duration of long waking bouts), suppress REM sleep (sect. IV), and enhance wakefulness in
periods of starvation (1452). Considerable evidence links them to the sleep disorder
narcolepsy (see sect. VII).
A) Orexins Promote Wakefulness: Early work showed that intracerebroventricular

application of orexin A dose-dependently increases wakefulness in rats (1005). More recent
work using light-activation of orexin neurons via viral vector- mediated introduction of
channelrhodopsins (6) found that excitation of orexin neurons in the lateral hypothalamus at
frequencies above 5 Hz increased the probability of a transition from sleep to wakefulness.
Conversely, administration of recently developed orexin receptor antagonists increased both
NREM and REM sleep in animals and humans at the expense of wakefulness (140).
B) Orexin Neurons Increase Waking in Response to Low Food Availability: One

function of the orexin system may be to integrate nutritional state with arousal (4, 1416,
1452). Orexin neurons respond to a wide variety of peripheral and central signals indicating

nutritional state (164, 268, 393, 1048, 1452). Several metabolic signals which increase with
feeding, such as glucose, leptin, and neuropeptide Y, inhibit orexin neurons in vitro (164,
393, 1452). In contrast, orexin neurons are activated by fasting in non-human primates
(308), and given their wake-promoting effects, they are likely to be primary mediators of the
increase in waking and suppression of sleep caused by limited availability of food. In fact,
orexin knockout mice fail to respond to fasting with an increase in waking and activity
(1452).
C) Orexin Neurons are Wake-Active: Orexin neurons are most active during waking as
assessed by Fos immunohistochemistry (351, 872) and measurements of peptide release
(641). In the squirrel monkey, which has a sleep-wake cycle similar to that of humans,
orexin levels peaked in the latter third of the day and remained elevated during 4 h of
extended wakefulness, consistent with a role for orexins in consolidating wakefulness in
opposition to accumulating sleep drive (1472). Single-unit recordings in the rat from the
area where orexin neurons are located revealed one group of slow-firing neurons that were
wake-active and REM-off (13, 666). Later recordings in freely moving rats confirmed that
this population corresponds to orexin neurons, determined by electrophysiological criteria
(856) or post hoc immunohistochemical staining (699, 1265). Orexin neurons fire fastest
during active waking, decrease firing during quiet waking, and cease firing during sleep,
except during microarousals or immediately preceding the arousal from sleep.
In vitro, intracellular recordings from identified orexin neurons revealed that they have a
depolarized resting membrane potential (333, 715), leading to spontaneous firing in the
absence of injected current or application of neurotransmitter agonists. In addition, they are
excited by a positive feedback loop involving local orexin release, activation of orexin type
2 receptors (1455), and excitation of local glutamatergic inputs (715). This positive feedback
loop may help to synchronize the firing of the whole orexin neuron population. Furthermore,
glutamatergic inputs to orexin neurons are potentiated via a cAMP-dependent mechanism
during prolonged waking (1047), which is a mechanism suggested to be important in the
maintenance of wakefulness in the face of increased sleep pressure (1299). However, recent
optogenetic stimulation experiments found that sleep deprivation blocks the ability of orexin
to activate its downstream targets and enhance waking (195).
D) Control of Orexin Neurons by Afferent Inputs: Orexin neurons receive afferent inputs
from other nodes of the sleep-wake circuitry (FIGURE 6) as well as from areas involved in
emotional regulation such as the amygdala and lateral septum (1102, 1466). They are
excited by acetylcholine via M3 muscarinic receptors (84, 947, 1454) but inhibited by
serotonin via a postsynaptic activation of 5-HT1A receptors (715, 905). This inhibitory
action is also observed in vivo since intracerebroventricular application of an 5-HT1A
antagonist, WAY100635, increased locomotor activity during the dark (active) phase in
wild-type mice, but not in orexin/ataxin-3 mice in which orexin neurons are ablated (905).
Both inhibitory (715, 716, 1453) and excitatory (84, 1453, 1454) effects of norepinephrine
on orexin neurons have been reported in recordings from mouse and rat brain slices. The
inhibitory response is mediated by α2 receptors activating inwardly rectifying potassium
conductance (716, 1453), whereas the excitatory action is due to activation of α1 receptors
and activation of a nonselective cationic current (1453). In the rat, it has been suggested that
the response to norepinephrine shifts from an excitation to an inhibition during a short
period (2 h) of sleep deprivation (452). In addition, norepinephrine increases the frequency
of inhibitory postsynaptic currents (IPSCs) via an effect on presynaptic GABAergic
terminals (716, 1453). In vitro, dopamine inhibits orexin neurons via D2 receptors (716),
whereas in vivo, systemic dopaminergic agonists increase their activity as assessed by Fos
immunohistochemistry, likely by an indirect action (161). Orexin neurons are unaffected by

histamine, which is somewhat surprising, considering the close proximity of histamine and
orexin neurons in the hypothalamus (342).
E) Inhibition of Orexin Neurons During Sleep: The spontaneous activity of orexin

neurons in vitro suggests that they must be actively inhibited during NREM and REM sleep
when their activity level slows markedly. This inhibition likely arises from GABAergic
neurons in the preoptic area and BF. Orexin neurons are postsynaptically inhibited by both
GABAA and GABAB receptors (15, 715, 1150, 1445), and GABAB receptors also mediate a
presynaptic inhibition of glutamatergic and GABAergic inputs (1445). In vivo, antagonism
of GABAA receptors increases the firing rate of wake-on (presumed orexinergic) neurons in
the perifornical hypothalamus during NREM sleep, indicating an inhibitory GABA receptor-
mediated tone during this state (15). Mutant mice with a constitutive loss of GABAB
receptors in orexin neurons (via knockout of the GABA-B1 gene) have fragmented sleep-
wake cycles, due to an upregulation of inhibitory tone which shunts (short-circuits)
excitatory and inhibitory inputs (811). Feedback control of orexin neurons may occur
through the release of coexpressed dynorphin peptides (223), which cause a
hyperpolarization, inhibition of calcium channels, and reduction of excitatory synaptic
inputs (717), although direct evidence for feedback control by this mechanism is lacking at
present. In addition, orexin neurons are inhibited by the sleep homeostatic factor adenosine
via A1 receptors (14, 1277) (see sect. III).
F) Downstream Effectors of Orexin Promotion of Wakefulness: How do the orexins

consolidate wakefulness? Anatomical studies demonstrated a strong innervation of
sleepwake circuitry by the orexin neurons, particularly the aminergic nuclei (273, 524,
1000). The strongest projection was found to the LC which expresses exclusively the type I
receptor, whereas most other sleep-wake nuclei express the type II receptor or both type I
and II (249, 506, 793, 853, 1307). In vivo, injections of orexin A into the LC enhanced
wakefulness at the expense of REM sleep (128, 467), whereas in vitro recordings revealed a
postsynaptic excitation mediated by activation of nonselective cation channels and blockade
of leak potassium channels (524, 552, 904, 1326). Similarly, in vitro studies showed that
orexins had excitatory effects on serotonergic DRN neurons (157, 158, 651, 735),
histaminergic tuberomammillary neurons (85, 342, 1456), BF (47, 334), and brain stem
cholinergic neurons (169, 651) and ventral tegmental area dopamine and GABA neurons
(660). Furthermore, orexins target neurons in the dorsal ARAS pathway, exciting neurons in
the reticular formation (160), nonspecific thalamic nuclei (83, 312, 436, 527),
thalamocortical terminals (685), and deep layer VI cortical neurons (86). In addition to the
LC, in vivo studies showed wake-promoting effects of orexins in the BF (348, 1279),
tuberomammillary nucleus (530), laterodorsal tegmentum (1442), and reticular formation
(1392). Orexins also directly increase muscle tone via excitation of spinal cord motoneurons
(1457).
It was proposed that orexins exert their wake-promoting action through stimulation of the
histamine system since orexins excite histamine neurons in vitro (342), and the wake-
promoting effect of intracerebroventricular orexin A is reduced/lost in HDC knockouts and
histamine H1 receptor knockouts (530) or with application of a histamine H1 receptor
antagonist (1163). Furthermore, low histamine levels have been reported in the brains of
narcoleptic dogs (922) and in the cerebrospinal fluid (CSF) of human narcoleptics,
particularly in unmedicated patients (597, 925). However, the dependence of the
intracerebroventricular effect of orexin A application on the histamine system may simply
reflect the close proximity of histamine neurons to the ventricular system, compared with
other postsynaptic targets. In contrast to orexin knockout animals, HDC or histamine H1
receptor knockout animals do not have reduced duration of sleep-wake states (29), and
optogenetic stimulation of orexin neurons is still able to increase the probability of

awakening in HDC knockout animals. However, expression of the orexin type II receptor in
histamine neurons and other areas surrounding the TMN in mice lacking type II receptors
was sufficient to consolidate wakefulness, although sleep was still fragmented (869).
Orexins actions at other sites are likely to be similarly important. For instance, optogenetic
inhibition of LC norepinephrine neurons inhibited the wake-promoting effect resulting from
optogenetic excitation of orexin neurons (196).
6. Neuropeptide S—Like the orexins, neuropeptide S (NPS) is a recently discovered

peptide activating a previously “orphan” G proteincoupled receptor activating phospholipase
C (1449). NPS is coexpressed in glutamate-producing neurons located just rostral to the LC
(precoeruleus region) which project to widespread areas of the brain, including sleep-wake
regulatory regions such as the midline thalamic nuclei, lateral hypothalamus, and preoptic
area (1448, 1449). Intracerebroventricular application of NPS increased locomotor activity
and decreased sleep in rats (1449), whereas NPS receptor knockout mice had reduced
exploratory activity in a novel environment (317). In addition to its role in promoting
wakefulness, recent experiments suggest a role for the peptide in controlling fear and
anxiety (586, 1449).
7. Dopamine—Pharmacological agents increasing dopaminergic tone such as

amphetamines and modafinil (Provigil) are the most potent wake-promoting substances
currently known. As such, they are commonly prescribed to treat sleep disorders involving
excessive daytime sleepiness (see sect. VII). Although these substances can enhance the
release of other neuromodulators such as serotonin and norepinephrine, their effects are
abolished in dopamine transporter (DAT) knockout animals (1425), confirming that their
main effect is on dopaminergic systems (129). Additional evidence supporting a role for
dopaminergic systems in promotion of wakefulness comes from analysis of D2 receptor
knockout mice that exhibit a significant decrease in waking amounts due to a shorter wake
bout duration and a concomitant increase in sleep (1032). One possible mechanism
explaining this effect is a disinhibition of intralaminar thalamic neurons via indirect basal
ganglia-thalamic pathways (1135). In Parkinson’s disease, where dopamine neurons in the
substantia nigra degenerate, waking is interrupted by sleep episodes (1087). However,
dopamine neurons are not the only neurons to be affected by this disease.
A) Ventral Tegmental Area Dopamine Neurons: While the average firing rate of
dopamine neurons in the ventral tegmental area (VTA) and substantia nigra does not vary
across sleep-wake states (858), VTA dopamine neurons fire more bursts during waking and
REM sleep, resulting in increased release of dopamine in target areas such as the nucleus
accumbens and prefrontal cortex (271). In particular, increased bursting is observed in the
presence of rewarding or aversive stimuli requiring an alerting response (1209). VTA
neurons are excited in vitro by several neuromodulators that promote arousal such as
orexins, substance P, and corticotrophin releasing hormone (658, 660).
B) Ventral Periaqueductal Gray Dopamine Neurons: Dopaminergic neurons in the

ventral periaqueductal gray (vPAG)/DRN (FIGURE 2) show Fos activity during waking but
not during sleep (757). Selective lesioning of these neurons by injections of 6-
hydroxydopamine (63% loss) or nonselective lesions with ibotenic acid (80% loss) resulted
in a marked (>20%) reduction in 24-h amounts of wakefulness, one of the most pronounced
effects of lesions on wakefulness reported to date (757). In contrast, lesions of the
serotonergic neurons in this area were without effect on 24-h amounts of sleep and waking.
Retrograde tracing studies showed that dopaminergic vPAG neurons project to other parts of
the ARAS such as the BF and midline thalamus, and receive input from sleep-active VLPO
neurons (757). These data all support a role for these neurons in control of wakefulness, but

electrophysiological recordings from these neurons across behavioral state are lacking at
present.
8. GABA—GABAergic neurons and glutamatergic neurons (reviewed below) are very

abundant and widely distributed in the brain. Hence, it is not surprising that some
populations of the neurons utilizing these two neurotransmitters are involved in promoting
wakefulness, whereas others are associated with sleep. Thus, although pharmacological
agents potentiating the activity of GABAergic systems have been most closely linked with
sleep (see sects. III and IV), select GABAergic subpopulations in the cortex (especially PV
interneurons, sect. IIA) and in subcortical sites, are thought to be critical in the production of
cortical LVFA. Cortically-projecting GABA neurons are located in the BF (386, 450, 500),
hypothalamus [colocalized in histamine (1371), and melanin-concentrating hormone
neurons (60)] and in the VTA (1206). Hypothalamic melanin-concentrating hormone
neurons fire predominantly during sleep (482) and so are unlikely to contribute to
wakefulness. While the activity of histamine neurons is correlated with wakefulness, the
function of GABA in histamine neurons is unclear, especially since it would be expected to
counteract excitatory actions of histamine on target neurons. GABAergic neurons in the
thalamic reticular nucleus play a crucial role in thalamocortical rhythms during sleep and
wakefulness (see sect. III).
A) Bf and Vta Gaba Neurons: GABAergic neurons in the BF and VTA (FIGURE 2) in
particular appear to be important for cortical LVFA since a fast-firing subpopulation of these
neurons increases their activity during waking and REM sleep (481, 700). Many
GABAergic BF neurons projecting to the cortex contain PV (451). Preliminary studies (154)
showed that identified cortically-projecting BF GABA neurons are excited by
neurotransmitters promoting cortical activation (acetylcholine, norepinephrine, histamine,
orexins), likely accounting for their faster firing rate during waking and REM sleep (481).
Rostral and caudal PV GABAergic projection neurons synapse onto hippocampal (385) and
neocortical PV-positive neurons (386) which control hippocampal and cortical gamma
rhythms, respectively (see sect. IIA). Other subpopulations of BF GABA neurons that are
likely sleep related project to the thalamic reticular nucleus (49) and lateral hypothalamus
(449). The firing of cortically projecting GABA neurons in the BF (481) but not VTA (700)
was correlated with gamma activity in the EEG. However, VTA GABA neurons increased
their firing prior to intracranial self-stimulation of the medial forebrain bundle, indicating
that they may be involved in the attentive processes related to brain reward (1205). VTA
GABA neurons are excited by the wake-promoting orexins (660) and by histamine (659).
Ibotenic acid lesions of the rostral BF (MS/vDB), which preferentially affect noncholinergic
neurons, abolish theta and gamma rhythms in the hippocampus (see sect. IIA). Similarly,
chemical lesions of the caudal BF have dramatic effects on cortical LVFA and attention that
are correlated with the loss of PV-positive GABA neurons (166, 397, 611).
B) Striatal Medium Spiny Neurons: GABAergic medium spiny neurons in the striatum
receive a massive glutamatergic cortical input and control the activity of thalamocortical
neurons. Transitions from NREM sleep to wakefulness convert the firing of striatal neurons
from fast cyclic firing, synchronized with cortical field potentials, to an irregular pattern of
action potentials triggered by disorganized depolarizing synaptic events of variable
amplitude (777). Cell body specific lesions of the rostral striatum reduce waking by ~15%
and produce cortical slowing of the EEG (1029). Conversely, lesions of the globus pallidus,
the main recipient of inhibitory striatal projections, increase waking by 46%. Improved
function in minimally conscious patients produced by stimulation of the nonspecific
thalamic nuclei (1136) may be mediated by increased cortico-striatal-thalamic interplay
(1135).

9. Glutamate—The vast majority (>90%) of glutamatergic projections to the cortex arise

from the thalamic relay nuclei innervating cortical layers III and IV, and from nonspecific
thalamic nuclei innervating layers I and VI (540, 750). In addition, the BF (500), claustrum,
amygdala, VTA, laterodorsal tegmentum, and hypothalamus (540) provide minor

glutamatergic projections to the cortex. Vesicular glutamate transporters are expressed in
cortically projecting orexin neurons in the perifornical hypothalamus (1077) and
serotonergic DRN neurons (439), suggesting that glutamate is a cotransmitter in these
neurons. Furthermore, glutamate is the major neurotransmitter released from rostral
midbrain brain stem reticular formation neurons projecting to the thalamus. Dissociative
anesthetic agents such as ketamine inhibit glutamatergic NMDA receptors, whereas
pharmacological agents that prolong the decay of AMPA receptor currents (AMPAkines)
are proposed to enhance attention and cognition.
A) Thalamic Intralaminar and Relay Neurons: The thalamus is an important component

of the dorsal branch of the ARAS involving the nonspecific thalamic nuclei (FIGURE 5), as
well as the specific relay nuclei which convey external sensory information to the cortex.
EEG rhythms typical of wakefulness are sculpted through interactions between the
thalamocortical relay neurons, corticothalamic pyramidal neurons, and GABAergic neurons
in the thalamic reticular nucleus. At the onset of conscious states (i.e., wakefulness and
REM sleep), thalamic relay neurons are excited by the action of acetylcholine,
norepinephrine, and histamine, leading to a switch in firing pattern from synchronized burst
firing (typical of NREM sleep) to tonic firing able to faithfully transmit sensory information
to the cortex (826, 828, 1228). This switch in firing pattern is due to a depolarization
mediated by a block of leak potassium conductance by Gq-coupled receptors (muscarinic
M1/3, norepinephrine α1, histamine H1) and a block of the pacemaker current Ih by Gs/
adenylyl cyclase-coupled receptors (muscarinic M2/M4, norepinephrine β, serotonin 5-
HT4,6, histamine H2). In a thalamocortical slice preparation, coincident stimulation of
nonspecific thalamic nuclei (centrolateral intralaminar nucleus) or direct stimulation of layer
I together with relay nucleus stimulation induced supralinear summation of the two inputs in
cortical output layer V, providing a possible mechanism by which the nonspecific nuclei
promote arousal (741).
10. Effector systems of neurotransmitters promoting wakefulness—The effector

systems used by the neurotransmitter systems involved in generation of wakefulness have
been studied by in vitro electrophysiology, pharmacology, and genetic methods (see sect.
VI). The majority of the receptors implicated in cortical LVFA and wakefulness are either
ionotropic (glutamatergic AMPA, kainate and NMDA receptors, GABAA receptors,
nicotinic acetylcholine and serotonin 5-HT3 receptors) or metabotropic receptors coupled to
Gq G proteins and the beta form of the enzyme phospholipase C (glutamatergic mGluR1 and
mGluR5, cholinergic muscarinic M1, M3, M5, norepinephrine α1, histamine H1, serotonin 5-
HT2, orexin type I and type II receptors). Phospholipase C (PLC)-β occurs in four isoforms.
Mice lacking the β1 or β4 subunits of PLC have disrupted theta rhythms and other EEG
abnormalities (595, 1166). Activation of these metabotropic receptors causes a
depolarization in target neurons mediated by one or a combination of three mechanisms: 1)
blockade of leak potassium conductances (two-pore potassium channels) (1348); similar to
deletion of PLC-β isoforms, mice lacking the TASK3 two-pore potassium channel have
deficient theta oscillations and altered sleep behavior (965); 2) activation of mixed cation
channels [likely of the transient receptor potential (TRP) family] (1151); and 3) activation of
electrogenic sodium-calcium exchangers (343, 1434). In addition, effects on other intrinsic
membrane currents contribute to the activation of thalamocortical and limbic neurons (828,
918). For the most part, the role of individual subunits of these channels/transporters in the
control of sleep-wake behavior remains to be determined.

D. Synthesis
Studies involving stimulation of the brain areas and neurotransmitter systems comprising the
ARAS consistently report EEG activation and wakefulness as a result. These studies include
both older techniques of electrical stimulation or infusion of pharmacological agents as well

as state-of-the-art optogenetic techniques where light-activated ion channels are introduced
into the desired neuronal population by genetic engineering techniques (6, 1473). In contrast
to the stimulation experiments, studies where localized inactivation of individual
neurotransmitter systems or nuclei of the ARAS have been performed (summarized in
TABLE 1) generally produce relatively minor changes in cortical EEG or the amount of
wakefulness in a 24-h period (see sect. IIC), with the possible exception of the parabrachial
nucleus (see sect. IIB). There are several possible explanations for this dichotomy between
stimulation and inactivation experiments. First, the ARAS systems are strongly
interconnected, mutually excitatory to each other (FIGURE 6) and converge onto common
effector systems at the level of thalamic and cortical neurons (826, 918). Thus there is
considerable redundancy in the system, and inactivation of any individual component of the
system is compensated for by the other systems. This is perhaps not surprising considering
the enormous adaptive advantage of wakefulness! A second possibility for the mild effects
of loss-of-function experiments is that the systems so far targeted are not absolutely required
for wakefulness. The majority of studies have focused on neuromodulatory systems,
whereas selective inactivation of glutamatergic and GABAergic systems projecting to the
neocortex have not been tested due to technical difficulties in targeting these systems. The
neuromodulatory systems are clearly able to generate cortical activation when stimulated but
may only be required for specific aspects of wakefulness. Specific roles for these systems
could be 1) facilitation of LVFA (acetylcholine); 2) inhibition of sleep-active neurons
(norepinephrine, serotonin, acetylcholine; see sect. III); 3) maintenance of high muscle tone
(norepinephrine) during waking (see sect. IVA); 4) consolidation of wake periods (orexins);
5) maintenance of waking in a novel environment (histamine); 6) enhanced arousal in the
presence of rewarding stimuli (dopamine, acetylcholine); 7) enhanced arousal in the
presence of aversive stimuli (norepinephrine, serotonin, histamine); and 8) consolidation of
memories through enhancement of synaptic plasticity (acetylcholine, norepinephrine,
serotonin, histamine, dopamine, orexins). Methods to selectively stimulate these systems
(e.g., using optogenetic techniques) together with whole brain imaging will be helpful in
further delineating their function.
III. NREM SLEEP

Subjectively experienced as a loss of conscious awareness, the onset of sleep is heralded in
the EEG by the replacement of LVFA by large-amplitude, slow (<4 Hz) waves and the
appearance of thalamocortical spindles (FIGURE 1). These EEG changes are due to the
progressive reduction in firing of neurons in the ARAS. This section describes the
mechanisms underlying the EEG signs of NREM sleep (also called slow-wave sleep) and
the mechanisms that cause the circadian and homeostatic inhibition of wake-promoting
ARAS neurons.
A. Electrographic Signs of NREM Sleep

In humans, the different stages of NREM sleep are classified according to the criteria
established by Rechtschaffen and Kales (1053) (FIGURE 1). Stage 1 NREM sleep exhibits
theta activity at frontal sites and alpha activity posteriorally, similar to drowsy waking (sect.
II). Stage 2 NREM sleep is characterized by the appearance of sleep spindles (7–15 Hz) and
K-complexes in the EEG. Stages 3 and 4 of NREM sleep (deep sleep) exhibit prominent,
high-amplitude slow, delta waves (1–4 Hz). The cortical slow oscillation (0.5–1 Hz)
discovered by Steriade and colleagues synchronizes the activity of cortical and thalamic

neurons that generate spindle and delta waves throughout NREM sleep (1217). In animals,
NREM sleep is not usually subdivided into these four stages, but deep (delta) sleep may be
distinguished from light NREM sleep. NREM sleep is also characterized by low skeletal
muscle tone and slow, rolling eye movements. Here we first describe phasic events
occurring during NREM sleep in the thalamocortical system (spindles) and hippocampal
formation (sharp wave-ripple complexes) and then discuss the delta and slow oscillations
typical of deep NREM sleep.
1. Thalamocortical spindles—Spindles and K-complexes are the defining features of

stage 2 NREM sleep in humans (FIGURE 1). K-complexes represent a combination of one
cycle of the neocortical slow oscillation followed by a spindle in thalamocortical neurons
(27, 28, 197). Several lines of evidence support the contention that spindles are generated in
the thalamic GABAergic reticular and perigeniculate nuclei (394, 1228): 1) spindles occur
even in the absence of the cerebral cortex (1215); 2) large thalamic lesions (177, 397, 1370)
or specific lesions/deafferentation of the thalamic reticular nucleus abolish spindles in
thalamocortical neurons (1223); 3) spindle activity can be recorded in the deafferented
reticular nucleus (1224); 4) spindles are absent in the anterior part of the thalamus, which
does not receive afferents from the thalamic reticular nucleus (i.e., the anterodorsal,
anteromedial, and anteroventral nuclei; Ref. 975), and in their projection areas (cingulate
cortex, habenular nucleus). Although the thalamic reticular nucleus is the generator of
spindles, in intact animals spindles are initiated and terminated in concert with delta and
slow oscillations in corticothalamic and thalamocortical neurons due to the extensive

interconnections of these cells (828).
A) Cellular Mechanisms Underlying Spindles: As aminergic inputs are slowly withdrawn

during early NREM sleep, long-lasting (50 ms) bursts of action potentials are generated in
reticular nucleus neurons due to activation of low-threshold (T-type) calcium channels.
These channels are of the Cav3.2 and CaV3.3 subtype (1269), which allow bursting at the
resting membrane potential. Bursts at spindle frequencies lead to large and long-lasting
inhibitory synaptic potentials (IPSPs) in thalamocortical neurons which remove the
inactivation of T-type (Cav3.1) (1269) calcium channels. Thus, at the offset of the IPSPs,
when the cell becomes more depolarized, the low-threshold calcium channels are activated,
calcium enters the cell, resulting in a low-threshold calcium spike crowned by a short (5–15
ms) burst of sodium-dependent action potentials in the thalamocortical neurons. This burst
in thalamocortical neurons leads to EPSPs in cortical neurons and to action potentials which
together make up the spindle recorded in the EEG. Synchronization of spindles is achieved
via recurrent inhibitory and electrical synaptic connections between thalamic reticular
neurons (828). Spindles can also be recorded in cortical projection sites such as the basal
ganglia (298), possibly providing a substrate for procedural learning during sleep. Spindles
decline during deep sleep due to the increased hyperpolarization of thalamocortical relay
neurons but may reappear just prior to the transition to REM sleep when thalamocortical
relay neurons become more depolarized again (due to increased ascending brain stem
excitation).
B) Inhibition of Spindles During Wakefulness and Rem: In vivo, extracellular and

intracellular recording studies revealed that thalamic reticular neurons fire tonically during
waking and switch to burst firing during NREM sleep, similar to thalamocortical relay
neurons (802, 1222). Tonic firing and inhibition of bursts/spindles during waking is likely
due to excitation of these thalamic reticular neurons by norepinephrine and serotonin (833)
released from ascending projections arising in the LC and DRN. Norepinephrine, acting via
α1 receptors and serotonin, acting via 5-HT2 receptors, causes a depolarization by block of a
leak potassium conductance leading to an inactivation of low-threshold calcium channels

responsible for bursting (833). Spindles can also be inhibited by input from other ARAS
systems, in particular brain stem cholinergic (974) and BF cholinergic and GABAergic
inputs (49, 976). The mechanism underlying inhibition of spindle activity during REM sleep
is less clear but has been proposed to be due to input from REM-on cholinergic neurons
which hyperpolarize thalamic reticular neurons via a muscarinic M2 receptor mediated
inhibition of leak potassium conductance (192, 831).
2. Hippocampal sharp waves and high-frequency ripples—High-frequency (100–

400 Hz) field potentials termed sharp wave-ripple complexes can be recorded in the
hippocampus and associated areas during quiet wakefulness and NREM sleep in rodents
(174, 180, 181) and in humans (132). Sharp-waves occur in the CA3 region of the
hippocampus when the highly interconnected CA3 pyramidal network is released from the
control exerted by subcortical inputs, especially the MS/vDB. Sharp-wave like epilepti-form
waves occur in the hippocampus following transection of the fimbria-fornix, the main fiber
bundle carrying ascending fibers from the MS/vDB and other ARAS systems (182). Ripple
occurrence is also increased by pharmacological blockade of histamine H1 receptors, which
mediate histaminergic excitation of MS/vDB neurons (647, 1012) or blockade of serotonin
5-HT3 receptors (1012), which excite inhibitory hippocampal/dentate interneurons. When
released from inhibition, the synchronized firing of CA3 pyramidal neurons leads to a
concerted activation of Schaffer-collateral synapses in the CA1 region and subsequently of
subicular and downstream retrohippocampal cortical structures (227). Feed-forward and
feedback activation of hippocampal GABAergic interneurons leads to a high-frequency

oscillation in the membrane potential of pyramidal neurons due to IPSPs, reflected as a high-
frequency ripple in the extracellular potential (1462). Phase-locked interneurons fire at high
frequencies on every cycle of the extracellularly recorded oscillation and entrain the firing of
pyramidal neurons, which fire at lower frequencies (643, 1462). Accordingly, ripple
frequency is reduced by pharmacological prolongation of GABAA receptor-mediated
currents (1013). Surprisingly, ripple amplitude and entrainment of pyramidal neurons were
increased in mice lacking the GluR1 subunit of AMPA-type glutamatergic receptors
specifically on PV-positive interneurons, possibly as a result of developmental
compensation (1035). Although many pyramidal neurons contribute to each sharp wave/
ripple, each wave of a ripple reflects the firing of a discrete subpopulation of these neurons
(228, 1462). Modeling studies suggest that electrical coupling between the axons of
pyramidal neurons is required to synchronize their activity (1306). In support of this idea,
the occurrence of ripples in vitro was reduced in mice lacking one type of gap junction
protein (connexin 36), and the intraripple frequency was reduced (781). However, in another
report, the occurrence of in vitro kainate-induced sharp waves was actually increased in
these mice (957).
3. Delta (1–4 Hz) and slow (<1 Hz) oscillations—Delta and slow oscillations in the
cortex and thalamus are typical of the deeper stages of NREM sleep (FIGURE 1). They
result from increased withdrawal of excitatory neuromodulatory inputs (primarily
cholinergic and aminergic), resulting in a more hyperpolarized membrane potential of the
pyramidal/thalamic relay neurons. Delta oscillations are best understood at the thalamic
level. Recordings in vivo from thalamocortical neurons revealed that stereotyped high-
frequency bursts of action potentials occur at delta frequencies interspersed with silent
periods (25, 314, 817, 932, 1225), a pattern which can be abolished by brain stem
cholinergic stimulation or by increases in ambient light (25, 932, 1225). The ability of
thalamocortical neurons to generate burst firing in the delta frequency range is due to their
intrinsic membrane properties (556, 557, 711, 830, 1199). Hyperpolarization resulting from
the activation of calcium-dependent potassium conductances after a burst of action
potentials or from inhibitory synaptic inputs leads to the opening of hyperpolarization-

activated, cAMP-modulated cation (HCN) channels causing the so-called H-current (Ih).
This slowly activating current provides a depolarizing drive towards the threshold for action
potentials and is a major contributor to the duration of the interburst interval (830, 968). Ih is
modulated during waking by activation of neurotransmitter receptors coupled to stimulation

of cAMP (e.g., norepinephrine β, histamine H2) and by release of NO from cholinergic
projections (967, 968) resulting in a shift in the activation curve to more positive membrane
potentials and reducing the ability of the cells to generate intrinsic oscillations (828, 829).
As well as activating Ih, hyperpolarizations result in deinactivation of low-threshold calcium
channels, allowing their subsequent activation once the membrane potential reaches less
negative potentials (828). Opening of these calcium channels leads to a low-threshold spike
(LTS) and a burst of action potentials (556–558). Bursts of action potentials in
thalamocortical neurons lead to a prominent burst in large numbers of cortical pyramidal
neurons. Bursting of corticothalamic neurons potentiates intrinsic rhythms in
thalamocortical neurons and entrains their firing through excitation of thalamic reticular
neurons leading to rhythmic hyperpolarizations in thalamocortical neurons, creating
increased network synchronization (25, 1225). Calcium influx through the low-threshold
channels allows activation of calcium-dependent potassium conductances, restarting the
cycle. Ascending influences during waking or REM sleep block this cycle by acting on
PLC-coupled receptors that block a leak potassium conductance causing inactivation of the
low-threshold calcium channels and bringing the membrane potential out of the range of the
H-current (826, 828).
A) Role of Low-Threshold Calcium Channels in Delta Waves: Low-threshold bursts in

thalamocortical neurons were abolished in mice constitutively lacking the Cav3.1 calcium-
channel gene (695) or in mice with a targeted deletion of Cav3.1 in rostral-midline thalamus
(32). Delta waves were abolished in these mice with knockouts in the whole brain or
thalamus, whereas deletions of Cav3.1 channels in cortical neurons did not affect delta
waves (32). Loss of delta waves was associated with fragmented sleep with a higher
incidence of brief arousals. Similar to thalamocortical neurons, bursting in thalamic reticular
neurons is regulated by calcium dynamics involving low-threshold calcium channels,
endoplasmic reticulum calcium ATPases which sequester intracellular calcium, and small-
conductance calcium-dependent potassium (SK) channels (266). Like Cav3.1 knockouts,
mice lacking the SK2 channels responsible for slow after hyperpolarizations in thalamic
reticular nucleus neurons had disrupted sleep and a threefold reduction of low-frequency
rhythms during NREM sleep (266).
B) The Neocortical Slow Oscillation (0.5–1 HZ): This phenomenon, discovered by

Steriade in anesthetized cats (1230), was subsequently observed in naturally sleeping
animals (28, 1237, 1289) and in humans (27, 272). Somewhat confusingly, despite its name,
the so-called slow oscillation does not necessarily imply rhythmicity. High-density EEG
recordings in humans revealed that each cycle of the slow oscillation represents a traveling
wave originating most frequently in prefrontal-orbitofrontal regions and propagating
towards more posterior cortical areas (809). The slow oscillation occurs throughout all
NREM sleep stages and serves to bind together the other EEG phenomena of NREM sleep
such as spindles and delta waves (1217, 1228, 1229). Slow-wave activity (SWA; 0.5–4 Hz),
a combination of EEG power in the frequency bands reflecting the slow oscillation and delta
oscillations, is widely considered to be a measure of sleep need and/or intensity (3, 1292).
Periods of sleep deprivation cause increases of SWA in the subsequent sleep period in both
animals and in humans. SWA is highest at the beginning of the sleep period and
progressively decreases during sleep. Naps during the day also reduce SWA in the
subsequent night (1292). The hypothesized relationship between SWA and synaptic strength
is discussed in section IIID. The slow oscillation is generated within the cortex since it is

abolished in thalamic neurons following removal of the cortex (1290), and it persists
following disconnection of subcortical inputs (1231) and can occur in vitro in cortical slices,
following manipulation of the ionic milieu bathing the slices (269, 1110). However, in intact
animals, the slow oscillation strongly influences the activity of the thalamus through
corticothalamic projections and conversely the thalamus influences the cortex through
thalamocortical projections (264, 535, 1229, 1231).
C) Cellular Mechanism Causing up and Down States: Intracellular recordings from

cortical neurons in vivo (259, 1374) and in vitro (1110) revealed that the slow oscillation
consists of prolonged depolarizations associated with extracellular gamma frequency
activity (UP states) separated by prolonged hyperpolarizations (DOWN states) when most
cortical neurons are silent (255, 256). These states are well-synchronized over widespread
areas of cortex (1374). The UP states are due to a barrage of excitatory synaptic inputs
mediated by glutamatergic AMPA/kainate and NMDA receptors and activation of a
persistent sodium current and usually begin in deeper cortical layers, possibly due to an
increased frequency of excitatory spontaneous synaptic potentials (211). Consistent with this
idea, the frequency and amplitude of miniature excitatory postsynaptic currents in pyramidal
neurons of frontal cortex was enhanced following waking and decreased following sleep
(737). Fast inhibitory GABAA receptor-mediated potentials also occur during the UP state
due to input from GABAergic interneurons activated by the firing of principal glutamatergic
neurons. The hyperpolarizing phase is due to withdrawal of excitatory input.
B. Generation and Maintenance of NREM Sleep

An involvement of the preoptic area (PO)/BF (FIGURE 2) in the control of sleep has been
inferred since the observations by Constantin von Economo of damage to this area in the
brains of patients with persistent insomnia following the influenza pandemic in the early
years of the 20th century (1377). Extensive lesions of the PO/BF led to long-lasting
insomnia in the cat (840, 1105), whereas warming caused increases in sleep (1068).
Whereas most brain neurons exhibit a wake-On, a wake/REM-on or state-indifferent firing
patterns across the sleep-wake cycle, the PO/BF is unusual in that it contains a large number
of neurons utilizing the neurotransmitter GABA which have sleep-on, wake-off firing
patterns. Many of the sleep-active neurons in the medial and lateral preoptic area are also
temperature sensitive, likely explaining the coupling of body temperature and sleep (16). In
the BF, caudally projecting, possibly sleep-active, GABA neurons (449) are intermingled
with cortically projecting cholinergic, GABAergic, and glutamatergic neurons (451) which
increase firing in association with cortical activation (481).
1. Ventrolateral preoptic nucleus—With the use of Fos immunohistochemistry to

identify neurons that had been recently active, a cluster of sleep-active neurons was
identified in the ventrolateral preoptic nucleus (VLPO) (FIGURE 2) of the rat (1162). These
neurons contained the inhibitory neurotransmitters GABA and galanin and projected heavily
to nuclei of the ARAS, especially the histaminergic tuberomammillary nucleus (406, 1161,
1162, 1210). Single-unit recordings targeting this area confirmed that it contains sleep-active
neurons (1254). Extensive neurotoxic lesions of the central cluster of the VLPO in the rat
led to a large decrease in delta power and NREM sleep time and a fragmentation of the
sleep-wake cycle (756), effects which persisted for at least 3 wk postlesion. Furthermore, the
number of remaining Fos-immunoreactive neurons was linearly related to NREM sleep time
and EEG delta power.
In vitro recordings in the rat determined that many VLPO neurons are multipolar, triangular-
shaped neurons, which exhibit a LTS. All of these were inhibited by norepinephrine and
acetylcholine, and the majority were also inhibited by serotonin (5-HT1A) (403). Activation

of non-α7 containing nicotinic receptors enhances the release of norepinephrine onto VLPO
neurons, indicating a synergistic inhibitory action of acetylcholine and norepinephrine
(1091). Other VLPO neurons, possibly local interneurons, had a fusiform/ bipolar shape,
lacked an LTS, and were excited by serotonin and an adenosine A2a receptor agonist (403,
404). Initial experiments suggested that histamine and orexin did not affect the firing rate of
VLPO neurons, but more recent experiments have revealed an indirect histaminergic
inhibition due to excitation of local inhibitory interneurons (736). Retrograde tracing
revealed surprisingly few cholinergic projections to VLPO but prominent projections from
the histaminergic tuberomammillary nucleus, norepinephrine neurons in the LC and
ventrolateral medulla, and serotonergic neurons in the dorsal median and central linear raphe
nuclei (222). However, somatodendritic release of acetylcholine from nearby cholinergic
neurons in the HDB and MCPO is a possibility. Interestingly, VLPO neurons also receive
direct inputs from the retina (759) and indirect projections from the suprachiasmatic nucleus
via the dorsomedial hypothalamus (222, 306, 1250), one pathway by which light exposure
could affect sleep. In vitro studies also revealed that VLPO neurons are excited by adenosine
through an indirect mechanism: A1 receptor-mediated presynaptic inhibition of inhibitory
synaptic inputs (203, 888). In addition, activation of adenosine A2a receptors by infusion of
an A2a agonist in the subarachnoid space underlying the VLPO area increases the activity of
VLPO neurons in vivo (1128).
2. Median preoptic area—Single-unit recordings and Fos studies have defined another
preoptic nucleus containing a large population of GABAergic sleep-active neurons, the

median preoptic nucleus (MnPO), located just dorsal to the third ventricle (FIGURE 2) (432,
1094, 1252). Like VLPO neurons, MnPO neurons project to and inhibit wake-promoting
neurons of the ARAS in the perifornical lateral hypothalamus, DRN, and LC (1251, 1321).
Inactivation of the MnPO by infusion of the GABAA receptor agonist muscimol led to a
prolonged waking state in rats (1251). On the other hand, high-frequency electrical
stimulation or perfusion with glutamate or the GABAA receptor antagonist bicuculline
enhanced NREM sleep and inhibited the activity of wake-active neurons in the perifornical
hypothalamus (1251). MnPO neurons recorded in vitro were dose-dependently inhibited by
norepinephrine via α2 receptor-mediated activation of inwardly rectifying potassium
channels (63), possibly explaining their silence during waking. Experiments comparing the
extent of Fos during spontaneous sleep, sleep deprivation, and recovery from sleep
deprivation suggest that MnPO neurons are active during sleep deprivation, whereas VLPO
neurons are mainly active during sleep (462, 871, 994). Thus MnPO neurons increase their
activity in response to increased homeostatic sleep pressure, whereas VLPO neurons may
function to consolidate and maintain sleep and regulate sleep depth (462).
3. Wake-NREM transitions and the flip-flop model—Von Economo (1378) was the
first to propose the existence of an anterior hypothalamic sleep-promoting area and a

posterior hypothalamic waking center. More recent anatomical tracing experiments revealed
that neurons in the core of the VLPO project heavily to wake-promoting histamine neurons
in the tuberomammillary nucleus (TMN) of the posterior hypothalamus and also to wake-
promoting serotonin DRN neurons and norepinephrine LC neurons in the brain stem (1161).
Around the same time, pharmacological and electrophysiological experiments showed that
GABA and galanin inhibit TMN, DR, and LC neurons (420, 421, 726, 1003, 1141), whereas
serotonin and norepinephrine inhibit most VLPO neurons (403). Similarly, histamine excites
a subpopulation of inhibitory interneurons in the VLPO via H1 and H2 receptors and thereby
causes an indirect inhibition of VLPO projection neurons (736). In addition, histamine
neurons appear to utilize GABA as a cotransmitter (677); thus TMN neurons can potentially
also inhibit VLPO neurons through release of GABA. These mutually inhibitory interactions
between VLPO neurons and TMN/DRN/LC neurons were conceptualized in the form of a

flip-flop switch (838, 1117) such that activation of VLPO leads to inactivity of TMN/ DRN/
LC neurons and promotes sleep, whereas activation of TMN/DRN/LC leads to inactivity of
VLPO neurons and promotes wakefulness (FIGURE 7). A crucial aspect of this model is
that the two halves of the switch, by strongly inhibiting each other, create a feedback loop
that is stable in only two states such that intermediate states of sleep and wakefulness are
very brief. A further component to the model was the proposal that orexins stabilize
behavioral state via their strong excitatory actions on wake-promoting neurons. Analysis of
orexin knockout mice revealed that they have many more transitions between wake, NREM,
and REM states than do wild-type mice, supporting this model (870). Although intuitively
appealing, this model has a few weaknesses. First, the model does not well represent the
changes in firing of all the neuronal subpopulations involved. While sleep-active preoptic
neurons have fast transitions around state-transitions (1266), the firing rate of wake-active
BF neurons changes more slowly (1266) and thus more closely resembles a latch than a
switch. Furthermore, recordings of histamine neurons showed that they begin firing after the
onset of EEG activation during NREM→Wake transitions (1264), which would seem
inconsistent with them being involved in causing the state change. Second, the mechanism
responsible for turning the switch on and off is unclear since a switch remains in one state
unless a third mechanism causes a transition. Possible candidates for facilitators of the
wake-sleep transition are sleep homeostatic factors that slowly build up during wakefulness
and are discussed in the following section.
C. NREM Sleep Homeostasis

Homeostatic control of sleep refers to the increased propensity for sleep during prolonged
waking and the prolonged sleep time and depth of sleep (reflected as increased EEG slow
wave activity) following a period of sleep deprivation (123, 311). Sleep homeostasis is
considered to reflect the accumulation of sleep homeostatic factors during waking,
particularly in the BF and cortex, in a manner related to brain energy usage (see sect. IIID).
Sleep homeostatic factors inhibit the activity of ARAS neurons as well as cortical neurons
and thereby facilitate the slow oscillations typical of NREM sleep.
1. Sleep factors—The search for sleep-promoting factors dates back 100 years when
Ishimori (548) and Legendre and Pieron (701) reported that injection of CSF from a sleep-
deprived dog into the cisterna magna of a normal animal induced sleep. Later in 1967,
Pappenheimer et al. (972) performed similar experiments where CSF from the cisterna
magna of goats deprived of sleep for 72 h induced sleep in cats and rats following
intraventricular application. These pioneering studies suggested that endogenous humoral
factors are induced and accumulate during waking and generate a homeostatic sleep
response. This led to a series of investigations in search of humoral sleep-promoting
substances (545), leading to the identification of several substances including 1) delta sleep
inducing peptide (438); 2) uridine (517); 3) oxidized glutathione, originally designated as
SPS-B (516); 4) muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine), originally
described as Factor S (971); and 5) prostaglandin D2 (1317). In the following years, a
variety of additional endogenous sleep-inducing substances were identified including
peptides, growth factors, and cytokines as well as neuromodulators such as adenosine and
NO. Homeostatic sleep factors should fulfill the following criteria: 1) administration of the
substance induces sleep; 2) the levels of the substance in the brain should increase with
increasing sleep propensity; and 3) the substance should act on brain regions and neurons
involved in the regulation of sleep or wakefulness. Recent studies have focused extensively
on the role of adenosine, nitric oxide, prostaglandin D2, and cytokines in sleep regulation
and the following sections will review the latest research on these factors.

A) Adenosine: The neuromodulator adenosine links energy metabolism, neuronal activity,

and sleep (79, 91, 319, 446). The hypnogenic effects of adenosine were first described in
cats by Feldberg and Sherwood (359) and later in dogs by Haulica et al. (483). Systemic and
central administrations of adenosine or adenosine A1 receptor agonists induced sleepiness

and impaired vigilance (91, 226, 320, 1022, 1037, 1038, 1373) by inhibition of wake-active
neurons. Adenosine A2A receptors are also implicated in mediating the somnogenic effects
of adenosine by excitation of sleep active neurons (485, 531, 1123). Stimulants such as
caffeine and theophylline counteract the sleep-inducing effects of adenosine by serving as
antagonists at both A1 and A2A adenosine receptors (384, 1192).
Adenosine levels correlate with time spent awake. Endogenous, extracellular adenosine
levels in the BF (102, 591, 843, 1017, 1018) and cortex (591, 1017) increase in proportion
with time spent awake (FIGURE 8). Thus adenosine induces sleep and adenosine levels
track sleep need, fulfilling the criteria for adenosine being a homeostatic sleep factor.
Measurements of extracellular adenosine levels across the sleep-wake cycle and in response
to sleep deprivation revealed that adenosine levels rise only in select regions of the brain
(1017, 1247). In particular, adenosine levels correlate with time awake in the region of the
caudal BF containing cortically projecting wake-active neurons, and in the cortex itself. In
contrast, adenosine levels did not follow this pattern in other brain areas such as the preoptic
area of the hypothalamus, ventral thalamus, DRN, or pedunculopontine tegmentum. BF
adenosine levels also rise when rats are exposed to a sleep fragmentation protocol (844),
possibly explaining excessive daytime sleepiness in sleep disorders where sleep is

fragmented (see sect. VII).
I) Mechanisms underlying adenosine increases during wakefulness. Increased levels of

extracellular adenosine during prolonged wakefulness are caused by interactions between
neuronal and glial mechanisms. Glutamatergic stimulation of the BF elevates extracellular
adenosine and increases sleep (1409). Selective activation of glutamatergic NMDA
receptors on hippocampal pyramidal (790) or on brain stem cholinergic neurons (134) also
leads to slow adenosine release and inhibition of neuronal activity. In the BF, cell-specific
lesion of cholinergic neurons attenuates the sleep deprivation-induced increase of adenosine
(102, 592), suggesting either that increases in extracellular adenosine are derived from these
neurons or that they release an essential signal for extracellular adenosine accumulation.
Such a signal may be NO (see next section). There is also strong recent evidence in support
of an astrocytic origin of adenosine via so-called “gliotransmission.” Neurotransmitter
release, especially glutamate release, triggers a rise in astrocytic calcium which triggers
gliotransmision of ATP along with other neurotransmitters such as glutamate and D-serine
(360, 979). In turn, breakdown of the extracellular ATP released by glia yields adenosine,
which depresses neuronal activity (981, 1474). Blockade of vesicular release via transgenic
expression of a dominant-negative SNARE domain specifically in astrocytes (dn-SNARE

mice) blocked the accumulation of homeostatic sleep pressure following sleep deprivation as
reflected by slow-wave activity and prevented the sleep-suppressing effects of an adenosine
A1 receptor antagonist (360, 472), suggesting that blocking gliotransmission affected sleep
by reducing the accumulation of extracellular adenosine.
II) Adenosine mediates its sleep-promoting effects through activation of both A1 and A2A
receptors. Electrophysiological, behavioral, and molecular evidence suggest that in wake-
active areas, the effects of adenosine are primarily mediated via A1 receptors. In vitro
studies have demonstrated inhibitory postsynaptic effects mediated by activation of inwardly
rectifying potassium channels on brain stem (48, 1041) and BF cholinergic neurons (45),
orexin neurons (738), and hippocampal/neocortical pyramidal neurons (417, 834). A weaker
postsynaptic inhibitory effect mediated via an A1 receptor-mediated shift of the activation
threshold of the hyperpolarization-activated current Ih is observed in thalamic relay neurons

(826) and BF noncholinergic neurons (45). Adenosine further dampens neuronal activity and
promotes sleep via presynaptic inhibitory effects on excitatory glutamatergic inputs to
cortical glutamatergic neurons (446) and wake-active cholinergic (48, 134, 897, 1332) and
orexin (1444) neurons, as well as on inhibitory GABAergic inputs to sleep-active VLPO

neurons (203, 888). Infusion of A1 receptor agonists in the BF, laterodorsal tegmentum,
lateral hypothalamus, and prefrontal cortex increases sleep, whereas infusion of A1 receptor
antagonists in the same areas increases waking (14, 1022, 1039, 1247, 1277, 1332).
Although adenosine A1 receptors have effects in multiple regions of the brain controlling
sleep-wakefulness, as mentioned above, to date adenosine levels have only been shown to
increase with prolonged wakefulness in the BF and neocortex. Consistent with the BF being
a crucial site mediating adenosine effects, local perfusion of an A1 receptor antagonist in this
region activated wake-active neurons (17, 1276), and localized suppression of A1 receptor
expression using antisense oligonucleotides significantly reduced spontaneous sleep time as
well as the homeostatic sleep response (1282). In contrast, adenosine A1 receptor blockade
in the lateral hypothalamus did not block the homeostatic sleep response (1277). While sleep
homeostasis was intact in constitutive A1 receptor knockout mice (1214), conditional
deletion of A1 receptor in forebrain and brain stem after 6–8 wk of age, circumventing
developmental compensation, not only resulted in a decreased homeostatic sleep response
after sleep restriction but also led to a failure in working memory consolidation (sect. V)
(99).
Prolonged sleep deprivation upregulates A1 receptor mRNA and protein in BF and cortex in
both rats and humans (74, 76, 340, 341). Upregulation of adenosine receptors provides an
additional level of homeostatic control beyond rises in extracellular adenosine levels. The
intracellular signaling pathway leading to this positive feedback regulation was revealed in
experiments in rat BF (79) (FIGURE 8). The A1 adenosine receptor, coupled to the
inhibitory Gi-3 G protein, is capable of “dual signaling,” i.e., inhibition of adenylyl cyclase
and stimulation of PLC (422). Increased stimulation of the A1 receptor during sleep
deprivation activates the PLC pathway, mobilizing intracellular calcium which in turn
activates the transcription factor NF-kB and upregulates A1 receptor expression (73, 74).
What is the involvement of the adenosine A2A receptor in the homeostatic sleep response of
adenosine? A2A receptors are coupled to the stimulatory Gs subunit and activate adenylyl
cyclase. In contrast to the A1 receptor with its wide distribution in brain, the distribution of
A2A receptor is more restricted to basal ganglia structures such as striatum, nucleus
accumbens, and olfactory tubercle with much lower abundance in other areas such as the
hippocampus, neocortex, BF, and other sleep-wake regulatory structures (1076). In rats,
selective A2A receptor agonists such as CGS21680 administered to the subarachnoid space
adjacent to BF and ventrolateral preoptic area (VLPO) induce NREM sleep (485, 1123,
1124, 1320). The local application of the A2A receptor selective agonist CGS21680
increases Fos expression in the VLPO (1128). Consistent with this are the observations that
adenosine excites one subpopulation of sleep-promoting VLPO neurons via A2A receptors
(404), and administration of CGS21680 into the lateral preoptic area close to the VLPO
induces sleep (850). In A2A receptor knockout mice, the homeostatic sleep response
following sleep deprivation (1320) and the wake-promoting effects of caffeine were blocked
(529), although given the strong expression of this receptor in the basal ganglia, effects on
motivation or motor behavior may confound these results. Accordingly, the locomotor
stimulatory effects of caffeine mediated via A2A receptor blockade were shown to require
the presence of A2A receptors in the nucleus accumbens (694).
The importance of adenosine as a sleep factor is supported by studies of enzymes involved

in adenosine metabolism. Adenosine deaminase is involved in clearance of adenosine from
the extracellular space. Blocking its activity using coformycin increased extracellular

adenosine and sleep (949). The enzyme adenosine kinase phosphorylates adenosine to
adenosine monophosphate, and blocking adenosine kinase activity with ABT-702 increased
sleep in rat (1036). These data from rats are consistent with findings in mice that a genomic
region encoding adenosine deaminase influences the rate at which NREM sleep need
accumulates during wakefulness (sect. VI) (378). In humans, a genetic variation of the
adenosine deaminase gene resulting in an amino acid substitution (asparagine for aspartic
acid) results in decreased enzyme activity and is associated with increased sleep time and
sleep intensity (687, 1059).
B) NO: NO is a small gaseous molecule with multiple roles in the control of sleep and
wakefulness (407) (see also sects. II and IV). In the brain, it is predominantly synthesized
under basal conditions by neuronal NO synthase (nNOS) and endothelial NO synthase
(eNOS) in blood vessels. nNOS is highly expressed in brain stem cholinergic neurons and
participates in their control of cortical activation and REM sleep. In this section we focus on
the role of NO in the homeostatic regulation of NREM sleep.
I) NO promotes NREM sleep. The enzymatic activity of NOS is highest in the rat brain
when animals are awake (57), and NO itself is detected in higher quantities in the cortex
during waking (167). Systemic or intracerebroventricular (icv) administration of NOS
inhibitors at light onset reduced NREM sleep within the first few hours in rats (199, 324,
325, 599, 882, 883, 1062) and in rabbits (601). Thus, although some studies (1347) provided
contradictory evidence, most evidence suggests that NO promotes NREM sleep. Recent
studies suggest that NO produced by the inducible isoform of NOS (iNOS), is responsible
for this effect. Microdialysis infusion of an iNOS selective inhibitor, during sleep
deprivation prevented NREM sleep rebound (593), while an inhibitor of nNOS decreased
REM recovery but did not affect NREM recovery (593). Consistent with these findings,
iNOS knockout mice had less NREM sleep during the dark period (218). The induction of
sleep deprivation-induced iNOS occurs in neurons within the BF (590). The iNOS
expressing neurons also express Fos during sleep deprivation, suggesting they are wake
active and the number of iNOS/Fos double-labeled neurons positively correlates with the
sleep pressure following prolonged sleep deprivation (590). Furthermore, NO itself also
rises during the early stages of sleep deprivation as assessed by the dye 4,5-
diaminofluorescein diacetate (DAF-2/DA), which fluoresces upon binding NO. Currently,
the cellular signaling pathway by which sleep deprivation leads to the induction of iNOS is
unknown.
II) How does NO produced by iNOS cause sleep in the BF?. NO has multiple cellular
effectors, but one which may be particularly important in the context of the homeostatic
sleep drive is release of adenosine (FIGURE 8). In vitro studies in culture and brain slices
have shown that NO donors cause release of adenosine, which in turn inhibits neuronal
activity (149, 352, 1075). Multiple pathways for NO-stimulated adenosine release may exist
including inhibition of adenosine kinase (1075), inhibition of glycolysis and the
mitochondrial electron-transport chain with a subsequent decrease in ATP/ADP ratio (150),
and stimulation of neurotransmitter release leading to corelease of ATP which is
subsequently degraded to adenosine (142). In vivo, NO production and adenosine increased
concurrently in the BF during sleep deprivation (589, 593). Furthermore, under nondeprived
conditions, microdialysis perfusion of an NO donor, DETA/NO, mimicked the ability of
sleep deprivation to increase adenosine and NREM sleep (589). Recent in vitro
electrophysiological evidence suggests that NO causes an initial excitation of cholinergic
and cortically projecting GABAergic BF neurons which is followed by a long-lasting
inhibition that can be reversed with an adenosine A1 receptor antagonist, suggesting
mediation by adenosine (154). Similarly, in vivo, the effects of NO donors on BF neurons
were found to be dose-dependent, with lower doses favoring excitation and higher doses

leading to more inhibition (662, 663). Similar mechanisms may also be active in the
perifornical lateral hypothalamus (661).
III) Sleep-active cortical interneurons contain nNOS. The presence of nNOS has been
recently described in a small subset of cortical interneurons which are sleep active as
determined by Fos immunohistochemistry (416, 620). In rats, mice, or hamsters, a majority
of cortical GABAergic interneurons that express nNOS also express Fos during the recovery
sleep that follows sleep deprivation. Fos expression in these sleep-active, nNOS-
immunoreactive neurons parallels changes in the intensity of slow-wave activity in the EEG,
and thus these neurons are suggested to be part of the neurobiological substrate that
underlies homeostatic sleep regulation (416, 620, 984).
C) Prostaglandin D2: Prostaglandins are lipid signaling molecules produced from

arachidonic acid through the cyclooxygenase pathway. The most abundant prostanoid in the
brain, prostaglandin D2 (PGD2), meets all the criteria of a potent sleep-factor (485, 531,
943). Infusion of PGD2 into the third ventricle or preoptic area of rats (546, 1316, 1317) or
the third ventricle of monkeys (953) increased sleep in a dose-dependent manner. Further
investigations in rats showed that the levels of PGD2 in CSF increase with increasing time
awake and propensity to sleep (963, 1043). The effects of PDG2 are mediated via the
prostaglandin receptor 1 (DP1 R) as shown by the absence of sleep-inducing effects of PGD2
infusions in DP1R knockout mice (867). Blocking the PGD2 receptor with a selective
antagonist, ONO-412, reduces sleep time (485). Lipocalin-type prostaglandin synthase (L-
PGDS) is expressed in the brain and has been associated with sleep-wake regulation (1031).
Animals that overexpress human L-PGDS show a significant increase in NREM sleep that is
positively correlated with the increases in PGD2 produced in the brain (1004). Inhibitors of
L-PGDS, such as selenium-based compounds, inhibit sleep, an effect that is reversed by
subsequent administration of PGD2 (812). In L-PGDS knockout mice, the PDG2 levels do
not increase following sleep deprivation (485).
The somnogenic effects of PGD2 are predominantly mediated via the membranes
surrounding the brain in the leptomeninges/ arachnoid space (485). The expression of both
L-PGDS and DP1R is mainly observed in the rostroventral area of the subarachnoid space
near the BF which is the most potent site for the sleep promoting effects of PGD2; in this
area, L-PGDS and DP1R expression is colocalized in arachnoid trabecular cells (95, 867)
along with the synthesizing and degradation enzymes for adenosine (949). PGD2 infusion
induces Fos expression in the sleep active neurons of the VLPO area (1126). Furthermore,
the sleep-promoting effects of PGD2 have been shown to be mediated by A2A receptors in
the VLPO. Subarachnoid administration of an A2A agonist induces Fos expression in the
VLPO and increases NREM sleep (1128). The activation of DP1R by PGD2 in the meninges
is followed by an increase in adenosine that acts on the A2A receptor in the sleep promoting
preoptic area (867). Blocking the A2A receptor with the selective antagonist KF17837 also
blocks the sleep-inducing effects of PGD2. The role of adenosine in the leptomeninges has
been demonstrated by infusion of A2A selective agonist CGS 21680, leading to increased
Fos expression in VLPO and increased sleep (518, 1128). Like adenosine, PGD2 is
implicated in the homeostatic sleep response as animals that lack L-PDGS or PGD2
receptors fail to exhibit a sleep rebound in response to sleep deprivation (484, 485) and
infusion of PGD2 mimics the effects of prolonged wakefulness in promoting sleep (1125).
Clinical data suggest that the PGD2-A2A sleep inducing system may be particularly
important in mediating enhanced sleep in pathological states. For instance, synthesis of
PGD2 was massively upregulated in the CSF of patients with African sleeping sickness
(991). L-PGDS was also upregulated in sleep apnea patients exhibiting excessive daytime
sleepiness (EDS) compared with controls or patients without EDS (70).

D) Cytokines: Cytokines are best known for their role in the immune system response to
infection which includes enhanced sleep (543). Several cytokines and their receptors are
present in the brain, and even in the absence of immune challenge, they are involved in sleep
regulation (543, 669). Among the different cytokines, the most convincing evidence for a
sleep-regulatory role is available for interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-
α). Administration of either of these cytokines increases NREM sleep in mice, rats, rabbits,
cats, and sheep (603, 669, 670, 943). In humans, IL-1 administration results in fatigue and
sleepiness (603, 669, 670, 943). Consistent with their somnogenic role, the endogenous
brain and plasma levels of IL-1 and TNF-α increase with increased propensity to sleep. For
example, in rat, the mRNA and protein expression of IL-1 and TNF-α in brain shows
diurnal variation with changes paralleling the amount of NREM sleep (135, 368, 1262). In
cat cerebrospinal fluid, the changes in IL-1-like activity correspond to sleep-wake behavior
(762). In humans, plasma concentrations of IL-1 peak at sleep onset (874). The mRNA
levels of these cytokines increase during sleep deprivation (1262).
The somnogenic effects of IL-1 and TNF-α are mediated through the IL-1 type 1 receptor
and the TNF 55-kDa receptor. Mice lacking these receptors showed reduced sleep and failed
to respond to IL-1 and TNF-α (353, 354). Antagonists against IL-1 and TNF-α receptors
reduce sleep (954, 1267, 1368). Reduction of sleep in IL-1 receptor knockout mice was
predominantly observed during the dark period, whereas TNF receptor knockout mice
showed decreased sleep during the transition from the dark to the light period, suggesting
involvement in the circadian component of sleep regulation. Accordingly, TNF-α has been
shown to inhibit the expression of clock genes by interfering with the interaction of
CLOCK-BMAL1 with the E-box regulatory element (198).
I) Mechanisms underlying cytokine-induced sleep. It has been suggested that the release of
extracellular ATP associated with neurotransmitter release during waking promotes
astrocytic production of IL-1 and TNF-α via activation of P2 purinergic receptors (97,
1253). In addition to effects on cortical synapses (see next section), cytokines may act to
induce sleep by affecting monoaminergic neurons that express the IL-1 receptor.
Administration of IL-1 into the DRN or LC (293) induces sleep (409, 788), and blocking the
5-HT2 receptor attenuates the sleep-inducing effects of IL-1 (542).
2. Local regulation of sleep homeostasis—Sleep is normally a global, coordinated

phenomenon affecting the whole organism and nervous system. However, recent evidence
suggests that slow waves and spindles can be induced or modulated locally in cortical areas
(532, 671, 921, 1383). The most striking example of local sleep is the unihemispheric sleep
exhibited by cetaceans (766). In rodents, multiunit recordings showed that groups of cortical
neurons display coordinated off-states, associated with local slow waves as the duration of
wakefulness increases, even while the scalp EEG shows a LVFA pattern typical of
wakefulness (1383). Dissociation of different sleep/wake phenomena is also a feature of
several sleep disorders (778). A number of cortically produced neuromodulators could be
involved in local modulation of sleep intensity. These include 1) adenosine and NO
(discussed above); 2) TNF-α, which is a regulator of sleep and sleep intensity and also
regulates synaptic homeostasis (1213); 3) brain-derived neurotrophic factor (BDNF), which
is involved in the establishment of neuronal circuitry during development and promotes
synaptic plasticity in the adult. Cortical infusion of BDNF locally enhances NREM slow-
wave activity, whereas infusion of a BDNF antibody or an inhibitor of trkB receptors causes
the reverse effect (355). 4) Cortistatin is a recently discovered peptide neuromodulator
structurally related to somatostatin which is expressed in cortical and hippocampal
interneurons and hyperpolarizes hippocampal pyramidal neurons (289). Intraventricular
administration of cortistatin increased cortical slow waves (127, 289). Furthermore, the
cortistatin transcript was upregulated following sleep deprivation (127, 232). 5) Growth

hormone releasing hormone (GHRH): local administration of a GHRH antagonist or siRNA

targeting GHRH to the somatosensory cortex increased EEG delta power during NREM
sleep but not during waking (718). Use-dependent alterations in the release of these
neuromodulators may account for local cortical changes in synaptic weights and/or cortical
region-dependent alterations in NREM delta activity (532, 609, 865, 1381).
D. Functional Aspects of NREM Sleep

1. Brain energy metabolism—The brain constitutes only 2% of the body mass.
However, brain oxygen and glucose utilization account for ~20% of those of the whole
organism (775), consistent with the high energetic costs incurred by neural tissue, both
whilst processing information and at rest (54). Compared with wakefulness, sleep reduces
brain energy demands, as suggested by the 44% reduction in the cerebral metabolic rate
(CMR) of glucose (791) and a 25% reduction in the CMR of O2 (774) during sleep.
A) Local Changes in Atp Usage During the Sleep-Wake Cycle: Under normal
physiological conditions, use-dependent variations in the CMR of glucose and O2 maintain a
balance in brain energetics at all times to maintain a stable level of the high-energy molecule
ATP. At the molecular level, this is achieved due to tightly coupled ATP biosynthesis/ usage
and an efficient buffering of ATP energy via paired creatine kinase reactions to conserve
ATP energy in the form of phosphocreatine and its release, as needed, in the cell (1477).
However, recent studies indicate that transient changes in brain ATP levels can occur in a
brain region specific- and treatment-dependent manner. For example, altered ATP levels
have been observed in response to localized electrical stimulation, glucose deprivation, or
manipulations of Na+-K+-ATPase activity (56, 225, 764, 773). In a recent rat study, ATP
tissue levels showed a surge in the initial hours of spontaneous sleep in wake-active but not
in sleep-active brain regions of rat (323). The surge was dependent on sleep but not on time
of day, since preventing sleep by gentle handling of rats for 3 or 6 h delayed the surge in
ATP. A significant positive correlation was observed between the surge in ATP and EEG
NREM delta activity (0.5–4.5 Hz) during spontaneous sleep. Inducing sleep and delta
activity by adenosine infusion into the BF during the normally active dark period also
increased tissue levels of ATP. Taken together, these observations suggest that a surge in
ATP occurs when the neuronal activity is reduced, as occurs during sleep. The levels of the
cellular energy sensor, phosphorylated AMP-activated protein kinase (P-AMPK), show
reciprocal changes to ATP levels. Thus P-AMPK levels are lower during the sleep-induced
ATP surge than during periods of wakefulness or sleep deprivation. Together, these results
suggest that the sleep-induced surge in ATP and the decrease in P-AMPK levels set the
stage for increased anabolic processes during sleep and provide insight into the molecular
events leading to the restorative biosynthetic processes occurring during sleep (323)
(FIGURE 9).
B) Adenosine as a Regulator of Brain Energy: One of the proposed functional theories for
adenosine’s role in sleep-wake behavior suggests that adenosine, a by product of energy
metabolism, may serve as a homeostatic regulator of brain energy during sleep (91, 1130).
Extracellular adenosine concentrations rise with increased metabolism and neural activity
(1027). Wakefulness has a greater metabolic rate than NREM sleep (774, 791), and
accordingly, extracellular adenosine levels in neostriatum and hippocampus were higher
during the circadian active period and lower during the circadian inactive period in rats
(541). Differential pulse voltammetry using a glucose sensor in cortex reveal that
extracellular glucose levels are higher during NREM sleep compared with waking, an
observation consistent with the idea that energy metabolism and glucose utilization/
breakdown decrease during NREM sleep compared with waking (915). Thus changes in

adenosine levels during spontaneous sleep-wake and sleep deprivation conditions may be
direct reflections of ATP breakdown.
C) Hypothalamic Neuromodulators Linking Metabolism and the Sleep-Wake Cycle:

Several hypothalamic neurotransmitter systems link energy usage and arousal (658). The
role of the orexins was discussed in section II. Several recent studies have suggested that the
GABAergic/MCH neurons may be involved in connecting metabolism and sleep (1353).
Mice lacking MCH or the MCH 1 receptor eat less, are lean, and have a higher metabolic
rate (804, 1164). Recordings from identified MCH neurons across the sleep-wake cycle
revealed that they are silent during wake and fire occasionally during NREM sleep but
maximally during REM sleep (482). This silence during waking is likely due to direct
inhibition by norepinephrine, serotonin, and acetylcholine (1325). Intracerebroventricular
injections of MCH increased REM sleep via an increase in the number of REM episodes and
increased NREM sleep to a lesser extent (1353), while an MCH1 receptor antagonist
decreased NREM and REM sleep (12). The mechanisms connecting the energy conservation
and sleep promoting functions of this peptide remain to be established.
2. Synaptic homeostasis—Together, the slow oscillation and cortical delta waves are
termed SWA. Recent evidence suggests that sleep intensity, as measured by SWA, can be
modulated locally in the cortex in a use-dependent fashion (532, 671, 1298). What might be
the function of such a local regulation? Learning and synaptic plasticity studies, together
with the results of experiments investigating genomic and proteomic changes during sleep
(see sect. V), led Cirelli and Tononi to propose the synaptic homeostasis theory of sleep
(1298). This theory proposes the following:
1) Wakefulness is associated with net synaptic potentiation. Gene and protein studies
showed that animals killed following prolonged periods of wakefulness have upregulated
levels of genes/proteins implicated in long-term potentiation, whereas genes/proteins
implicated in long-term depression were increased following periods of sleep (241, 242). A
recent ex vivo slice study showed that the frequency and amplitude of miniature excitatory
postsynaptic currents (EPSCs) recorded from pyramidal neurons in the prefrontal cortex
were higher following a prolonged period of waking and decreased after sleep, independent
of time of day (737). Although consistent with the hypothesis, it should be noted that
changes in miniature EPSCs may not accurately reflect action potential-dependent changes
in synaptic strength. Several other theories of sleep and memory are based on the premise
that long-term potentiation is induced during sleep (53, 175, 1417), especially during the
sharp-wave/ripple complexes and spindles of NREM sleep (175, 179) or in association with
the theta rhythm during REM sleep (534) (sect. V). More direct evidence of synaptic
potentiation was found in Drosophila (172), where synapse size and number increased with
waking and decreased during sleep.
2) Synaptic potentiation is coupled with the homeostatic regulation of cortical slow-wave

activity. This idea is supported by large-scale computational models of the thalamocortical
system (350, 507). It is further bolstered by experiments in which application of
neuromodulators previously shown to enhance LTP, locally enhanced SWA in subsequent
sleep periods (see sect. IIIC above) and learning experiments showing local increases in
SWA in cortical areas following learning of a particular task (532). For instance, in an
experiment pairing transcranial magnetic stimulation of the motor cortex with median nerve
stimulation, subjects showing a potentiation of local field potentials also had a local increase
in slow-wave activity during subsequent sleep (533).
3) SWA leads to synaptic downscaling, allowing improved cognitive performance following

NREM sleep. Local neocortical field potential recordings in rats (1385) and high-density

EEG recordings in humans (1063) showed that the slope and amplitude of slow waves were
lower at the end of the sleep phase compared with those during sleep at the beginning of the
sleep phase, findings which are consistent with synaptic downscaling if, as suggested by
modeling studies, slow wave slope and amplitude reflect synaptic strength. Furthermore,
single and multiunit recordings showed that the firing rate of neocortical neurons was higher
following a period of sustained wakefulness, whereas firing rates and synchrony decreased
following a period of sustained sleep (1384). These findings are also consistent with the
increased energetic cost of wakefulness discussed in the previous section.
Although the synaptic homeostasis theory is an attractive hypothesis supported by a large

amount of evidence, several questions remain. 1) Many different forms of NMDA receptor-
dependent and NMDA receptor-independent synaptic plasticity have been described. Which
of these are involved in sleep-dependent changes? 2) Are homeostatic changes restricted to
synapses between glutamatergic neurons? So far experiments have targeted cortical regions
and not investigated other brain areas such as the striatum and cerebellum where GABA
neurons predominate and homosynaptic long-term depression of glutamatergic synapses is
the predominant form of synaptic modification associated with learning. Furthermore, how
inhibitory synapses change across the sleep-wake cycle remains unclear. Experiments in
zebrafish revealed circadian and homeostatic changes in synapses from orexin neurons (36),
suggesting that neuromodulatory synapses also change according to the sleep-wake cycle. 3)
What happens to synapses during REM sleep?
E. Synthesis
The induction of sleep is mediated by the build-up of homeostatic sleep factors such as
adenosine and NO in the BF and cortex and by increased activity of median preoptic nucleus
GABA neurons that inhibit the wake-promoting neurons of the ARAS. Circadian influences
are mediated by retinal and indirect SCN projections to GABAergic sleep-promoting
neurons in the VLPO and other regions of the preoptic area and BF. Once initiated, sleep
and the silence of cortically projecting wake-active neurons is maintained by increased
firing of VLPO and other preoptic/BF GABA neurons and subsequent postsynaptic
inhibition of ARAS neurons via activation of GABA and galanin receptors. As ascending
excitatory influences are progressively withdrawn, cortical and thalamic neurons become
increasingly hyperpolarized entering into the range of membrane potentials conducive to
rhythmic bursting due to activation of Ih and It currents and leading to the characteristic
EEG phenomena of NREM sleep. During early NREM sleep, effective cortical connectivity
(assessed by transcranial magnetic stimulation) begins to break down (808), and in deep
sleep, the activity of the brain regions comprising the default network becomes decoupled,
in particular the frontal cortex (523). Local cortical differences in delta power during NREM
sleep reflect the extent to which that cortical area was active during the prior waking period
and the duration of prior waking, possibly reflective of increased synaptic potentiation
during waking with respect to sleep. Energy usage is high during waking and during sleep
deprivation, due to increased neuronal firing, synaptic activity, and synaptic potentiation.
This increased energy usage of waking is reflected in increased release of sleep homeostatic
factors such as adenosine during waking and a surge of ATP production which occurs
during the early NREM sleep that follows waking. Synaptic activity and plasticity are major
components of brain energy usage (775), potentially tying together the proposed energetic
and synaptic plasticity functions of NREM sleep. Under normal conditions, wakefulness
transitions first into NREM sleep and then later transitions into REM sleep. The mechanisms
underlying REM sleep and the cyclic oscillation of NREM and REM sleep during the night
are described next.

IV. REM SLEEP

Dreaming, which occurs most frequently in REM sleep, has inspired and fascinated artists,
writers, and scientists for centuries. However, REM sleep was only defined as a separate
brain state relatively recently. Experiments by Aserinsky, Dement, and Kleitmann in
humans (50, 299) and Jouvet in animals (580) showed that REM sleep is defined by a
distinct constellation of tonic and phasic features of the EEG and EMG. The association of
an activated cortical EEG reminiscent of waking, together with paralysis of antigravity
muscles (FIGURE 1), led Jouvet to term this state Le sommeil paradoxal paradoxical sleep).
In young animals, where REM is the predominant sleep state (585, 1070), it is also known as
active sleep (NREM sleep is called quiet sleep in this terminology). Awakening human
subjects during REM sleep commonly led to reports of dreaming (300); thus REM sleep has
also been called dream sleep, although some dreaming also occurs in NREM sleep (509).
Since the discovery of REM sleep, research on REM sleep can be subdivided into three
main areas: 1) delineation of the neurons, circuits, and neurotransmitter effector systems
responsible for the individual signs of REM sleep; 2) control of when and for how long
REM sleep is expressed (REM sleep master control mechanisms); and 3) investigation of the
relation of REM sleep to learning and memory. In this section we focus on the first two of
these areas and the relation of REM sleep to dreaming; studies of REM sleep and learning
and memory are covered in section V.
The terminology used to describe the reticular formation regions involved in REM-sleep
control (FIGURE 2) differs between brain atlases, between species, and between different
investigators. In the cat, the REM control area was defined as a region immediately ventral
to the main cluster of noradrenergic neurons in the LC and dorsal to the gigantocellular
tegmental field (FTG). This region was termed subcoeruleus (SubC) which is the term used
in this review. A subset of this area, containing caudally projecting neurons involved in
REM muscle atonia, and with tonic firing patterns very specific to REM sleep (1093) was
termed the peri-LC alpha. Slightly lateral to this area, neurons with burst firing patterns
correlated with PGO waves were found in the parabrachial area (276, 824, 1092), which at
its most rostral extent also includes the cholinergic PPT area. In the rat and mouse brain
atlases of Paxinos and colleagues (988, 989) the REM control region is also termed SubC
(dorsal or alpha parts); however, in these species the region immediately ventral to the LC is
cell-poor and the REM-control neurons (particularly those involved in muscle atonia) appear
to be located slightly more rostrally, ventral to the cholinergic neurons of the laterodorsal
tegmental nucleus (LDT). Hence, the functionally equivalent region in the rat or mouse has
been termed the sublaterodorsal nucleus (SLD). This area corresponds to the rostral part of
the subcoeruleus area as defined by Paxinos and Watson in the rat (160). REM-on neurons
in this area are primarily glutamatergic, as indicated by vGLUT2 in situ hybridization and
Fos immunohistochemistry (248). Other nearby reticular formation areas containing

glutamatergic neurons such as the nucleus pontis oralis (PnO) and nucleus pontis caudalis
(PnC) play a role in particular aspects of REM sleep such as theta rhythm generation or
rapid eye movements.
I) Spike discharge characteristics of neurons in regions of the brain stem involved in REM
control see also sect. IVB) Intracellular recordings from medullary and pontine reticular
formation neurons in naturally sleeping cats revealed that the excitability of these neurons
was greater during REM than during NREM sleep or waking, i.e., there is a tonic
depolarization during REM (209, 549) (FIGURE 10). Phasic depolarizations associated with
action potential firing were superimposed upon this tonic depolarization (549). In contrast,
the membrane potential was more hyperpolarized during waking and NREM sleep with
phasic depolarizations occurring with motor activity during waking. When recorded in vitro,
SubC “reticular” neurons fire tonically at high rates with little adaptation when depolarized

(160), as in other reticular areas (418, 934). Identified GABAergic neurons in this area show
similar properties (156), making it difficult to distinguish GABAergic from glutamatergic
neurons solely on the basis of intrinsic membrane properties. A subset of the reticular
formation neurons fire stereotyped high-frequency bursts of action potentials due to the
presence of low-threshold calcium channels that are deinactivated by hyperpolarization
(160, 448). Cholinergic neurons also exhibit this property (whereas most aminergic brain
stem neurons do not). These neurons may be involved in phasic phenomena of REM sleep
such as PGO waves. Interestingly, many presumed REM-on neurons in the SubC exhibit
“spikelets” (small alterations in membrane potential resembling low-pass filtered action
potentials), indicating that they are likely to be electrically coupled (489) and suggesting a
possible mechanism by which their firing may be synchronized.
A. REM Sleep Signs

1. Electrographic signs of REM sleep—Ascending pathways from the brain stem
areas that control activation of the neocortex during waking and REM sleep were covered in
section II. We focus here on REM specific aspects of hippocampal theta rhythms and PGO
waves, which appear prior to the REM state and define the transitional REM period (t-REM)
in between NREM and REM sleep.
A) Theta Activity: Theta rhythmic activity is a prominent feature of the EEG during REM
sleep in rodents (FIGURE 1) and other lower mammals (1069). Early studies in rats and
Type I (4–7 Hz) was observed when the animals were under urethane or ether anesthesia and
during behavioral immobility and was abolished by systemic administration of the
muscarinic antagonist atropine sulfate (667). A higher frequency form of theta (type II theta,
7–12 Hz) was observed during waking associated with movement and was abolished by
urethane anesthesia. Theta occurring during REM sleep appears to represent a combination
of type I and type II, since atropine sulfate abolished continuous lower-frequency theta
during tonic REM periods whilst leaving intact intermittent, higher frequency hippocampal
theta during periods with muscle twitches (1069, 1166). Similarly, mice with a knockout of
phospholipase β1 (an effector for M1-type muscarinic receptors) lacked type I theta activity
and had only intermittent theta activity during REM sleep (1166). A recent genetic study
suggests that theta generation during REM is different from theta during waking. A
deficiency in short-chain fatty acid β-oxidation (affecting the enzyme short-chain
acylcoenzyme A dehydrogenase, Acads) caused a slowing (by ~1 Hz) of peak theta
frequency during REM sleep in mice but did not affect waking theta (1260).
I) Theta rhythm during REM sleep in humans. Low-frequency (4–7 Hz) theta activity has
also been observed in the human hippocampus (of epileptic patients) during sleep but, in
contrast to rodents, theta rhythm was not observed continuously but rather was limited to
short (1 s) epochs (188). The occurrence of these short theta epochs in humans was not
correlated with the occurrence of rapid eye movements. A further contrast to rodents was the
finding that theta activity was not observed in the basal temporal lobe or frontal cortex
during REM (188). Another study has demonstrated a type of rhythmic slow activity in the
hippocampus during REM sleep with a slightly lower peak frequency (1.5–3 Hz; delta),
leaving open the possibility that these EEG signals in humans are equivalent to the type I
and type II theta but that the peak frequencies for the two types are shifted to lower values
(113).
II) Brain stem generation of theta rhythm during REM sleep. The ascending pathways
controlling forebrain theta rhythm are discussed in section IIA. One recent study (758)
suggested that a region just dorsal to the LC termed precoeruleus is necessary for theta
activity during REM sleep. This region was found to provide the major glutamatergic input

to the MS/vDB and contained cells that were active during REM sleep (contained Fos
immunoreactivity). Ibotenic acid lesions of this area abolished theta rhythm during
REMsleep (758). However, this part of the study was based on a small number of animals,
and no quantification of damage to surrounding regions containing cholinergic neurons

(known to be important for control of theta rhythm) was reported. Therefore, the precise role
of the precoeruleus in theta rhythm generation during REM sleep awaits further
confirmation with more targeted lesions (i.e., lesions affecting only glutamatergic neurons).
B) Pgo Waves: Synchronized electrical field potentials in the pons, lateral geniculate
nucleus, and occipital cortex (PGO waves) occur singly at high amplitude in the period
immediately preceding the onset of REM sleep (transitional REM period; 30–90 s) and in
bursts of lower amplitude during REM sleep itself (98, 146, 274, 580, 584, 1228). They are
considered the source of dreaming episodes and visual imagery during REM sleep (1228)
since they occur simultaneously with rapid eye movements associated with gaze direction in
dream imagery (300, 825) and are prominent in visual thalamocortical circuits (144, 145,
901). PGO waves have been studied most intensively in cats, where the largest potentials
can be recorded in the LGN and occipital cortex. However, more recent studies in both
animals and humans describe a widespread activation of limbic, parahippocampal and many
thalamocortical systems during these phasic REM events (26, 274, 1395). The pontine
component of PGO waves has been recorded in rats (286, 356, 610, 1113), but the thalamic
(dLGN) component is difficult or impossible to record in rodents, likely due to the smaller
size of this region and the fact that rodents are not very visual animals. However, phasic
potentials during REM sleep can be recorded in several other forebrain areas in this species
(274). In non-human primates, PGO wavelike phasic field potentials have been recorded
from the LGN and pons of macaques (251) and the LGN of baboons (1380). In humans, two
recent studies recorded phasic field potentials during REM sleep in the pons (720) and
subthalamic nucleus (364), respectively. Furthermore, event-related fMRI showed activation
of the thalamus and occipital cortex, as well as limbic regions such as the hippocampus and
amygdala phase-locked to rapid eye movements (866, 1395). Thus phasic activations of
thalamocortical and limbicbrain regions generated by synchronized activation in the pons
appear to be typical of both animals and humans, although the pattern of forebrain activation
may vary according to the species studied.
I) The thalamocortical component of PGO waves. Thalamic PGO waves are biphasic field
potentials with an initial negative-going component (1228). Although the thalamic
component can be recorded most easily in the lateral geniculate nucleus (LGN) due to its
laminated structure (and resulting summation of extracellular field potentials), they also
occur in other thalamic nuclei such as the pulvinar, rostral intralaminar, and anterior nuclei.
In humans, PGO waves have also been observed with depth recordings from the subthalamic
nucleus (364). The cellular mechanisms underlying the thalamic component of PGO waves
were investigated by Hu, Steriade and Deschenes using intracellular recordings in urethane-
anesthetized and reserpine-treated cats (526). In these animals, each PGO wave was
accompanied by a depolarization of relay neurons lasting 200–300 ms, interrupted by a
short-lasting (50–60 ms) hyperpolarization occurring 40–80 ms after the onset of the
depolarization due to the coactivation of GABAergic geniculate interneurons. Action
potential firing may precede or follow the brief hyperpolarization. The negative-going
component of the field component correlates with the early depolarization recorded
intracellularly, whereas the subsequent positive-going component reflects the subsequent
hyperpolarization. In recordings from naturally sleeping animals, single PGO waves of high
amplitude can be recorded during the period of NREM immediately preceding REM when
thalamic relay neurons are still hyperpolarized (1233). The firing of relay cells causes the
depolarization of pyramidal neurons in the primary visual cortex (occipital cortex), the
cortical component of PGO waves.

II) PGO waves require cholinergic input to the thalamus. The following evidence suggests
that the induction of PGO waves in the thalamus is due to a strong cholinergic input from
the brain stem, acting on ionotropic nicotinic receptors (274, 277, 1228): 1) brain stem
cholinergic neurons send a massive projection to the LGN and other thalamic nuclei (291,
974, 1235). 2) Electrical stimulation of the brain stem in the region of cholinergic neurons
elicits PGO-like waves in the LGN (1100). 3) Lesions in the region of brain stem
cholinergic neurons abolish PGO waves (1394). 4) Neurons of the cholinergic LDT/PPT
area fire in bursts that are correlated with thalamic PGO waves (336, 615, 665, 1099, 1234).
These PGO burst neurons are inhibited by the cholinergic agonist carbachol, suggesting
activation of inhibitory muscarinic autoreceptors (337, 665, 1097). 5) Systemic (1081) or
iontophoretic (525) application of nicotinic antagonists into the lateral geniculate nucleus
blocks the thalamic component of PGO waves. 6) Nicotinic receptor agonists depolarize
LGN neurons (1476) and also pre-synaptically facilitate glutamatergic synaptic inputs (457).
Together these pieces of evidence strongly support the idea that bursting of cholinergic brain
stem neurons leads to a nicotinic receptor-mediated depolarization of LGN and other
thalamic neurons which underlies the negative-going component of the field potential at the
thalamic level.
III) Noncholinergic brain stem neurons generate the pontine component of PGO waves. The
initial study of the pontine component of PGO field potentials (so-called P-waves) found
that they can be recorded in a large swathe of the brain stem reticular formation, most
prominently the part of the reticular formation close to the abducens nucleus (146). More
recent studies in rats have focused on the SubC/parabrachial (PB) area (356, 610, 801)
where there are relatively few cholinergic neurons (160) and on the equivalent caudolateral
peribrachial region of the cat. This site is the most sensitive site for carbachol to enhance P-
wave frequency (1033) and a concomitant facilitation of learning and memory formation
(280, 286, 813). Conversely, neurotoxic lesions of this area abolish PGO waves (277).
Neurons in the SubC/PB area fire synchronized bursts of action potentials preceding and
phase-locked to PGO waves (274, 824, 1098, 1234). PGO-burst neurons in this region
exhibit a longer latency (50–150 ms) to thalamic PGO waves than those in the regions with
high concentration of cholinergic neurons projecting to the thalamus (10–25 ms). The
stereotyped nature of the bursts in PGO burst neurons led Steriade and colleagues (973) to
conclude that the bursts were mediated by a low-threshold calcium spike. Low-threshold
bursts are present in brain stem cholinergic neurons (596, 763, 1410) and in noncholinergic
neurons in the SubC region (160). Neurons with low-threshold calcium spikes in the SubC
are hyperpolarized by carbachol (160). The inhibition of SubC neurons by acetylcholine
during REM sleep will deinactivate their low-threshold calcium current and allow them to
fire bursts of action potentials. This would also be consistent with the block of carbachol-
induced PGO waves in the cat by a M2 receptor antagonist (283), since activation ofM2
receptors usually causes a hyperpolarizing response (332, 419). Low-threshold bursts in

brain stem cholinergic neurons are inhibited by serotonin (763), likely explaining the
inhibitory action of serotonin on PGO-wave generation (sect. IVB). Together, the data
suggest that P-waves are initiated in the SubC/PB area and trigger bursts in cholinergic
neurons projecting to the thalamus (274).
2. Muscle atonia and twitches—Atonia of skeletal muscles is one of the cardinal,

defining features of REM sleep. The dramatic consequences of a malfunction in the brain
mechanisms controlling atonia can be observed in the sleep disorders narcolepsy and REM
sleep behavior disorder (RBD) (sect. VII). In narcolepsy, atonia is activated at inappropriate
times, resulting in cataplexy (atonia triggered by emotional arousal) during waking, and
sleep paralysis at the transition from sleep to wakefulness (923). Conversely, in RBD, atonia
fails and patients act out their dreams, resulting in injury to themselves and their bed
partners (1131).

A) Inhibition of Motoneurons During Rem Sleep: Intracellular recordings by Chase and

colleagues in somatic (trigeminal) and spinal (lumbar) motoneurons of unanesthetized cats
showed that REM atonia is accompanied by a hyperpolarization caused by a barrage of
IPSPs, as well as a decrease in input resistance, making the motoneurons relatively

insensitive to excitatory inputs (210, 889, 910). The IPSPs were completely blocked by local
iontophoretic application of strychnine, an antagonist of glycine receptors but not by
antagonists of GABAA receptors (picrotoxin or bicuculline methiodide), suggesting that
glycine is the neurotransmitter involved (889, 1196). Opening of these chloride-permeable
channels is likely responsible for the observed decrease in input resistance and reduced
responsivity to synaptic inputs. Overall, the evidence that glycinergic inhibition is necessary
for REM atonia remains strong (208, 1195). Nevertheless, although Chase and colleagues
showed that local application of strychnine blocked all the effects observed during REM in
the motoneurons they recorded, they did not show that an antagonism of glycine receptors
blocks muscle atonia.
Recently, the well-accepted role of glycine in generating atonia has been challenged by
Brooks and Peever (147), although their conclusions have been disputed (208, 398, 767,
1195). Brooks and Peever monitored the activity of masseter motoneurons extracellularly
whilst using reverse microdialysis to apply pharmacological agents at the trigeminal motor
pool (which innervates the masseter muscle). Antagonism of glycine receptors with
strychnine or GABAA receptors with bicuculline increased masseter muscle tone during
waking and non-REM sleep but not during the tonic periods of REM sleep. Thus they
concluded that glycine and GABAA receptors are not involved in REM atonia (at least for
somatic motoneurons). Similar results were described by others for respiratory hypoglossal
motoneurons and associated genioglossus muscle activity (894, 895). Kubin and co-workers
showed in the carbachol model of REM sleep that coantagonism of norepinephrine,
serotonin, and GABA receptors abolished REM-sleep like depression of hypoglossal motor
neuronal activity (361). However, Horner and colleagues (894) report contrasting results
suggesting that GABAA receptors are important in control of hypoglossal muscle tone
during NREM but not during REM sleep.
I) Disfacilitation of excitatory inputs during REM. Using the same methodology described
above, Peever and colleagues (165) showed that trigeminal motoneurons receive a
glutamatergic input during waking which helps maintain muscle tone. Motoneurons also
receive excitatory input from brain stem norepinephrine and serotonin neurons during
waking which depolarize them and increase their response to excitatory input (1403, 1404).
During REM sleep, these neurons are silent so this excitatory influence is lost
(disfacilitation). Indeed, antagonism of both norepinephrine and serotonin receptors at the
hypoglossal motor nucleus abolished the REM-sleep like reduction of muscle tone induced
by pontine carbachol in anesthetized rats (362). The shut-off of norepinephrine LC neurons

(564, 1435) and reduced firing of DRN neurons (564) during REM-like cataplectic attacks
in dogs support the importance of this mechanism.
Disfacilitation and active inhibition contribute to atonia. Although glycinergic inhibition

may be the most important mechanism producing decreased firing of motoneurons during
NREM and their silence during REM sleep, a combination of mechanisms including
disfacilitation (reduced norepinephrine, serotonin, glutamate release) and active inhibition
(increased glycine, GABA) is likely to be involved. In addition to these direct effects on
motoneurons, a presynaptic inhibition of excitatory inputs could be important. In fact, in
vitro evidence for a presynaptic inhibition mediated by muscarinic M2 receptors has been
demonstrated for hypoglossal motoneurons (90). It is also worth recognizing the possibility
that mechanisms controlling atonia and muscle twitches may differ between somatic
(particularly respiratory) and spinal motoneuron pools (376, 398).

II) Muscle twitches are caused by phasic glutamatergic input. During REM, occasional
bursts of muscle activity occur (muscle twitches). These twitches, particularly in developing
animals, have been suggested to be important in the refinement of spinal cord connectivity
(996). In intracellular recordings from lumbar motoneurons, twitches are accompanied by

brief depolarizing events that can be blocked by the non-NMDA glutamate receptor
antagonist kynurenate, but not the selective NMDA receptor antagonist APV (1197).
Similarly, muscle twitches in masseter muscles were blocked by an AMPA/kainate receptor
antagonist (CNQX) into the trigeminal motoneurons pool (165). Thus twitches during REM
sleep are due to bursts of excitatory, glutamatergic AMPA/kainate receptor-mediated
synaptic potentials.
B) Brain Stem Control of Atonia and Muscle Twitches: Increased activity of neurons in
the SubC region of the pons causes muscle atonia. Lesions of several areas of the brain stem
reticular formation cause a loss of muscle atonia during REM sleep and may lead to
expression of motor behaviors during sleep (569, 893). Similarly, injections of carbachol at
a variety of dorsal and ventral brain stem sites can lead to atonia (504, 798, 1057). However,
the area most consistently implicated in atonia in both adult (119, 580, 758, 893, 1358) and
neonatal animals (606) is the SubC/SLD of the dorsolateral pons (FIGURE 11): 1) small
electrolytic lesions of the SubC abolish REM muscle atonia in the cat and in the rat, whilst
larger lesions encompassing more widespread areas of the reticular formation are required
for the expression of dreamlike (“oneiric”) behavior (606, 893, 900, 1111) typical of RBD
(sect. VII). 2) Selective inactivation of glutamatergic neurotransmission of neurons in the

SubC and neighboring LDT region in mice strongly reduced atonia and led to motor
behaviors during REM sleep (668). 3) Rats receiving infusions of the fiber-sparing
neurotoxin orexin-2-saporin into the SubC in the rat have increased limb movements during
REM sleep (100), whereas injections of antisense oligonucleotides directed against the type
II orexin receptor in the pontine reticular formation near the SubC cause cataplexy and
increased REM sleep (1278). 4) Neurons have been recorded in the SubC in the cat (1099)
and neonatal rat (606) which fire tonically at increased rates just prior to and during the
muscle atonia of REM sleep. 5) Electrical stimulation of the SubC in rats which have had
the forebrain removed (470) (i.e., decerebrate) elicits bilateral muscle atonia. 6) Application
of the cholinergic agonist carbachol to this area in the cat causes, at short latency, a
pharmacologically induced state virtually indistinguishable from REM sleep, including the
muscle atonia component (62, 863, 1340, 1450). In the rat, carbachol does not consistently
cause a REM-like state when injected into the SubC (119, 675), but a state similar to REM
can be induced by SubC application of the GABAA receptor antagonists bicuculline and
GABAzine (119, 1009).
I) Descending projections of the SubC mediate atonia. Earlier work (119, 210, 681, 684,
776, 1458) suggested that the SubC region causes glycinergic inhibition of motoneurons via
a glutamatergic activation of glycine neurons in the ventral medulla (1045) which project to
the spinal cord (515) (FIGURE 11). Indeed, glycine-containing neurons in the nucleus
reticularis gigantocellularis (NRGc)/nucleus magnocellularis (NMC) and nucleus
paramedianus reticularis (nPR) express REM-sleep related Fos immunoreactivity (890), and
electrical stimulation of the NRGc leads to IPSPs in spinal α-motoneurons (466, 1268).
Glutamatergic stimulation of the NMC or cholinergic stimulation of the nPR in decerebrate
cats is effective in eliciting muscle atonia (684). However, this pathway does not appear to
be essential for REM atonia. In fact, transection at the pontomedullary junction abolishes
inhibition of muscle tone produced by stimulation of the ventromedial medulla (1179),
suggesting that stimulation of the medulla may in fact cause atonia via ascending activation
of the SubC. Furthermore, recent experiments by Lu and colleagues found that functional
lesions of GABA and glycine containing neurons in the medulla (through genetic
inactivation of the gene for the vesicular GABA/glycine transporter, vGAT) did not abolish

muscle atonia (758, 1367). Instead, these authors proposed that REM-on glutamatergic
[vesicular glutamate transporter 2 (vGluT2) mRNA positive] neurons in the dorsal SubC
project directly to glycinergic neurons in the spinal cord (758), which, in turn, inhibit spinal
motoneurons during REM (FIGURE 11). Consistent with this interpretation, inactivation of
glycinergic/GABAergic neurotransmission from local neurons in the ventral horn in the
mouse reduced atonia (668). Inactivation of supraolivary medulla glutamatergic (VGluT2-
positive) neurons caused exaggerated muscle twitches during REM sleep (1367), suggesting
that glutamatergic projections from the medulla may participate in control of motoneuron
excitability.
3. Rapid eye movements—The observation of rapid eye movements during sleep led to
the discovery of this distinct brain state (50). Eye movements during REM sleep are
characterized by both tonic and phasic components (347, 803, 1339). The tonic component
consists of a strong downward and convergent movement of the two eyes due to a relaxation
of the lateral recti muscles and a tonic contraction of the medial muscles. The relaxation of
the lateral recti is due to a tonic inhibition and reduction of firing of the abducens
motoneurons similar to that seen in other motoneurons during this phase of sleep (347). The
phasic component consists of rapid eye movements that are either isolated or in bursts
occurring simultaneously with PGO waves (347, 803, 1339). Lesion, stimulation, and
recording experiments have identified the paramedian reticular formation regions
immediately rostral and caudal to the abducens motor nucleus as being responsible for
REMs. These fast movements are due to a burst of action potentials in abducens
motoneurons as a result of inputs from excitatory and inhibitory burst neurons that are also
responsible for saccades during alertness (1245, 1246). The mechanisms responsible for
long-lasting bursts of action potentials in these “short-lead burst neurons” remain to be
determined, but it is noteworthy they are much longer (1245, 1246) (4–24 action potentials)
than the bursts typically produced by low-threshold calcium channel activation (typically 1–
4 action potentials) seen in P-wave related neurons. The activity of burst neurons is normally
inhibited by omnipause neurons (OPNs), which are characterized by pauses in firing that
begin ~13–16 ms before saccades. These neurons are located on either side of the midline in
the caudal pons (nucleus raphe interpositus in the monkey) at the same level as the
descending fibers of the sixth nerve.
4. Other REM phenomena—Sleep-related penile erections (SRE) are a prominent

feature of REM sleep in sexually potent males and can be a useful diagnostic tool to
differentiate between psychogenic and organic erectile dysfunction (508). In healthy adult
males the erection begins near the onset of REM sleep, persists throughout the REM
episode, and then ends rapidly at the exit from REM sleep. Similarly, in females, increased
blood pressure is observed in the vagina during REM sleep (1, 1072). The development of
methods to measure erections in rats (1140) has allowed some delineation of the brain
circuits involved, although research in this area is sparse. In contrast to most other REM
sleep signs, SREs require the activation of the forebrain, in particular the lateral preoptic
area (LPOA)/ventral bed nucleus of the stria terminalis since lesions of this area abolished
SREs whilst leaving waking erections unchanged (1139). Current models (508) suggest two
output pathways from the LPOA: one from the LPOA to serotonergic paragigantocellularis
neurons in the ventral medulla, which in turn excite thoracolumbar (T11-L2) sympathetic
preganglionic neurons innervating the penis, and another via the paraventricular nucleus of
the hypothalamus which send oxytocinergic projections to parasympathetic preganglionic
neurons in the sacral (S2-S4) spinal cord. Recent evidence also suggests a role for another
forebrain site, the lateral septum, presumably acting through projections to the hypothalamic
sites described above. Electrical stimulation in dorsal and intermediate aspects of the lateral
septum was effective in triggering SRE during REM (456).

REM sleep is also associated with increased rate and variability of heart rate, breathing, and
autonomic nervous system function as well as with altered body temperature regulation.
These alterations are likely to be important in the context of cardiovascular disease, sleep
apnea, and other disorders (see sect. VII).
B. REM Sleep Master Control Mechanisms

1. Location and neurotransmitter content of REM sleep controlling neurons in
the brain stem—Seminal work by Jouvet (580) in cats revealed that a knife cut placed at
the junction of the brain stem and midbrain eliminated forebrain signs of REM sleep
(cortical LVFA, hippocampal theta) whereas muscle atonia and REMs were preserved,
suggesting that the REM sleep generating neurons are located in the brain stem. Further
work using electrolytic lesions or cell body selective neurotoxins showed that the most
important region is the dorsolateral pons (570) (TABLE 1); in particular, the region
surrounding and including the LC and laterodorsal tegmental nucleus as well as the reticular
formation immediately ventral to these areas. Large lesions of this area led to substantial
reductions in the amount of REM sleep (570), whereas smaller, more discrete lesions could
abolish particular features of REM sleep such as muscle atonia (893, 1358). The
development of histochemical techniques in the 1960s and immunohistochemical techniques
in the 1970s/80s revealed the presence of norepinephrine, serotonin, and cholinergic neurons
in the REM-sleep control area (570). The ability to visualize these neurons, together with
their large size and clustering into distinct nuclei, led to an explosion of interest in their role
in REM sleep control. Only relatively recently have improved immunohistochemical, in situ
hybridization, and transgenic techniques allowed the visualization of GABA-ergic and
glutamatergic neurons in the REM control area (118, 156, 248, 248, 372, 758, 784, 785).
Thus less is understood of these GABAergic and glutamatergic systems, although recent
studies suggest that they are likely to be of comparable importance.
2. Mechanisms controlling NREM-REM transitions—One of the most consistent

features of human sleep is the alternation between NREM and REM sleep during the night.
Early sleep is characterized by a progression from light NREM to deeper stages of NREM
sleep with the first REM episode occurring ~90 min into sleep. The 90-min cycles of NREM
and REM sleep continue through the night with the proportion of REM sleep steadily
increasing and the proportion of deep NREM declining over the course of a night’s sleep.
Lower mammals, including rats, mice, and cats, do not have such long consolidated periods
of sleep as humans; each of the behavioral states is much shorter and more transitions occur
between states. However, the general sleep architecture is similar in that, with the exception
of disease states (especially narcolepsy), sleep following a period of prolonged wakefulness
is initially NREM sleep. REM sleep follows a period of NREM and is not entered into
directly from wakefulness.
A) Reciprocal Interaction Model (Cholinergic and Aminergic Mechanisms: Based on

extracellular recordings of neuronal activity from the REM sleep zone in the dorsolateral
pons, McCarley and Hobson proposed a mechanistic explanation for the alternation of
NREM and REM during the night - the reciprocal interaction model (511, 819), involving
two populations of neurons (FIGURE 12A). REM-on neurons increased their firing just
prior to and during REM, whereas REM-off neurons showed the reverse pattern. REM-off
neurons were proposed to be norepinephrine neurons (serotonin neurons show a similar
pattern of firing), whereas REM-on reticular neurons were proposed (erroneously) o be
cholinergic neurons. Subsequently, the REM-on cholinergic neurons were localized to the
LDT and PPT regions and were proposed to direct the firing of glutamatergic effector
neurons in the reticular formation responsible for the different aspects of REM sleep (e.g.,
muscle atonia) (FIGURE 13). A mathematical model using Lotka-Volterra equations

(derived from population models of predator/prey interactions) was able to capture the basic
structure of the oscillation between NREM and REM sleep (819) (FIGURE 12A). The
essence of this model is that REM-off neurons (norepinephrine and serotonin neurons)
inhibit REM-on neurons (cholinergic neurons) during waking and NREM sleep, but as these
neurons reduce their firing during NREM, REM-on neurons are disinhibited and REM sleep
is generated. Positive feedback between REM-on neurons (cholinergic and glutamatergic
reticular neurons) stabilizes the REM state (Figs. 12 and 13). A key feature of this model,
not reproduced in other more recent models of REM-sleep control [e.g., REM sleep flip-flop
model of Lu et al. (758)] is that REM-on neurons are proposed to be excitatory to REM-off
neurons so that as the REM state continues, REM-off neurons gradually become more
active, terminating the REM bout and giving a mechanistic explanation for changes in state.
A more sophisticated version of this model has been produced by McCarley and Massaquoi
(821) (the limit cycle model) which incorporates circadian influences on the REM oscillator
(these may be mediated by the orexins; see below) as well as local GABAergic neurons
(next section, FIGURE 12B), which are likely to be important in shutting off REM-off
neurons as well as in controlling the activity of REM-on neurons (807, 816, 821–823).
I) Evidence supporting the reciprocal interaction model: state-dependent firing patterns and
neurotransmitter release. A large body of evidence supports the reciprocal interaction model
ofREMsleep (816) and is summarized here (contrary evidence is discussed subsequently).
Confirming the initial recording data, multiple studies support the contention that the
discharge of presumed cholinergic and aminergic neurons shows an activity profile

consistent with causality, i.e., these neurons show an increase or decrease in firing rate,
respectively, prior to the beginning of REM sleep (336, 511, 615, 768, 1280). In these
studies, neurons were identified based on location, extracellular action potential
characteristics, and antidromic activation. In the future it will be important to confirm the
neurotransmitter phenotype of the cell recorded using juxtacellular labeling/post hoc
immunohistochemistry techniques together with recordings of activity across sleep-wake
cycles. So far, this has only been achieved in anesthetized preparations (126), which do not
show the full range of sleep-wake behaviors. Confirming the single-unit recording data,
measurements of extracellular neurotransmitter levels show that the firing pattern of the
cholinergic and aminergic neurons are translated into the predicted pattern of release across
the sleep-wake cycle (560, 704, 709, 1020, 1172, 1411, 1412). In contrast to the single-unit
recording data, these measurements are limited in temporal resolution, so with current
methodologies cannot provide evidence of causality.
II) Evidence supporting the reciprocal interaction model: cholinergic modulation of reticular
formation neurons. Anatomical and electrophysiological experiments have confirmed the
existence of many of the proposed interconnections of this model. Cholinergic modulation
of reticular formation neurons: anatomical and electrical stimulation studies have

demonstrated prominent cholinergic projections from the LDT and pedunculopontine
tegmentum (PPT) to the reticular formation areas involved in REM sleep control (544, 861).
Early in vitro intracellular recording studies in the PnO and PnC regions of the reticular
formation revealed excitatory effects of cholinergic agonists mediated by nicotinic and
muscarinic receptors in approximately two-thirds of reticular neurons (447, 1241), acting via
nonselective cation channels and blockade of leak potassium, channels, respectively. Thus
these neurons likely represent REM-on or wake/REM-on neurons. In contrast, one-quarter
of the neurons were inhibited via activation of an inwardly rectifying potassium conductance
(419), consistent with immunohistochemical evidence for the presence of inhibitoryM2
muscarinic receptors on a substantial proportion of non-GABAergic PnO and PnC reticular
neurons (141). More recent studies specifically targeting the REM control SubC region in
the rat (160, 490) showed that similar mechanisms also operate in this region. The majority
of “reticular” (i.e., noncholinergic, nonnoradrenergic) neurons in the SubC were excited by

carbachol. Pharmacological analysis revealed that this action is mediated by both ionotropic
nicotinic receptors and muscarinic M1-type (likely M3) receptors (490). A large subset
(~40%) of SubC neurons were silent at rest (i.e., in the absence of current injection through
the recording electrode), were hyperpolarized further by carbachol, and fired in bursts of
several action potentials at the offset of hyperpolarizations due to the presence of low-
threshold calcium channels (160). Pharmacological analysis revealed that M2 muscarinic
receptors and activation of a potassium current mediate the outward current responsible for
this hyperpolarization (490). These neurons could play a role in PGO-wave generation since
hyperpolarization by carbachol would allow deinactivation of the low-threshold calcium
currents responsible for burst firing.
III) Evidence supporting the reciprocal interaction model: aminergic inhibition of brain stem
cholinergic neurons. Extensive projections exist from brain stem serotonin neurons in the
DR and MR to cholinergic LDT/PPT neurons (1149, 1211). Activation of 5-HT1A receptors
leads to inhibition of cholinergic LDT neurons in vitro, via activation of inwardly rectifying
potassium channels (763). Similarly, LC neurons project to and partially overlap
neighboring cholinergic brain stem regions (571, 731, 1001), and norepinephrine inhibits
mesopontine cholinergic neurons via activation of α2 adrenoceptors (1413). In vivo, the
firing of REM-on LDT/PPT neurons in the cat was inhibited by application of the 5-HT1A
receptor agonist 8-OH-DPAT (presumably explaining their silence during wake), whereas
wake/REM-on neurons were unaffected by this agent (1280). Autoradiographic studies in
the mouse did not find evidence for 5-HT1A receptors in brain stem cholinergic neurons
(120), suggesting either a species difference or mediation of serotonin effects by other
receptor subtypes or indirect mechanisms.
IV) Evidence supporting the reciprocal interaction model: cholinergic excitation of

aminergic neurons. Cholinergic neurons directly excite LC neurons (1160). Cholinergic
agonists acting on nicotinic receptors indirectly excite DRN serotonin neurons via a
presynaptic facilitation of excitatory noradrenergic inputs (714).
V) Evidence supporting the reciprocal interaction model: pharmacological experiments. In

animals, early studies suggested a REM-promoting role for acetylcholine (410, 504)
particularly when monoamines had been previously depleted by use of the agent reserpine
(605). In humans, enhancement of cholinergic tone by systemic application of
acetylcholinesterase inhibitors or muscarinic agonists (93, 513, 692, 1065, 1185, 1186)
consistently decreases REM sleep latency and enhances REM sleep amount, particularly
phasic REM events, whereas muscarinic antagonists cause the reverse effect (428, 625,
1051). Enhancement of monoaminergic tone with antidepressants is well known to result in
a long-lasting suppression of REM in humans and animals. Following the localization of
REM generating sites to the brain stem by Jouvet, enhancement of cholinergic tone or
stimulation of cholinergic receptors in the pontine reticular formation of cats or dogs was
found to cause a REM-like state (675, 1055, 1228). In rats and mice, a similar effect can be
induced, although it is often less robust in these species, perhaps as a result of difficulty in
localizing the drug applications in the smaller brains of rodents and the interaction with
circadian control or descending forebrain influences (675, 800, 1228). Activation of the
inhibitory 5-HT1A receptor, via perfusion of the serotonin 5-HT1A agonist 8-OH-DPAT,
caused increased REM sleep due to activation of autoreceptors when infused in the DRN
(1021), whereas perfusion of serotonin in the LDT decreased REM via activation of
inhibitory 5-HT1A receptors on cholinergic neurons (522).
VI) Evidence opposing the reciprocal interaction model. Although a large body of evidence
supports the suggestion that cholinergic neurons promote REM and aminergic neurons
inhibit REM, several lines of evidence appear to contradict this model. However, in each

case alternative explanations are also possible: 1) lesions encompassing the PPT or LDT
regions where the majority of brain stem cholinergic neurons are located did not
significantly alter the amount of REM sleep (758). Combined lesions of both areas were not
performed. Thus, in theory, one area could compensate for the other. We note that large
lesions of the LDT/PPT and surrounding areas led to substantial reductions in REM sleep,
and these reductions were correlated with the extent of loss of cholinergic neurons (1394). 2)
Knockout mice lacking M2/M4, M3, or both M3 and M2/M4 muscarinic receptors (the main
subtypes present in the brain stem) still show REM sleep (434), although REM sleep was
reduced by 22% in M3 receptor knockouts. Since these are constitutive knockouts,
compensatory responses of the other cholinergic receptors may occur. 3) Using Fos as a
marker of neuronal activation, the Luppi lab did not find activation of ChAT-positive
neurons in REM rebound following relatively selective REM sleep deprivation (1354),
although these results apparently contradict those of the Jones group (784). Furthermore,
Fos is acknowledged as an imperfect marker of neuronal activity, particularly for neurons
with complex firing patterns (664). 4) Inconsistent effects of carbachol in promoting REM
sleep in rats and mice may be due to close proximity of REM promoting and REM-
inhibiting neurons in these species, making it difficult to restrict the effect to the neurons
targeted and due to injections of carbachol during the daytime when rats and mice already
sleep maximally, i.e., a ceiling effect. 5) Lesions/inactivation of norepinephrine neurons do
not affect REM sleep amounts. Studies performing neurotoxic or electrolytic lesions of the
LC reported no change in the daily amounts of REM sleep (100, 576, 758). Mice lacking
dopamine-β-hydroxylase, the enzyme necessary to convert dopamine to norepinephrine,

were shown to either have unchanged baseline sleep-wake parameters (539) or a decrease in
REM sleep, opposite that predicted by the reciprocal-interaction theory (956). As with other
knockouts, compensatory changes may occur, and the differences between these two studies
suggest that genetic background or other technical factors may influence the effect.
Contradictory effects were also found using neurotoxic lesions of norepinephrine neurons
with DSP-4. Monti et al. (881) found an increase of REM sleep several days after
administration, whereas Cirelli and Tononi (244) reported no baseline sleep-wake changes.
In all of these studies, it is possible that the activity of serotonin neurons could have masked
the loss of norepinephrine neurons since serotonin has similar effects on the REM control
neurons as norepinephrine. In contrast to the rather drastic manipulations described above,
we have recently found that a partial, reversible knockdown of orexin receptors in LC
neurons using RNAi increased REM sleep during the dark period (219). Similarly,
reversible inactivation of the LC or DR by cooling increases REM sleep (201).
VII) Alternative models for the contribution of cholinergic and aminergic neurons to REM
sleep control. Overall, the question of whether activation of cholinergic neurons and
silencing of aminergic neurons are essential for the induction of REM sleep is still not
completely resolved. An alternative but related hypothesis is that cholinergic and aminergic
neurons are not absolutely required for REM sleep generation but instead bias the system in
one direction or another. Another possibility is that these neurotransmitter systems may
control particular aspects of REM sleep. For instance, cholinergic agonists consistently
promote theta rhythm and PGO waves in rats and cats. In contrast, serotonergic neurons
inhibit theta rhythm and PGO waves. The discharge of serotonin neurons is very closely
(inversely) correlated with the occurrence of PGO waves (768), and systemic application of
the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA) in the cat leads to the
appearance of PGO waves during the waking state (555). Furthermore, injection of serotonin
into the SubC region in the rat suppressed the pontine component of PGO waves (P-waves)
without affecting other components of REM sleep (279). Similarly, the silencing of
noradrenergic LC neurons has been closely linked to muscle atonia. Cataplexy seen in the
sleep disorder narcolepsy is thought to represent inappropriate inactivation of REM muscle
atonia. LC neurons completely shut off prior to attacks of cataplexy in genetically

narcoleptic dogs, whereas other aminergic neurons (serotonergic and histaminergic) do not
reduce their firing to the same extent (564, 1435). These attacks can be reduced by use of
norepinephrine selective reuptake inhibitors increasing norepinephrine tone (923). In the
future, new techniques (e.g., optogenetics) to selectively excite or inhibit cholinergic and
aminergic neurons, in particular the caudally projecting cholinergic neurons, will be of great
help in resolving their exact role in REM sleep control.
B) Gabaergic Control of Rem Sleep: Recently, there has been increased interest in the role
of GABAergic neurons in the control of REM sleep. A large number of mainly small or
medium-sized GABA neurons are present in the brain stem, and many of them project to,
surround, or are located within brain stem areas involved in REM control (118, 156, 372,
784, 785, 1118). At least two functional groups of brain stem GABAergic neurons seem to
be involved in REM control, namely, REM-off GABA neurons preventing activation of
REM-on reticular neurons during wakefulness and REM-on GABA neurons inhibiting the
activity of aminergic neurons (FIGURE 12B). GABAergic inhibition of cholinergic neurons
during wake and/or NREM sleep is also a factor in regulating their state-dependent
discharge (1303) and neurotransmitter release (1344). Other groups of GABA neurons
outside the brain stem regulate the circadian timing and homeostatic control of REM sleep.
Although mounting evidence supports a role for these different groups of GABA neurons in
controlling REM sleep (reviewed below), we note that in most cases, direct evidence that
selective stimulation or inhibition of particular subsets of GABA neurons affects REM sleep
occurrence is lacking. Similarly, electrophysiological recordings of identified GABA

neurons showing that they have the appropriate discharge patterns to cause a change in state
are not available. Thus, as with the cholinergic and aminergic neurons, not all criteria
required for firmly establishing the role of GABAergic neurons in REM control have been
fulfilled.
I) REM-off GABA neurons. Application of the GABAA receptor antagonist bicuculline to

the SubC or PnO/FTP regions induced a REM-like state in both cats (1441, 1443) and rats
(119, 1009, 1112). These results suggested that the REM effector neurons located in this
region are normally under inhibitory GABAergic control and are consistent with
microdialysis measurement of extracellular GABA levels in the reticular formation across
behavioral state which are ordered wake > NREM > REM (1281, 1337). Retrograde tracer
injection into the SubC of rats revealed prominent GABAergic inputs from the PnO,
ventrolateral periaqueductal grey matter (vlPAG), and the lateral pontine tegmentum (LPT)
(118, 758). On the basis of Fos studies and anatomical tracing, it was suggested that
GABAergic neurons in the vlPAG and in the LPT region (which encompasses
mesencephalic components and is also termed the deep mesencephalic reticular nucleus;
DpMe) might be particularly important (758, 1118). Early work in the cat showed that
inhibition of this area with the GABAA receptor agonist muscimol led to a large increase in
REM sleep (1120). These findings were confirmed more recently in the rat (1118) and
guinea pig (1336). Cell body specific lesions of either the vlPAG or the LPT cause an
increase in the amount of REM sleep in rats (758) and in mice (612). The vlPAG lesions
increased both REM sleep duration and the number of REM sleep bouts during the dark
(active period), whereas the LPT lesions increased the number of REM bouts during the
light period and caused occasional episodes of sleep-onset REM/cataplexy-like states.
Although the evidence for this region being a REM-inhibiting area is quite strong, a recent
study suggests that GABAergic neurons in this region are not involved since inactivation of
GABAergic (and glycinergic) neurotransmission did not alter REM sleep (668). Presumably
glutamatergic neurons in this region excite GABAergic neurons located elsewhere in the
brain stem, which then inhibit REM-on neurons.

II) REM-on GABA neurons. Another group of GABAergic neurons within the brain stem
RF likely play a role in the silencing of REM-off neurons located within the LC and DRN.
Microdialysis experiments showed that GABA levels rise in these areas during REM sleep
compared with wakefulness (926, 927). Injections of GABA receptor antagonists into the
DRN or LC reverse the cessation of firing of 5-HT and NE neurons normally seen during
REM (420, 421). However, in the case of the DR, disfacilitation (withdrawal of excitatory
noradrenergic, histaminergic, and orexinergic inputs) is also likely to be important (158,
713, 1095). Retrograde tracing studies combined with GAD immunohistochemistry showed
that GABAergic neurons in the rostral PnO and vlPAG/LPT region project to the DRN
(421) and may be involved in silencing them during REM. GABAergic neurons surrounding
the LC norepinephrine neurons express Fos following recovery from REM deprivation (784)
and may thus inhibit them during REM sleep. Consistent with this idea, identified SubC
GABA neurons were excited by the cholinergic agonist carbachol (156). In addition, the LC
receives input from more distally located REM-on GABAergic neurons (1118, 1352). In
particular, GABAergic neurons in the dorsal paragigantocellular (DPGi) nucleus of the
medulla may be important in silencing the LC (and DR) during REM sleep, since single-unit
recordings in this area in unanesthetized rats revealed a population of (unidentified)
tonically firing REM-on neurons whose activity preceded the onset of the REM state (435)
and Fos studies revealed GABAergic, REM-on neurons in this area (1118).
III) Models of REM sleep control incorporating GABAergic neurons. How can these
findings involving REM controlling GABA neurons be reconciled with the

cholinergicaminergic reciprocal interaction theory? It has been hypothesized that
acetylcholine and amines modulate the activity of REM-on and REM-off GABAergic
neurons and thereby affect REM sleep occurrence (156, 574, 816, 1443) (FIGURE 12B).
Several lines of evidence suggest that acetylcholine-excited GABA neurons in the SubC/
PnO/LPT areas are REM-on neurons that inhibit LC and DRN neurons. Conversely,
acetylcholine-inhibited GABA neurons in the LPT/PnO regions are REM-off neurons which
inhibit REM-effector neurons in the PRF during waking/NREM sleep. Muscarinic inhibition
of the GABAergic inhibitor neurons would thus disinhibit REM-promoting reticular
neurons. This model also resolves the puzzling reports of muscarinic M2 receptor promotion
of REM sleep (61, 252) and cataplexy in narcoleptic dogs (1056), findings that were
puzzling in view of the generally hyperpolarizing, inhibitory M2 actions (332). Unlike the
reciprocal-interaction model incorporating GABAergic neurons, two recent models of REM
sleep control involve only GABAergic and glutamatergic neurons (758) (REM flip-flop
model) or GABA, glutamate, and aminergic/orexin/MCH neurons (765). Aside from the
evidence presented above which supports the cholinergic promotion of REM sleep
(especially in the cat), these models suffer from the weakness that they do not provide any
explanation for how a change in state is achieved or any explanation for the timing of REM-
NREM transitions.
C) Nitric Oxide Control of Rem Sleep: nNOS is localized within REM sleep control
structures such as the PPT, LDT, and DRN (702, 705). nNOS knockout mice have
substantially lower levels of REM sleep than their wild-type controls (218). Microinjection
of NG-nitro-L-arginine methyl ester (L-NAME), a nonspecific inhibitor of NOS, into the PPT
reduced REM sleep (281), whereas another NOS inhibitor, NG-nitro-L-arginine p-
nitroanilide (L-NAPNA), reduced both NREM and REM sleep (480). Moreover,
microinjection of nNOS inhibitor 7-nitroindazole (7–NI) into DRN, in rats, decreased REM
sleep (168), and microinjection of L-arginine, a precursor of NO, into PPT increased the
duration of NREM sleep and the number of REM sleep episodes (480). Inhibition of NO
production in mPRF reduced acetylcholine release and decreased the amount of REM sleep
(708, 709). Overall these data suggest that NO, produced by nNOS, mainly in brain stem
cholinergic neurons, promotes REM sleep.

3. Forebrain control of REM sleep timing—Although the brain stem appears to be

sufficient for generation of REM sleep and NREM-REM cycles (580), other factors
controlled by forebrain inputs to the brain stem affect the timing and amount of REM sleep
such as the time of day, light exposure, stress, emotion, temperature, nutritional state, and
sleep homeostasis (1116). We here focus on diurnal/circadian control. REM sleep occurs
predominantly in the inactive period, i.e., night-time in humans and daytime in rats and mice
(1439). In an extension of the reciprocal-interaction model of REM sleep (limit cycle
model), McCarley and Massaquoi introduced an additional factor to account for the
circadian variation in REM sleep across the day. This term provided an excitatory input to
REM-off neurons, suppressing REM during the day (in humans) and causing a smaller
amplitude and shorter initial first NREM-REM cycle (807, 821, 822).
A) Orexinergic Control of Rem Sleep: Several strong lines of evidence support orexin
neurons in the lateral hypothalamus as providing this circadian factor (598). 1) Orexin
neurons receive direct input from the SCN and indirect input via the dorsomedial
hypothalamus (52, 224). 2) Orexin neurons show a wake-on, REM-off pattern of firing
(except during phasic periods of REM) (699, 856). Measurements of orexin levels in the
squirrel monkey (1472) and rat (296) are consistent with the proposed diurnal fluctuation. 3)
As hypothesized in the model, orexins excite wake-active, REM inhibiting, serotonergic
DRN neurons (157, 158, 735) and noradrenergic LC neurons (524). Surprisingly, they also
seem to excite cholinergic brain stem neurons in vitro (169). 4) The loss of orexins causes
narcolepsy (215, 727), a sleep disorder characterized by the presence of excessive daytime
sleepiness and several symptoms related to abnormal timing of REM sleep signs (see sect.
VII) and loss of diurnal REM control in humans (983). 5) Orexin loss-of-function
experiments in animals (TABLE 1) result in increased REM during the normally REM-poor
dark period, arguing strongly that orexinergic activity suppresses the occurrence of REM
sleep during the diurnal active phase.
B) Preoptic Hypothalamus Control of Rem Sleep: In addition to the orexin systems, the
preoptic hypothalamic area also plays a role in circadian control of sleep. The preoptic area
receives indirect projections from the SCN via the medial preoptic area and dorsomedial
hypothalamus (222, 224, 306). Lesion of the area medial and dorsal to the ventrolateral
preoptic area (VLPO) of the hypothalamus, an important area in NREM control, was
correlated with loss of REM sleep (756). The loss of REM sleep occurred predominantly
during the light period (756) (the rat’s inactive period). Furthermore, after periods of dark
exposure that triggered enrichment of REM sleep, the number of Fos-positive cells in this
extended VLPO area was correlated with the amount of REM sleep (755). Thus diurnal
variation in REM sleep is caused by an orexin-mediated suppression of REM during the
active period and a promotion of REM by the extended VLPO during the inactive period.
C. Relation of REM to Dreams

The lay public is interested in REM sleep largely as a result of its close association with
dreaming. Interpretation of dreams is ascribed great significance in many cultures and
predates modern science. In western societies, the work of Freud and his counterparts led to
a widespread acceptance of dreams as giving important insights into “psychic disturbance.”
However, the findings of modern neuroscience have led to a view of dreaming which asserts
that the features of dreams arise from internally generated patterns of brain activation and
deactivation during REM sleep, and dream content does not necessarily have any meaning
or message for the individual (509, 510, 815, 820).
A) Activation-Synthesis Hypothesis of Dream Generation—The modern

neuroscience view of dreams was laid out by Hobson and McCarley as the activation-

synthesis hypothesis (510, 815, 820). An expanded state-space version of this hypothesis,
the AIM (activation, input gating, modulation) model was developed by Hobson to
characterize all conscious states (588). In the activation-synthesis view of dreaming, during
the REM state, the brain is activated internally by the activity of the brain stem (described
above).
Sensory systems, in particular visual systems (activated by PGO activity), and vestibular
systems are activated. Sensations and feedback from the neuronal command signals for
muscular activity influence the dream experience, although motor output is inhibited by
brain stem muscle atonia generating systems. This mismatch between motor programs and
motor output may contribute to common dream experiences of floating, flying, or an
inability to flee a dangerous situation. Brain areas involved in emotional behavior and
memory formation such as the hippocampus and amygdala are “reactivated” during REM
sleep, possibly reflecting memory consolidation processes (562, 1089, 1391) and provide
content (especially emotional content) to the dream. The synthesis of these different
elements of brain activity, together with their conscious awareness, causes the dream
experience. The synthesis process occurring in dreams is in some ways similar to the
“confabulation” of patients with various kinds of neurological injuries, which can also be
bizarre and nonsensical and makes little sense to observers (1143). An intriguing recent
theory of REM sleep and dreams suggests that they represent an evolutionarily early form of
conscious awareness (proto-consciousness), a precursor of the conscious awareness seen
during the waking state (509).
B) Brain Imaging of the Rem/Dreaming State—Positron emission tomography (PET)

and functional magnetic resonance imaging (fMRI) duringREMsleep and dreaming in
humans have supported the scheme proposed in the activation-synthesis hypothesis, which
was originally based on animal work (1143). These studies reported increased blood flow/
oxygen utilization in a network of interconnected regions during REM sleep: the pontine
tegmentum, thalamus, amygdala, basal ganglia and anterior cingulate and occipital cortex
(512, 754, 792, 1143). Amygdala activation is likely responsible for the high percentage of
dreams featuring negative emotions such as anxiety and fear. In contrast, decreased activity
was seen in the dorsolateral prefrontal cortex, parietal cortex, posterior cingulate cortex, and
precuneus. Deactivation of frontal areas likely accounts for the lack of insight, distortion of
time perception, and difficulty in remembering dreams upon waking (512, 1143). The
mechanism responsible for this deactivation is unclear since cholinergic projections to the
cortex, thought to be responsible for activation during REM, target prefrontal as well as
other cortical areas (500). Another, still to be resolved issue, is how particular dream
elements are selected among the massive number of possibilities available to the brain.
C) Do Dreams Represent Internal Drives?—Unlike Freud’s model, the brain activity

in the Hobson/McCarley activation-synthesis model of dreaming was considered
motivationally neutral, since it was due to the turning on of a brain stem neural oscillator.
However, brain stem cholinergic neurons activated during REM sleep provide a strong
excitatory input to dopaminergic midbrain neurons involved in reward processes, and others
have argued that dreaming is closely linked to activation of these pathways (1198).
Although the average firing rate of dopamine neurons in the VTA does not vary with
behavioral state (858), increased bursting occurs in VTA neurons during REM sleep (271),
and an increased number of Fos-positive dopamine neurons was observed in the VTA during
REM-rich periods following REM deprivation (786). Furthermore, REM involves a strong
activation of limbic brain regions (792), which may feedback onto the brain stem oscillator,
although there is no evidence for this. Thus processing of emotionally relevant events may
occur during the REM state (1388), as do many other complex functions such as alterations
in learning and memory. However, the regular generation of this cyclic state does not

depend on motivationally relevant stimuli, such as protection against repressed and

forbidden wishes (Freud’s hypothesis).
V. SLEEP LOSS AND COGNITION

In humans, sleep loss/disruption alters cognition and performance in a wide variety of
behavioral domains including attention/vigilance, executive function, emotional reactivity,
memory formation, decision making, risk taking behavior, and judgment (835). In addition,
a substantial body of literature supports the intuitive notion that a good night’s sleep can
facilitate human cognitive performance (339), a literature not to be covered in detail in this
review. This section focuses on mechanistic aspects of sleep loss/sleep disruption.
Methodological consideration related to rodent models of sleep disruption are covered in a
recent review (835).
A. Attention and Executive Function

Executive function is a broad and poorly defined term that is used to describe a set of higher
order cognitive functions that involve the prefrontal cortex. Impairments of attention and
other aspects of executive function following sleep disruption have been well documented in
humans in both experimental and patient populations (396, 621). The mechanisms by which
sleep disruption alters executive function are unknown but likely involve functional
impairment of the prefrontal cortex and/or its afferents (907). Sleep disturbances in humans
alter normal functioning of the prefrontal cortex as well as the posterior parietal cortex,
which has dense interconnections to the frontal lobe (1287). Imaging studies have revealed
altered activity in the default network, resulting in a dissociation of anterior and posterior
midline regions during sleep deprivation (212, 454, 1107, 1108). Sleep deprivation (SD)
also increases activity in thalamic regions that project to the cortex and may be involved in
maintaining cortical activity in the face of increasing sleep pressure (322, 1297, 1433).
Lapses of attention during SD are associated with reduced thalamic and frontal/parietal
cortical activity that contrast with activation of these same regions during successful
performance (213). Possible mechanisms underlying impaired prefrontal cortex function
during sleep disruption are described next.
1. Sleep loss-induced impairment of high-frequency oscillations—Slowing of

the EEG during sleep deprivation is particularly prominent in the frontal cortex and is
accompanied by a concurrent reduction in higher frequency beta/gamma rhythms important
for normal cognition (see sect. II). Modeling, electrophysiological, and optogenetic studies
all support the idea that beta/gamma oscillations and gamma-theta coupling have important
functions in attention-dependent stimulus selection (193, 297, 391, 1194) via their ability to
synchronize firing between functionally related cortical and subcortical brain areas, reduce
noise, and enhance signal transmission. The firing of principal cells relative to the phase of
the gamma rhythm has been proposed as a mechanism for coding of information (390, 732).
In addition, the frequency of gamma oscillations affects the direction of information flow
between brain areas (253).
Changes in the activity of neocortical or allocortical neurons themselves are likely to

contribute to the disruption of EEG oscillations. For example, SD or sleep fragmentation
(SF) in rats leads to reduced excitability of pyramidal neurons in area CA1 of the
hippocampus (837, 1271). In the neocortex, a recent study found that as wake duration
increases, individual cortical neurons can enter OFF states, accompanied by slow waves in
the local field potentials, similar to NREM sleep, while other nearby neurons show normal
wake activity and overall the EEG shows a wake pattern (1383). The incidence of these
local OFF states increases with the duration of the wake state and is correlated with
impairments in a sugar pellet reaching task (1383). Thus alterations in the excitability of

cortical neurons lead to a disruption of higher frequency EEG rhythms, impacting attention
and higher cognitive function.
2. Inhibition of cholinergic and other BF projections to prefrontal cortex—

Inhibition of BF cholinergic neurons by adenosine and/or NOduring SD (see sect. IIIC) is
likely to impair beta/gamma oscillations, since acetylcholine released from these neurons is
a potent facilitator of such rhythms (see sect. IIC). Aside from their major role in basic
cortical arousal and behavioral activation, evidence suggests that the BF and pontine
cholinergic systems play a significant role in visual attention, short-term spatial (working)
memory, and responsiveness to novel and motivationally relevant stimuli during the
acquisition of new associations (1066). Thus the BF cholinergic system figures prominently
in models of the effects of sleep disruption on behavior and cognition (1119). As reviewed
in section III, an upregulation of BF adenosine and adenosine A1 receptors occurs during SD
or SF, which may lead to inhibition of BF cholinergic and noncholinergic neurons. Also,
during SD, adenosine A1 receptors are upregulated in the human PFC, which may
consequently produce inhibition of PFC activity (341). The role of BF adenosine in
attentional deficits following sleep disruption were directly investigated using a rat model of
the human psychomotor vigilance task (PVT) (226). Microdialysis administration of
adenosine directly into the BF mimicked the effect of 24 h of sleep deprivation, producing
an increase in vigilance lapses relative to baseline, or to control perfusion of artificial
cerebrospinal fluid (ACSF). This effect of AD was reversed by the coperfusion of AD with
an A1 receptor antagonist. Thus an inhibition of cholinergic neurons by adenosine during

sleep deprivation causes deficits in attention.
3. Alterations in catecholaminergic systems—Dopaminergic and noradrenergic

arousal systems projecting to the PFC and striatum have also been strongly implicated in
working memory and attention (1066, 1067). The level of dopamine required for optimal
function follows an inverted U-shaped curve; thus increases or decreases may negatively
impact function. Early animal studies suggested that SD causes an increase in dopamine
levels (424) and a supersensitivity of dopamine receptors (1310). More recent human studies
support increased striatal dopamine levels (1376) that correlate negatively with performance
on a visual attention task (1375). Pharmacological treatment of the behavioral consequences
of SD also suggests a role for dopaminergic mechanisms. Thus the stimulants commonly
used for the treatment of sleep disorders (sect. VII), such as modafinil, inhibit the dopamine
transporter leading to increased catecholamine levels (1425). Similarly, in Drosophila,
dopamine is important in the control of arousal and the response to SD (679, 1153, 1438).
Dopamine D1 receptor activation in the mushroom bodies rescues sleep loss-induced
learning impairments (1154). Changes in the norepinephrine system may also be involved in
sleep disruption-induced deficits. One day of REM SD produced a decrease of activity in the
LC and a decrease of NA release (783, 1016). A more extended REM SD showed the
opposite effect, as NA levels and turnover increased (77, 992, 1016). Studies monitoring
changes in norepinephrine receptors report inconsistent results (745, 1423). Overall, the data
suggest that changes in dopamine systems may be more important than changes in
norepinephrine or its receptors in causing behavioral alaterations.
4. Interindividual differences—The neurobehavioral response to SD shows large

interindividual differences in both humans and rats (1330, 1331). Very recent genetic studies
suggest that polymorphisms in genes related to adenosine metabolism or signaling (59)
affect interindividual differences in susceptibility to cognitive disruption following SD. In
addition, a polymorphism of the gene that encodes catechol-O-methyltransferase (COMT),
an enzyme which degrades catecholamines, was predictive of the interindividual variability

in performance of an executive function task after SD, as well as EEG alpha frequency
activity during wakefulness (112).
B. Emotion
1. Mood—Changes in mood and motivation are common subjective experiences during
sleep disruption. Recent human studies have begun to investigate these changes under
controlled experimental conditions. Mood is often elevated during SD (108, 521),
particularly in subjects with a evening-type circadian profile (1147). The effect of acute SD
can be used to treat severely depressed patients (sect. VII), although unfortunately the effect
is reversible once the patients are allowed to sleep. At the same time as the basal mood
changes, sleepdeprived subjects show increased reactivity to negative stimuli (31, 1274,
1334), reduced facial expressiveness (859), and impaired recognition of human emotions
(622, 1328). The mechanisms underlying these changes are largely unknown but have been
hypothesized to reflect a loss of REM sleep (453), since REM sleep is characterized by a
strong activation of brain areas regulating emotional responses such as the amygdala,
hippocampus, and frontal cortex (sect. IV). Emotional memory is enhanced across sleep
intervals with high amounts of REM sleep (1387), and a recent imaging study showed that
sleep enhanced the memory of emotional pictures by increasing functional connectivity
between the ventromedial PFC and the precuneus, amygdala, and occipital cortex (1240).
Increased amygdala activation due to a loss of top-down control from the medial prefrontal
cortex may explain the increased response to negative emotional stimuli (455, 1465). At the
same time, activity in brain mesolimbic reward networks is also enhanced (455), consistent
with reports of increased dopamine release (1375, 1376) and positive effects on mood and
motivation.
2. Anxiety/fear—Both anxiogenic (1088, 1180) and anxiolytic (806, 1248) effects have
been reported in experimental investigations of sleep disruption. Self-reported increases in
anxiety have been observed in humans after SD (58, 1088), consistent with reports of the
increased reactivity to negative stimuli described above. Several studies have examined
negative emotional memory formation in animals in association with sleep disruption.
Contextual fear conditioning, a hippocampus-dependent task, was impaired by 72 h of SD
before training (1085) or by REM (441) or total SD (468) 5–6 h following training. REM
SD was also reported to impair extinction of cued fear extinction, a prefrontal cortex and
amygdala-dependent task (1181). In humans, recollection of negative emotional stimuli 72 h
later was associated with increased amygdala activation in subjects sleepdeprived on the
night following initial exposure (1239). The relevant factors that predict whether sleep
disturbance will increase or decrease anxiety are not known. Duration of exposure, method
used to disrupt sleep, type of sleep disturbance, and how the findings are interpreted are
potential factors that may help to explain seemingly contradictory findings.
C. Learning and Memory

A substantial body of evidence from both humans and experimental animals suggests that
normal sleep facilitates certain forms of learning and memory (309, 339, 1007, 1389),
although these data, particularly the link between REM sleep and memory, have been
criticized (1173, 1361). A full review of the controversial topic of the role of sleep in
learning and memory is beyond the scope of this review, and the reader is referred to the
reviews cited above. A more consistent literature describes impairments in learning and
memory produced by sleep disruption (339, 835). A variety of mechanisms could mediate
deficits in learning and memory associated with sleep disruption. These mechanisms are
discussed next.

1. Role of hormonal stress responses—A problem inherent in conducting

experiments to assess behavioral and cognitive impairments associated with sleep disruption
is that the reported deficits might be due to a stress response associated with the method
employed to disrupt sleep. Sleep deprivation induced by the treadmill method (1272),
rotating wheels (846), or the flowerpot method (1469) enhance corticosterone levels. It is
important to point out, however, that the effects of stress on learning and memory are not
always deleterious, but instead are dose-dependent. High levels of chronic stress (258) or
chronic administration of the adrenal stress hormone corticosterone (114) impair spatial
learning and memory. Conversely, stressors of lessor intensity sometimes facilitate learning
and memory and long-term potentiation (307). Thus stressors may facilitate or inhibit
learning and memory processes, depending on the type, magnitude, and timing of the
stressor. Although an indirect effect of stress is always possible, several lines of evidence
suggest that the effects of sleep disturbance on learning and memory are predominantly
direct. For instance, there are REM sleep periods, or “windows” of time during which prior
learning is highly sensitive to selective REM SD (1190, 1191). Such time-dependent sleep
disturbances would not likely result from a nonspecific stress response.
The most compelling evidence that effects of sleep disturbance on learning and memory are
independent of stress is from studies on adrenalectomized animals. In rats, 72 h of SD prior
to training impaired acquisition on the water maze task (1084), but surgical removal of the
adrenal glands (with corticosterone replacement to normal, nonstressed levels) did not
significantly alter this effect. Similarly, at the cellular level, 96 h of SD was found to inhibit
adult hippocampal neurogenesis, but this effect was also observed in adrenalectomized rats
that were maintained via subcutaneous minipumps on continuous low-dose corticosterone
replacement (902). Hence, the effect of sleep loss on adult neurogenesis was independent of
adrenal stress hormones (902). Another study found that adrenalectomy and subsequent
corticosterone replacement significantly altered sleep architecture but did not alter the
homeostatic sleep response to 6 h of SD (131). Taken together, these studies suggest that
both the homeostatic response to sleep disruption as well as the subsequent deficits in
learning and memory are mediated by mechanisms that are largely independent of endocrine
status.
2. Sleep loss impacts cellular mechanisms of learning and memory occurring

during NREM sleep—Sleep disruption could prevent memory consolidation by impacting
the following mechanisms that normally occur during NREM sleep: 1) synaptic
homeostasis. The synaptic homeostasis theory of sleep posits that the amplitude and slope of
delta and slow oscillations downregulate synapses so as to avoid a ceiling effect of synaptic
potentiation occurring during waking (sect. III). Increases of delta waves during waking are
a prominent feature of short-term SD and mounting sleep pressure, suggesting that they are
important for maintaining function. Indeed, boosting slow oscillations during sleep
potentiates memory (805) and EEG delta power during recovery sleep after SD predicts
cognitive recovery (787). 2) Replay of firing patterns: hippocampal CA1 pyramidal place
cells, which are known to fire together when an animal occupies a specific spatial location
(939), were also found to fire together during subsequent sleep (985). Moreover, cells that
were not active during wake, or that were active but had nonoverlapping spatial patterns of
firing, did not show increased firing during subsequent sleep (1417). Hippocampal place
cells also encode temporal information concerning the order of events; replay of the firing of
these neurons in sleep has been shown to exhibit a pattern that reflects the temporal order in
which these cells fired initially during waking exploration (1188). Hence, reactivation of
these hippocampal neuronal ensembles during sleep is postulated to represent the
“consolidation” of labile memories into more stable forms. This reactivation of hippocampal
neurons occurs in a compressed manner during high-frequency ripples occurring in the
hippocampus during NREM sleep, a possible endogenous mechanism for the generation of

LTP (175, 179) and sleep loss will impact this process. 3) Sharp-wave ripple complexes: the
large and high-frequency depolarization of CA1 neurons occurring during sharp-wave-ripple
complexes (sect. III) induces synaptic potentiation in a Hebbian manner reminiscent of in
vitro tetanic stimulation protocols used to induce long-term potentiation (LTP) (179, 628).
LTP-like stimuli induce sharp waves in vitro (89), and LTP is occluded in hippocampal
slices that produce spontaneous sharp waves (254), supporting the idea that sharp waves
represent an endogenous trigger for LTP-like synaptic plasticity. Buzsaki (1989) proposed in
his two-process model of memory formation that these events are involved in the
consolidation and transfer of short-term memory traces from the hippocampus to the
neocortex during sleep (175). Hippocampal sharp waves occur just prior to the transition
from neocortical down states to up states, suggesting that they facilitate down-to-up
transitions. Furthermore, in combined recordings from hippocampus and prefrontal cortex in
naturally sleeping rats, prefrontal neurons consistently fired 100 ms following hippocampal
neurons participating in hippocampal sharp waves, suggesting a hippocampal-neocortical
dialogue (875, 1408). In animals, an elevated sleep spindle density has been observed after
learning in rats (345, 346, 876). Several human studies suggest that disruption of stage 2
sleep, when spindles occur, is linked with impairments in procedural memory (1390). 4)
Reduced acetylcholine levels: low acetylcholine levels occurring duringNREMsleep are
important for declarative memory consolidation (402).
3. Sleep loss impacts cellular mechanisms of learning and memory occurring

during REM sleep—Disruption of REM sleep neuronal processing events represents

another potential mechanism affecting learning and memory formation. 1) Neuronal replay
during REM sleep may reflect neocortical activation of hippocampal circuits during a later
stage of the memory consolidation process (499, 1244) since the duration of replay of
hippocampal neuronal ensemble activity during REM sleep was comparable to that during
waking task performance (753) (i.e., on the order of tens of seconds to minutes), much
longer than replay recorded during NREM sleep. The existence of replay of hippocampal
ensemble activity during REM sleep leads to speculation concerning the information content
in dream states (linked to REM sleep) and its potential significance in memory processing,
perhaps especially for procedural memory which is known to be REM sleep-dependent
(607). 2) Theta rhythms: behavior-dependent modifications of subcortically driven theta
rhythms are also reproduced during REM sleep. 3) P-waves: work from Datta and
colleagues has shown that activation of the P-wave generator in the dorsolateral pons (sect.
IV) facilitates learning and memory, particularly involving dorsal hippocampus activation,
whereas inhibition causes the reverse effect (275, 280, 284, 285, 813, 814). Disruption of
any of these three processes during sleep disruption may affect memory formation.
4. Inhibition of synaptic plasticity—It is generally accepted that long-lasting changes

in hippocampal synaptic efficacy, examined experimentally in LTP or LTD paradigms,

underlie declarative memory formation (109). Multiple studies in recent years have shown
an impairment of the induction or maintenance of LTP by periods of total SD (184, 1074,
1350), REM SD (288, 749, 797, 837, 1074, 1155), or sleep fragmentation (46, 1273).
Interestingly, the sleep disruption effects on synaptic plasticity appear to be specific for LTP
since short-term presynaptic plasticity (paired-pulse facilitation) and long-term depression
were unaffected (837, 1273). In addition to these physiological changes in LTP and LTD,
sleep disruption reduces hippocampal neurogenesis (459–461, 469).
A) Nmda Receptor Composition and Ltp/Ltd: One likely mechanism underlying the loss
of LTP by sleep disruption is altered subunit composition ofNMDAreceptors (216, 655,
746). Following long-periods of REM SD (24 or 72 h), a reduction in the NMDA receptor-
mediated component of excitatory synaptic currents was shown in the CA1 region of the

hippocampus (836) and dentate gyrus (216). This reduction was associated with reductions
in the surface expression of the obligatory NR1 subunit of the NMDA receptor (216, 836).
An increased NR2A/NR2B subunit ratio was observed in the CA1 region using a milder
form of SD (4–6 h) and electrophysiological analysis of isolated synaptic currents and

immunoblot analysis of purified synaptosomes (655). Furthermore, immunogold labeling of
NR2A and NR2B subunits and electron microscopy revealed a 1.6-fold increase in the
amount of NR2A subunits at synaptic sites in the CA1 region. Greater NR2A receptor
content was shown to facilitate the induction of LTD elicited by stimulation in the theta-
frequency range (746). Thus the sliding threshold for inducing LTD or LTP was shifted in
the direction of LTD by SD (655, 746). Changes in LTP/LTD were not observed following
SD in NR2A knock-out mice, suggesting that the change in NR2A subunits was sufficient to
explain the changes in synaptic plasticity by sleep loss (746). Theoretically, reduced LTP
produced by NMDA receptor downregulation or altered composition could be overcome by
increasing the amplitude or duration of depolarization produced by the AMPA/kainate
subtype of glutamate receptors so that increased calcium enters the postsynaptic cell either
via NMDA receptors or voltagedependent calcium channels. Along these lines, a positive
allosteric modulator of AMPA receptors (AMPAkine CX717), which prolongs AMPA
receptor-mediated EPSP decay time, was shown to strikingly enhance the performance of
monkeys following a single night of sleep deprivation (477, 1019). In addition to alterations
in NMDA receptors, SD also impairs the late-phase of hippocampal LTP via impaired
cAMP signaling (1350), perhaps suggestive of impaired cellular energy (323). Consistent
with this idea, the energy sensor AMPK regulates the late phase of hippocampal LTP
(1023).
B) Ltp And Ltd During Normal Sleep and Wakefulness: In contrast to the well-replicated
inhibition of LTP with sleep loss, there is less consensus regarding synaptic plasticity
processes occurring during natural waking and different stages of sleep. Early studies
showed that the strength of synaptic transmission varies according to the time of day (72).
More recently, Cirelli and Tononi, based on an examination of gene transcripts expressed
during waking and sleep, proposed that LTP occurs mainly during waking, whereas LTD
occurs mainly during sleep (sect. III). Buzsaki, on the other hand, based on hippocampal
neuronal activity patterns proposed a two-stage model of memory formation which
postulated that sharp waves occurring during NREMsleep in the CA3 region would be an
ideal trigger for LTP-like processes in the CA1 region (175). Also in line with the idea that
synaptic strengthening can occur during sleep are findings of strengthened cortical responses
in the visual system of developing cats which required NMDA receptors and PKA activity
(53, 561).
5. Increases in extracellular adenosine—Adenosine can inhibit LTP via A1 receptors

(38), and both extracellular adenosine levels and A1 receptors have been shown to increase
in cortical areas during SD (sect. III). Several experiments have shown that disruption of this
process leads to deficits in working or spatial memory: 1) conditional knock-out mice for the
adenosine A1 receptor (99); 2) rats with VLPO lesions had disruption in LTP that could be
partially rescued by adenosine A1 receptor antagonism (46); and 3) dn-SNARE mice which
cannot release adenosine from astrocytes also had disrupted cortical slow waves (360) and
memory formation (367).
E. Conclusion
Sleep disruption-induced impairments in cognitive performance have many real world
consequences. Increased industrial and car accidents are an obvious correlate, but sleep
disruption also has more subtle effects that affect individuals and the economy. For instance,
recent studies showed that acute SD increases risk-taking behavior (623, 841, 1351) and

impairs the ability to integrate emotion and cognition to guide moral, emotionally evocative,
judgements (624). On the positive side, acute SD has a rapid mood-elevating effect in some
depressed patients. Current evidence suggests changes in synaptic transmission, neuronal
oscillations, and neuromodulatory projections to the cortex, in particular cholinergic and

dopaminergic systems, may be particularly important in mediating the behavioral alterations
which result from sleep loss.
VI. GENOMICS AND PROTEOMICS

The description of sleep and wakefulness described in sections II-V of this review has
primarily relied on electrophysiological, behavioral, and pharmacological studies. However,
there are multiple aspects of sleep and wakefulness that are regulated in concert, suggesting
contributions of genes and their protein products. Thus many recent studies have focused on
the genetics and proteomics of sleep.
The earliest indications of genetic influences on sleep were from studies of mono- and
dizygotic twins in the 1930s (287). Although most early twin studies used relatively small
numbers of subjects, many aspects of sleep, such as sleep latency, awakening measures,
amount of REM sleep, and temporal pattern of eye movement, were significantly correlated
in mono- but not in dizygotic twins. Moreover, the EEG spectral patterns showed striking
similarities between monozygotic twins (287). More recent genomic studies have utilized
various techniques including: 1) subtractive hybridization, 2) nylon membrane macroarrays,

3) microarrays used in conjunction with specific quantitative methods such as in situ
hybridization and real time polymerase chain reaction, and 4) transgenic mice with
constitutive or conditional loss or gain of gene function. Several animal model systems have
been used to understand the fundamental nature of sleep including sparrows, mice, the fruit
fly Drosophila melanogaster, the nematode round worm Caenorhabditis elegans, and
zebrafish. In the past decade, several reviews have been written on this topic of genome-
wide gene expression (230, 287, 1145). Similarities in the sleep markers (genes and
proteins) across different species have not only underscored the universal nature and the
need for sleep but also revealed a plethora of information on various functional categories of
genes and proteins. In this section we review the genes and proteins associated with sleep
and wakefulness in humans and animals, grouped according to function at the cellular or
network level.
A. Genes Associated With Sleep-Wake Regulation

1. EEG—Zung and Wilson in 1966 (1479) were the first to perform polysomnographic
studies in twins. These authors demonstrated striking similarities in the temporal pattern of
sleep stages between monozygotic twins. One of the first genetic loci responsible for low
voltage EEG was mapped to human chromosome 20q (1212). Later, several twin studies
reported that EEG delta, theta, alpha, and beta frequencies are heritable traits that are highly
correlated in monozygotic twins (24, 34, 292, 1324). These results were corroborated by
findings in rodents, showing strong heritability in EEG traits in inbred mice (382, 383, 1258,
1322). Quantitative trait loci (QTL, stretches ofDNAthat have clusters of genes related to a
trait, in this case “sleep”) studies among different strains of mice identified several heritable
genes for specific sleep parameters (383, 938, 1258), especially different EEG frequencies.
QTL analysis identified a single gene encoding the retinoic acid receptor beta (Rarb),
located on chromosome 14, that controls delta frequency EEG activity (796). Targeted
disruption of this gene confirmed the importance of retinoic acid signaling in control of EEG
delta frequencies (796), although the mechanism remains unclear. Theta frequency (5–8 Hz)
activity during REM sleep is controlled by a single autosomal recessive gene, known as
acylcoenzyme A dehydrogenase for short chain fatty acids (Acads) that is localized to

chromosome 5 in mice (1260). The ion channels that contribute significantly to the
characteristic EEG frequency bands of NREM and REM sleep are discussed in detail below.
2. Neurotransmitter systems
A) Acetylcholine: Few genetic studies of sleep and wakefulness have targeted the
cholinergic system, although, as described in other sections of this review this system has
been extensively investigated with other methodologies. In muscarinic receptor 3 (M3)
knockout mice, REM sleep was decreased, whereas M2/M4 double knockouts had normal
sleep (434). Brain stem cholinergic neurons provide a strong innervation of midbrain
dopamine neurons involved in brain reward processes (see sects. II and IV). The VTA
dopamine neurons express exclusively the M5 muscarinic receptor (1207) and not other
muscarinic receptor subtypes. A reduced activation of dopamine midbrain neurons
projecting to the nucleus accumbens was seen in M5 knockout mice (374). These mice also
showed a reduced locomotor response to morphine (1207). Similarly, rats that had M5
antisense oligonucleotides injected into the VTA had reduced lateral hypothalamic self-
stimulation (1461). Cholinergic nicotinic receptor mutations have little impact on sleep
wake behavior (371, 703), possibly due to the large number of alternative subunits. The
complexity of the gene encoding the synthesizing enzyme choline acetyltransferase (ChAT)
has precluded a genetic analysis of its role in sleep-wake control.
B) Serotonin: Genetic studies confirm that the serotonergic system has important roles in
arousal, suppression of REM sleep, and the sleep response to restraint stress. Mice in which
serotonin neurons are deleted by deletion of the LIM homeobox transcription factor Lmx1b
revealed a deficit in thermoregulation that led to an increase in wakefulness due to increased
movement to generate heat (162). Furthermore, in these animals there was an impaired
arousal response to CO2 reminiscent of sudden infant death syndrome (sect. VII). Serotonin
5-HT1A and 5-HT1B receptor knockout mice exhibited higher amounts ofREMsleep during
both the light and dark periods, consistent with the inhibitory role of serotonin in REM sleep
control (sect. IV). In addition, a reduced rebound REM sleep response following restraint
stress was observed in these animals (8, 130). Similarly, genetic ablation of the serotonin
transporter in mice led to enhanced spontaneous REM sleep (19, 1427) and a blunted REM
sleep response to stress. Attenuation of restraint stress-induced enhancement of REM sleep
in these animals was attributed to an overproduction of orexin, since it was reversed by
blocking orexin receptors (1034). 5-HT2A receptor knockout mice showed a significant
decrease in NREM sleep, with an increase in wake that was attributed to a decreased
sensitivity of 5-HT2B receptors due to developmental alterations (1014), an important
consideration in constitutive knockout studies. The homeostatic sleep response following 6 h
of sleep deprivation was also attenuated in 5-HT2A mutant mice while changes in REM
sleep were minimal. In Drosophila, mutations of 5-HT1A receptors resulted in short and
fragmented sleep that was rescued by expressing the receptor in the mushroom bodies, a
structure associated with learning and memory. On the other hand, 5-HT1B and 5-HT2
receptor mutations did not impact sleep wake behavior in this species (1471).
C) Norepinephrine: The noradrenergic system modulates the expression of several

immediate early genes in brain regions that receive projections from the LC. In rats, lesions
of noradrenergic neurons of the LC using the neurotoxin 6-hydroxydopamine downregulated
the expression of Fos, nerve growth factor-induced A (NGF-IA), and the phosphorylation of
CREB protein, to levels similar to those observed during sleep (238). On the contrary, in
transgenic mice with disinhibition of NE neurons by conditional expression of chlorotoxin
(Cltx), a scorpion venom that partially blocks small-conductance chloride channels
preventing inhibitory GABAergic and glycinergic input, the level of NGF-IA expression
was increased (1104). In both of these conditions the sleep-wake behavior was not altered,

but the wakefulness-associated gene expression patterns were changed, suggesting

norepinephrine is important for coding for arousal-dependent gene expression that promotes
synaptic plasticity.
D) Histamine: Genetic studies suggest that histamine neurons are involved in the control of
cognitive aspects of wakefulness (29). Mice with a knockout of the histamine synthesizing
enzyme histamine decarboxylase (HDC) displayed reduced brain histamine, shortened sleep
latencies, and a deficiency of wakefulness and exploration when mice are faced with the
behavioral challenge of a novel environment (978). During the light period, sleep in these
mice is fragmented whereas REM sleep increases (29). These mice show impaired cortical
activation and a reduction in the differentiation of EEG signals seen between NREM sleep
and wakefulness.
E) Orexins: One of the most significant genetic contributions to sleep research is the
identification of the gene and receptors of the orexin (hypocretin) peptide and their role in
sleep. The orexins were discovered simultaneously by two groups in 1998 (290, 1101). The
study of De Lecea (290) reported the isolation of two novel peptides expressed at high levels
in the hypothalamus using directional tag PCR subtraction technology. They named these
peptides hypocretins based on their hypothalamic localization and weak homology to the
secretin/incretin family of peptides. Simultaneously Sakurai and colleagues used a reverse
pharmacology approach to identify ligands for the orphan G proteincoupled receptor
HFGAN72 (now renamed OX1R or Hcrtr1) and named the peptides orexin A and orexin B
(from the Latin orexis = appetite) since their cell bodies were located within the lateral
hypothalamic feeding area and because they stimulated feeding upon intracerebroventricular
administration (1101). They also discovered a second receptor for these peptides: OX2R or
hcrt2. Shortly after, two laboratories independently linked the orexin system to narcolepsy
(sect. VII). In dogs, the gene responsible for narcolepsy was mapped to the gene encoding
orexin receptor 2 (hcrtr2) (727). On the other hand in mice, orexin peptide mutation was
associated with narcoleptic behavior (214). In humans, narcolepsy results from the selective
loss of orexin-producing neurons in lateral hypothalamus (475, 924, 999, 1284). The
prominent reduction in orexin peptides in the cerebrospinal fluid is associated with the
human leukocyte antigen haplotype DQB1*0602, leading to the suggestion that narcolepsy
in humans is the result of an autoimmune attack on orexin-producing neurons (270, 520,
855) (see sect. VII). For a detailed discussion of the effects of orexin knockout/knockdown
on wakefulness and REM sleep in rodents, see sections II, IV, and VII.
I) Orexin system in zebrafish. Orexins also play an important role in fish behavior (966).
The orexin gene from zebrafish was cloned in 2004 (608). As in mammals, this gene is
expressed in a localized manner within a cluster of hypothalamic cells and encodes for two
peptides. The orexin-expressing neurons innervate several aminergic nuclei involved in

sleep-wake regulation (608), and orexins are needed for promoting wakefulness as well as
sleep consolidation. Overexpression of the orexin peptides in transgenic fish increases
wakefulness (1024), while orexin knockout mutants display sleep fragmentation (1464).
Studies in zebrafish orexin knockouts suggest that orexin regulates sleep-wake via
regulating the pineal melatonin production (37). In Drosophila melanogaster, no genes with
close homology to preproorexin have been found, but a group of cells which may serve a
similar functional role to the orexins express the pigment dispersing factor (PDF). PDF
released from central clock neurons promotes waking and consolidates sleep (977, 1157).
Mutation in the PDF gene or its receptors, or ablation of PDF neurons leads to reduced
activity at the beginning of the day, resulting in increased sleep and increased transitions
from wake to sleep (1157).

F) Dopamine: In mice, knocking out the D2 receptor gene leads to decreased wakefulness
with a concomitant increase in NREM and REM sleep and an increase in NREM delta
power. Sleep-wake durations were shorter during spontaneous sleep, but the homeostatic
sleep response following 2, 4, or 6 h of sleep deprivation was not affected by the absence of
the D2 receptor (1032). Conversely, in the absence of dopamine uptake from the synapse in
dopamine transporter (DAT) knockout mice, waking was increased and NREM sleep was
reduced (1425). Similarly, flies with DAT mutation were short sleepers and lacked a
homeostatic sleep response (679).
G) Gaba: The receptors for the inhibitory neurotransmitter GABA are the major target of
hypnotic agents. However, genetic manipulations of the GABAergic system have so far
shown only minor effects on spontaneous sleep wake regulation. At the receptor level, the
large number of possible subunit compositions seems to allow compensatory changes in
other subunits in response to the absence of one subunit. Such a strong compensatory
response reflects a resistance to change and possibly emphasizes the importance for normal
functioning of the GABAergic system in the brain. Point mutations in GABAA receptor
alpha1–3 subunits failed to alter sleep-wake pattern (656, 657, 1295), although gene linkage
analysis indicates significant linkage between the β frequencies of the human EEG and
GABAA receptor genes (1015). GABAA receptor alpha3 subunit knockout mice also
showed no gross changes in the EEG spectral analysis during sleep and wake (1421).
However, EEG power in the spindle frequency range (10–15 Hz) was significantly lower at
NREM-REM transitions in mutants. The homeostatic sleep response was normal in these
mice (1421). GABA receptors containing the delta subunit show a predominant
extrasynaptic localization (936, 1249) and mediate nondesensitizing “tonic” inhibition, in
contrast to “phasic” inhibition controlled by synaptic GABAA receptors (357). GABAA
delta receptor subunit knockouts did not show any differences in EEG (1422). In one study,
GABAA receptor beta3 subunit knockout mice showed no difference in 24-h baseline sleep-
wake recordings compared with wild-type mice (689), although another group of researchers
reported that NREM delta and REM sleep were significantly increased in knockouts (1424).
Mice lacking GABAB receptor 1 or 2 had an altered distribution of sleep across the day,
suggesting that GABAB receptors play a role in the diurnal regulation of sleep (1369).
3. Sleep factors
A) Adenosine: Considerable genetic evidence in mice and humans supports the role of
adenosine in spontaneous sleep-wake control and in the homeostatic sleep response
(discussed in sect. IIIC). QTL studies in mice demonstrated that a genomic region
containing the genes of two adenosine metabolizing enzymes, adenosine deaminase and S-
adenosyl-homocysteine hydrolase, impact the rate at which sleep need accumulates during
wakefulness (378). In humans, a homologous region in chromosome 20 containing an

adenosine deaminase gene polymorphism at nucleotide 22 (coding DNA 22G→A, leading
to a substitution of asparagine for aspartic acid at codon 8) influences sleep. Individuals with
the G/A genotype reported fewer awakenings at night, spent longer in NREM sleep, and
showed higher delta power during sleep than individuals with the G/G genotype (1059). The
enzyme adenosine kinase, responsible for conversion of adenosine to adenosine
monophosphate, is also important in the regulation of adenosine metabolism and sleep-wake
behavior. A transgenic mouse model, Adk-tg, with enhanced constitutive expression and
activity of cytoplasmic adenosine kinase, had reduced adenosine tone, suggested to be due to
enhanced intracellular conversion of adenosine to adenosine monophosphate, which in turn
facilitates adenosine uptake into the cell resulting in lower levels of extracellular adenosine
(358). A recent study of these mice (960) showed a significant reduction of EEG power at
low frequencies in all vigilance states and in theta activity (6.25–11 Hz) in REM sleep and
waking. These mice spent significantly less time in NREM and REMsleep compared with

wild-type mice. The homeostatic delta power response following 6 h of sleep deprivation
was attenuated compared with the wild-type mice (960).
I) Adenosine receptor knockouts and polymorphisms. Both A1 and A2A adenosine receptors
are implicated in mediating the sleep-inducing effects of adenosine. Studies in receptor
knockout mice highlight the possible confounds arising from developmental compensations
for the absence of a specific gene. For example, despite ample physiological,
pharmacological, and electrophysiological evidence for the role of A1 adenosine receptor in
sleep wake regulation, constitutive A1 receptor knockout mice failed to show any changes in
the sleep patterns and EEG parameters under baseline conditions or following sleep
deprivation (1214). However, in the absence of any developmental compensatory changes,
mice with a conditional A1 receptor deletion in forebrain and brain stem after 6–8 wk of age
showed a decreased homeostatic sleep response after sleep disruption (99). In A2A receptor
knockout mice, the homeostatic sleep response was attenuated (485). A comparative study
of the A1 and A2A receptor knockout mice showed that the wakepromoting effect of caffeine
was absent only in A2A knockout mice but not in A1 knockouts, suggesting that A2A has a
more prominent role in sleep-wake regulation (529). However, in light of the pronounced
A2A receptor-mediated locomotor effects of caffeine (338, 1460, 1470), the reported
decrease in wakefulness in A2A but not A1 knockout mice in response to caffeine, needs
careful interpretation. In humans, self-rated, caffeine-sensitive individuals showed impaired
performance on a psychomotor vigilance task after one night without sleep. Individuals with
the lowest sensitivity to caffeine were least sensitive to the detrimental effects of sleep debt
(1058). Further investigations reported that a distinct polymorphism within the A2A receptor
gene (c.1083T>C) determines the caffeine responsiveness to sleep in humans (1060).
Together, these genetic studies strongly support the importance of adenosinergic
mechanisms in sleep-wake regulation.
B) Nitric Oxide: As discussed in other sections of this review, nitric oxide produced by
nNOS or iNOS plays an important role in several aspects of sleep-wake control. Mice
lacking nNOS showed a significant reduction in REM sleep during 24 h baseline sleep
recording. In contrast, iNOS knockout mice showed a significant increase in REM sleep
during 24 h baseline sleep and a decrease in NREM sleep during the dark period (218).
Consistent with these observations are the results from studies performed to evaluate the
effect of selective inhibitors of nNOS and iNOS on recovery NREM and REM sleep that
follows prolonged sleep deprivation (589, 593). In rats, in vivo microdialysis of specific
inhibitors of iNOS, 1400W, prevented NREM recovery, while an inhibitor of nNOS, L-N-
propyl-arginine, decreased REM recovery but did not affect NREM recovery (589, 593).
C) Cytokines and Other Humoral Factors: Cytokines involved in host defense

mechanisms have been implicated as sleep factors (see sect. IIIC). The effect of the loss of
function of many of these cytokines on sleep-wake pattern has been studied using specific
gene knockout mouse models. Mice lacking the IL-1β receptor spent less time in NREM
sleep during the light period (354), whereas IL-6-deficient mice spent 30% more time in
REM sleep during 24 h of baseline without any significant change in NREM sleep or
wakefulness (896). In response to SD, IL-6 knockout mice took much longer to recover
from the sleep loss, suggesting a role for IL-6 in the dynamics of responses to SD. Like
IL-1β receptor knockout mice, the TNF receptor 1 knockout mice also sleep less during the
light period (353). The levels of TNF mRNA and protein increase during the light periods in
rats suggesting their involvement in sleep (135, 368). TNF and lymphotoxin-α are the
ligands for two TNF receptors (TNFR1, 55 kDa; TNFR2, 75 kDa in size). In mice deficient
in both of the ligands, a 15% decrease in REM sleep during the baseline light period was
observed. A similar reduction in REM sleep is also observed in TNFR2 knockout mice
(295). The slow wave parameters of the recovery sleep that followed 6 h of sleep

deprivation varied in different mice. In the double ligand knockout and TNFR2 knockout
mice, the SWA activity selectively increased in the 2.75–4.0 Hz range, whereas in TNFR1-
deficient mice, the intensity of low range SWA (0.75–2.5 Hz) increased during recovery
sleep (295). In mice lacking both IL-1β type 1 receptor and TNFR1, the power spectra of the
NREM sleep EEG showed differences compared with wildtype mice for 24 h. Following
sleep deprivation, the increase in delta power during NREM sleep of IL-1R1/TNFR1
knockout mice was of greater magnitude and of longer duration than that observed in control
mice (69). These genetic experiments suggest a role for these cytokines in normal sleep-
wake regulation in addition to their more well-known role in the response to infection.
D) Growth Hormone and Growth Hormone Releasing Hormone: Growth hormone (GH)
and GH releasing hormone (GHRH) are additional factors associated with sleep. Rats with
mutation of the GH gene exhibit stunted growth and a higher expression of GHRH in the
hypothalamus (995) as well as higher NREM sleep and decreased REM sleep during the
light period. While the homeostatic NREM sleep response was normal in these rats, the
NREM delta activity was not enhanced during the recovery sleep that follows sleep
deprivation (995). On the other hand, dwarf rats (207) show reduced responsiveness to
GHRH and thus exhibit moderate growth retardation and decreased plasma and pituitary GH
(207). The dwarf rats show decreased spontaneous sleep compared with wild-type controls
(942). Decreased spontaneous sleep was also reported for a mouse model with a point
mutation in GHRH receptor (941). Thus genetic studies support a role for the GH/GHRH
system in the control of sleep.
4. Transcription factors—Transcription factors, a large class of DNA binding proteins,

respond to the transduced intracellular signals originating from membrane proteins
(receptors, ion channels) and induce the expression of specific target gene(s) that code for
different physiological processes.
A) Fos: One of the first, and most commonly studied transcription factors with respect to the
sleep-wake cycle, is the immediate early gene Fos (243). Many studies have investigated the
distribution of Fos protein in specific populations of neurons to determine their activity
during spontaneous wake or sleep or in sleep homeostasis (78, 235–237, 440, 444, 842, 930,
1010, 1011, 1162, 1169–1171, 1459). Although lacking in temporal resolution, this
technique has been extremely useful in identifying the location and neuronal phenotype of
neurons involved in sleep-wake control. However, it should be noted that typically only a
small subset of any particular neuronal subpopulation is labeled with Fos in any particular
behavioral state (243). Fos expression primarily reflects intracellular calcium increases
rather than neuronal firing per se (664). Fos controls the expression of other genes, some of
which are listed below and may be involved in functions related to sleep-wakefulness
control such as synaptic plasticity (243). Fos knockout mice have increased wakefulness
with a concomitant reduction in NREM sleep, whereas REM sleep is not affected (1167).
Knockout of another member of the Fos family, fosB, caused decreased REM sleep without
other changes in sleep or wake (1167).
B) Camp Response Element-Binding Protein: Another stimulus-induced transcription

factor, the cAMP responsive element binding protein (CREB), is implicated in memory
formation and sleep in both flies (496) and rodents (442). Flies with mutations resulting in
increased cAMP (resulting in increased CREB activity) rested significantly less, whereas
mutations that abolish CREB activity rested more with increased recovery sleep (496).
Similarly, mice lacking the alpha and delta isoforms of CREB had reduced time spent awake
and more NREM sleep (442).

C) Transcription Factors Associated with the Circadian Pacemaker: Several

transcription factors and inhibitors of transcription factors involved in circadian behavior
also directly impact the sleep EEG parameters associated with sleep homeostasis (379).
Homeostatic sleep regulation is considered independent of the circadian regulation since it is

intact in animals with lesions of the SCN, the circadian pacemaker (860, 1293, 1305).
However, in animals with intact SCN, several transcription factors originally recognized as
circadian factors also impact homeostatic sleep parameters, as described next.
I) The neuronal Per-Arnt-Sim-type (NPAS) and cryptochromes. The NPAS domain protein
2 combines sensor and effector functions by sensing the redox state of the cell (1086) and
regulating the transcription of metabolic genes such as lactose dehydrogenase1 ldh1) and the
period gene (per-2 gene), the latter of which is also implicated in sleep homeostasis. Sleep
characteristics are altered in the absence of Npas-2 as demonstrated by the study of NPAS2-
GENE knockout mice. These mice showed a decrease in NREM sleep time, even after
periods of sleep deprivation (380). During NREM sleep, the spindle activity was reduced
and the EEG activity within the delta range was shifted to faster frequencies. Sleep is also
altered in mice lacking cryptochromes (Cry), transcriptional regulators integral to circadian
oscillations. Cry 1 and 2 knockout mice exhibit longer bouts of NREM sleep and higher
EEG delta power during NREM sleep (1426). In these mutants, the absence of
transcriptional inhibition of Clock and NPAS2 proteins is suggested to cause the increased
sleep duration. In contrast, in clock gene knockout mice, NREM sleep durations are
decreased, as was observed in NPAS-2 gene knockout mice (912). The deletion of yet
another transcription factor associated with circadian rhythmicity, the albumin D-binding
protein (Dbp), results in decreased sleep consolidation and NREM sleep delta power (381).
Regulators of circadian rhythms can impact sleep timing, duration, and intensity. The
transcriptional factor NPAS2 regulates the expression of the Period proteins, per1 and per2.
Per1 and per2 mutant mice have altered circadian rhythmicity (18), but sleep homeostasis is
unaltered (654). In humans, per2 gene mutations were shown to contribute to 4 h advance of
the sleep/wake rhythm in some cases of familial advanced sleep-phase syndrome (1296). A
recent report further confirmed the role of Per proteins in sleep timing in relation to the
light-dark cycle. A polymorphism in the Per3 gene has been associated with morning/
evening sleep-wake preferences. Individuals with a 5-repeat allele (per35/5) show increases
in alpha activity in REM sleep, theta/alpha activity during wakefulness, and slow wave
activity in NREM sleep (310). Sleep deprivation results in greater cognitive deficits, as
demonstrated by brain fMRI-assessed responses to executive tasks compared with
individuals with the wild-type allele (310). In one family, a mutation in the casein kinase 1δ
gene which interacts with the Per protein, and a per mutation in another family, were
associated with familial advanced sleep phase syndrome (1296, 1447). Another protein,
Dec2, suggested to repress the expression of Clock/Bmal1, was shown to regulate sleep time
in humans. Point mutations in the dec2 gene were identified in a family of short sleepers (6
h sleep) (487). These reports in humans collectively suggest interactions between
regulations of circadian rhythms and sleep timing, duration, and intensity.
5. Ion channels
A) Potassium Channels: Voltage-dependent potassium channels (Kv channels). The Kv
channels are activated by depolarization and are present in a wide range of tissues. They are
composed of four alpha units that form a pore and four beta units closely associated with the
alpha units, forming an octameric channel. Nine Kv channel alpha subunit families (Kv1–9)
have been described (250). Genetic studies have shown strong associations of some of these
Kv channels with sleep-wake regulation.

I) The voltage-gated potassium channel, Shaker. This channel has been shown to play a
major role in sleep in Drosophila melanogaster 231). Shaker mutants had reduced sleep and
were resistant to the effects of sleep deprivation (231). Further studies in Drosophila
identified a novel glycosylphosphatidyl-inositol-anchored protein/gene, which as indicated

by the name, SLEEPLESS (SSS), prevents sleep (650) and regulates the function of Shaker
(1437). Flies carrying a defective shaker gene, the null allele minisleep (Shakermns), or other
null alleles of Shaker, are short sleepers (3–4 h/day), while the wild-type controls sleep 8–14
h/day (231). Similarly, loss-of-function mutations in another gene, Hyperkinetic, that codes
for the regulatory (beta) subunit of the Shaker channel, results in reduced sleep (170). Thus
there is ample evidence in flies demonstrating the importance of voltage-gated potassium
channels in normal sleep-wake regulation. In mice, the Kv1 alpha subunit family of
potassium channels is closely related to Shaker in flies. A null mutation in the Kv1.2 gene,
Kcna2, in mice, when homozygous, generates seizures in pups after P17 and the pups die at
a young age (postnatal day 28). However, sleep measured at P17 shows significantly less
NREM sleep (315). The sleep studies in these mutant mice, while limited to young ages, are
nevertheless indicative of the importance of the Kv1.2 channels in sleep regulation.
II) Delayed rectifier Kv3.1 and Kv3.3 channels. Subunits of fast-activating/deactivating,

high-threshold voltage-gated potassium channels, encoded by the genes Kcnc1 and Kcnc3,
are widely expressed in several brain regions including the thalamus, basal ganglia, and
cerebellum, areas implicated in the control and modulation of arousal states and motor
activity (1083). Although Kv3.1 and Kv3.3 subunits are expressed throughout the brain,
their expression is restricted to distinct neuronal subpopulations (204, 1146, 1396, 1397). In
neocortex, thalamus, hippocampus, and striatum, Kv3-type channels are found in
GABAergic cells that also express the calcium-binding protein parvalbumin (PV), a marker
for fast-spiking neurons. Kv3-type channels are involved in the rapid repolarization of the
action potential, and their presence in neurons correlates with narrow action potentials, fast
afterhyperpolarization, and high-frequency firing. Single Kv3.1 mutation or double Kv3.1/
Kv3.3 mutations led to an increase in action potential duration of 20 and 60%, respectively
(349). Mutation of these genes showed profound effects on sleep-wake patterns in mice.
Mice with a knockout of Kv3.1 show increased gamma oscillations and markedly reduced
delta oscillations (566). Mice with double mutations display severe sleep loss (40% decrease
in the light period and 22% decrease in the dark period) as a result of unstable slow-wave
sleep (349, 567). Absence of these two gene products led to a 70% reduction in the cortical
spectral power at frequencies <15 Hz. In addition, the number of sleep spindles in vivo as
well as rhythmic rebound firing of thalamic reticular neurons in vitro is diminished in
double mutant mice (349). The mice show a 70% reduction in the absolute power in the
delta band and fail to show a homeostatic sleep response following 6 h of acute SD (349). It
was suggested that the Kv3.1 and Kv3.3 channels in the GABAergic thalamic reticular
neurons play an important role in the thalamocortical network in generating oscillations

typical for sleep (567).
Another member of the voltage-gated potassium channel family, Kv3.2, is also expressed
abundantly in the thalamus, neocortex, and hippocampus and is moderately expressed in
medial septum, LC, and basal ganglia (1082, 1397). Deletion of the Kv3.2 gene in mice
results in reduced power in the NREM EEG frequency range 3.25–6 Hz, suggested to be a
consequence of decreased efficacy of GABAergic interneurons that express Kv3.2 in cortex.
Unlike the deletion of Kv3.1 subtype channels which increases wake EEG at gamma
frequencies (20–60 Hz)(566), the Kv3.2 deletions do not affect waking EEG parameters
(1382).
III) Potassium-selective leak channels. Potassium-selective leak channels possess two pore-
forming domains in each subunit (431). The leak currents generated by these channels (also

known as resting or background conductances) control the resting membrane potential and
input conductance, thereby influencing the excitability of the neurons (431). As described in
section II, many neurotransmitters excite neurons by inhibition of resting K+leak currents.
This is crucial to the regulation of “state-switching” in cortical and thalamic neurons.

Recently, one such acid-sensitive and anesthetic activated, two-pore domain potassium
channel subtype, TASK-3, was shown to be involved in the regulation of cortical type II
theta oscillation (also known as arousal theta) in the frequency range 4–9 Hz (965). Mice
with TASK-3 gene knockout showed an absence of such type II theta oscillations. They
displayed a slower progression into sleep (increased sleep latency) during spontaneous sleep
in the lights-on period. In these mice sleep was also fragmented, with a higher number but
shorter duration of sleep episodes.
B) Calcium Channels: Genetic evidence suggests that the lowthreshold, voltage-activated,

T-type calcium channels are involved in the regulation of sleep and particularly in sleep
rhythms. Low-threshold calcium channels are crucial for shaping subthreshold membrane
fluctuations and thereby contribute to such behaviors as rebound burst firing (740) and
rhythmic oscillation (64, 458). The α1G subunit of T-type calcium channels is widely
expressed in the brain, including thalamocortical neurons, and thalamic reticular neurons
and cortex (1269). Both constitutive and targeted deletions of the α1G (Cav3.1) subunit of
T-type channels have been studied in the context of sleep regulation. Conflicting
observations in sleep parameters were reported. In one study, power spectral analysis
showed that the power of low frequencies (2– 6.5 Hz) in NREM sleep was significantly
reduced compared with their wild-type littermates (695). Another study showed that in mice
with either a α1G constitutive knockout or a localized thalamic specific knockout, the
cortical EEG delta power during NREM sleep was increased (32). These mice have
difficulty in initiating and maintaining sleep. The differences in the observations may reflect
differences in the manner the knockout mice were constructed.
In the dendrites of thalamic reticular neurons, the calciumdependent small-conductance

(SK)-type K+ SK2, Kcnn2) channels and the T-type calcium channels act in concert with the
sarco/endoplasmic reticulum calcium-ATPases (SERCAs) to influence the characteristic
frequency bands of NREM sleep (55, 64). In SK2−/− knockout mice NREM sleep is
fragmented, with more frequent awakenings, indicative of decreased sleep depth (266).
Consistent with this behavior, the EEG spectral profile showed a fourfold reduction in the
delta (1–4 Hz) frequency range and a more than threefold reduction in the sleep spindle (10–
15 Hz) band. During waking and REM sleep, a pronounced reduction was observed in the
10-Hz range, i.e., a slowing of EEG theta oscillations.
6. Genes implicated in sleep functions

A) Synaptic Plasticity, Learning, and Memory: Cellular functions such as transcription,

cell signaling, and synaptic plasticity are integral to learning and memory. Alteration of
these functions also affects sleep-wake regulation. Mutations in many of the genes
associated with the molecular cascades underlying learning and memory have been shown to
alter sleep-wake cycles. On the other hand, alterations in sleep-wake patterns impact
learning and memory (see sect. V) (503).
One signaling pathway implicated in both processes involves the signaling molecule cAMP
and cAMP-dependent protein kinase A (1350). Activation of the cAMP signaling pathway
promotes waking. In flies, the expression of cAMP and protein kinase A in the mushroom
bodies, an important region for memory formation (488), regulates sleep (568, 1006). In
transgenic mice, with a dominant negative mutation in the regulatory subunit of protein
kinase A in neurons, NREM sleep is fragmented with increased NREM delta activity and

reduced spindle amplitude, whereas REM sleep is increased, suggesting protein kinase A is
involved in sleep-wake regulation (491). cAMP affects gene expression via the cAMP
response element binding protein (CREB). Mice lacking CREB have reduced LTP and
memory formation and exhibit shorter wake bouts, whereas NREM bouts are longer (441,
442). These studies are broadly consistent with the idea that synaptic potentiation
predominates during waking as discussed in section III, in the context of the synaptic
homeostasis theory of sleep.
Another protein involved in synaptic plasticity that has been investigated in the context of
sleep is Homer1a. The Homer proteins are a family of proteins broadly expressed in the
brain where they serve as molecular scaffolds at synapses. Increased expression of Homer
1a reduces glutamate-induced intracellular calcium release and thus down-regulates synapse
formation (1103, 1432). All the homer proteins are expressed constitutively except for
Homer1a, an immediate early gene originally isolated as a neural activity-regulated gene
product from seizure-stimulated rat hippocampus. In rodents, the expression of Homer1a is
modulated during sleep and wakefulness and is highly upregulated during sleep deprivation
(233, 914). Further evidence for sleep deprivation-induced upregulation of Homer1a comes
from transcriptome profiling of inbred mouse strains where Homer1a is consistently
increased in all strains following sleep deprivation (795). QTL analysis showed a significant
association of Homer1a with sleep-wake regulation and sleep homeostasis (771).
A recent study (425) monitored the expression of synaptic genes over the course of the
normal sleep-wake cycle, as well as following periods of sleep deprivation in Drosophila.
The expression of synaptic proteins decreased in a sleep-dependent manner (425). The
Drosophila Fragile X mental retardation gene (dfmr) is one synaptic plasticity related gene
that has been shown to regulate sleep need, although the exact mechanism is unknown
(171). This gene codes for a protein (dFMRP) that is present in dendritic spines. The
expression of this gene is high during development when sleep is higher and synaptic
plasticity is high. Increased expression of dFMRP, even if restricted to mushroom bodies,
decreases daily sleep and decreased expression increases sleep. Both gain and loss of
dFRMP expression result in loss of sleep homeostasis (171).
B) Sleep and Energy: Brain energy use varies between sleep and wakefulness. During
waking, higher levels of energy are consumed compared with sleep (see sect. IIID). Gene
expression studies have shown that increased ATP use during waking leads to the
upregulation of enzymes involved in the synthesis of ATP by oxidative phosphorylation.
Five, multsubunit enzyme complexes, complexes I to V (Cox I-V) constitute the
mitochondrial oxidative phosphorylation system, and enzymes belonging to each complex
are upregulated during waking, indicating an increased need for ATP synthesis. For
example, the expression of Nadh2, cytochrome c oxidase (CoxI), Cox4, and Atp5a genes
increase during sleep deprivation in mammalian cortex (233, 239, 240, 242). A concurrent
increase in the activity of cytochrome c oxidase has been reported in mice and rats (919,
920). The expression of mitochondrial uncoupler protein 2 is also increased during sleep
deprivation (245). The nuclear transcription factors Nrf1 and 2 (known as nuclear
respiratory factors) involved in the transcription of the components of oxidative
phosphorylation are also upregulated during sleep deprivation (919). The essential nature of
the genes coding for oxidative phosphorylation prevents any studies using knockout mice,
but conditional knockouts may prove useful in further examining the effect of these genes in
the regulation of sleep and wakefulness.

B. Proteomic Studies
Changes in gene expression are suggestive of potential cellular alterations associated with
different vigilance states. However, the complexity of the regulation of downstream
processes such as translation of mRNA into protein, posttranslational modifications of

translated proteins, and protein-protein interactions prevents a direct assessment of the effect
of gene expression on physiological processes. Since proteins are the ultimate players
capable of influencing vigilance states, it is important to understand their regulation.
Proteomics is an experimental approach to examine the proteins involved in the control of
biological processes and pathways. The proteome indicates the quantitative expression
profile of a cell, an organism, or a tissue under defined conditions. In contrast to the
temporally constant genome, the proteome is dependent on intracellular and extracellular
parameters. Thus the analysis of a proteome represents an important supplement to the
genome analysis.
The use of proteomic approaches for investigating the regulation of vigilance states is
relatively new. As the efficiency of proteomic methodology is being refined for increased
sensitivity and inclusion of a wider range of proteins, a few attempts have already been
made to explore overall protein changes during sleep-wake cycle or during prolonged
waking (75, 234, 986, 1008, 1345, 1346). Most of these studies in the cortex, BF, or
hippocampus of rat brain have compared protein profiles during sleep with those during
prolonged sleep deprivation. So far, only two studies have examined protein changes after
10 min of spontaneous sleep or wake (1345, 1346), and no studies have examined proteomic
changes selective to REM sleep. Major challenges for such studies originate from the short
durations of sleep-wake episodes in rodents, especially REM sleep. During spontaneous
sleep-wakefulness and prolonged waking, the major groups of proteins in the rat BF and
cerebral cortex that showed alterations were associated with the following four functions: 1)
synaptic plasticity, e.g., SNAP25, Amphyphysin, and vesicular N-ethylmaleimide fusion
(NSF) protein; 2) the cytoskeleton, e.g., RhoB and GTP binding protein rab3D, Cofilin; and
3) cellular energy metabolism, e.g., creatine kinase, NADH dehydrogenase, pyruvate
dehydrogenase, glutathione synthase, and glyceradehyde-3-phosphate dehydrogenase (75,
1345). Surface-enhanced laser desorption-ionization (SELDI) studies identified increases in
hemoglobin alpha 1/2 and beta as well as cytochrome c in rat cerebral cortex (234). 4)
Cellular stress responses, as discussed next.
Taking a lead from the wide-spectrum genomic and proteomic screening, one group of
proteins, the heat shock/chaperone proteins, has been studied in more detail. Short periods of
sleep deprivation (3–12 h) result in an increase in these proteins that are involved in
preventing misfolding of proteins in the endoplasmic reticulum (153, 909). This unfolded
protein response is considered to be a protective action that counteracts the cellular stress
associated with sleep deprivation (153). The mRNA level of one such protein, the
immunoglobulin binding protein, BiP, the most abundant protein in the endoplasmic
reticulum (also known as glucose regulated protein 78, GRP78 or heat shock protein 5A,
HSP5A) increases with prolonged wakefulness (229, 233, 772, 795, 1275). BiP binds to the
hydrophobic domains of the nascent peptides and helps to prevent misfolding while the rest
of the protein is being synthesized (423). In Drosophila, BiP levels regulate the quantity of
recovery sleep (908). Transgenic animals that overexpressed BiP displayed increased
recovery sleep following deprivation compared with animals that had reduced BiP levels.
C. Summary
A variety of genes and proteins have been associated with sleep and wakefulness by means
of genetic and proteomic studies. Comparative studies have underscored the universal nature
of sleep-wake regulation in different species. Perhaps unsurprisingly, mutations or

knockouts of genes encoding ion channels or proteins involved in neurotransmitter release/

uptake/transduction exert major effects on the sleep-wake cycle. In addition, genetic
techniques have been instrumental in the identification of novel peptide neurotransmitters
controlling the sleep-wake cycle such as the orexins, and their connections to human sleep
physiology and pathophysiology. Furthermore, genetic and proteomic studies have provided
important clues as to sleep function by identifying the major classes of genes and proteins
that vary according to the sleep-wake cycle, in particular those involved in synaptic
plasticity, cytoskeletal function, and cellular stress and energy regulation.
VII. SLEEP PATHOLOGY AND TREATMENT

In this section we summarize current knowledge of disorders of wakefulness and sleep and
how they relate to the brain mechanisms of waking as well as NREM and REM sleep
described in previous sections. Although epilepsy can be considered a disorder of
wakefulness, this large topic is beyond the scope of this review (for more information, see
Steriade and McCarley, Ref. 1228).
A. Coma
Profound changes in wakefulness and consciousness occur in patients with brain injury
resulting in comatose, vegetative, or minimally conscious states. The EEG shows variable
changes depending on the type and stage of coma, with alpha/theta rhythms, spindles, and
triphasic/delta waves most common (139, 602). In general, faster rhythms typical of
wakefulness are diminished and unresponsive to external stimuli.
In those coma patients who do not have widespread, diffuse loss of forebrain neurons, coma
is normally associated with loss of activity and neurons at the origin or along the pathways
of the ARAS, as described in section II. In the upper brain stem, damage is observed along
the midline at the origin of the ARAS encompassing raphe nuclei, LC, LDT, parabrachial
nucleus, and PnO (980). In rodents, cell-specific lesions of parabrachial but not neighboring
brain stem neurons caused a comalike state (see sect. IIB), suggesting that this nucleus may
be particularly important in maintaining wakefulness (397). Glutamatergic neurons in this
region were shown to provide a major input to the BF (397). Surprisingly, a cat model of
unconsciousness induced by cerebral concussion reported increased glucose utilization in
the dorsomedial tegmentum adjacent to the VTG, suggesting that neurons in this
dorsomedial area were activated (486). Infusions of carbachol in this area produced
behavioral suppression (486), similar to cat models of REM sleep utilizing this
pharmacological agent (see sect. IV). Along the ascending dorsal pathway, coma is observed
following bilateral lesions of the regions of the thalamus supplied by the paramedian artery,
i.e., dorsomedial nuclei and intralaminar centromedial, parafascicular and centrolateral
nuclei (1137). Surprisingly, in rodents, extensive lesions of the thalamus failed to have
pronounced effects on the EEG (397).
In some brain-damaged patients, imaging studies have indicated appropriate brain

responsiveness to external commands or stimuli, indicating some preservation of function
(1135, 1136). In these patients, partial restoration of function has been observed following
deep brain stimulation of the central thalamus, administration of dopaminergic agents, or
administration of the sleep aid and GABAergic receptor modulator zolpidem (Ambien). It
has recently been postulated (1135) that all of these interventions act by enhancing activity
in nonspecific thalamic projections to the cortex either directly (deep brain stimulation) or
by reducing the inhibitory input from the basal ganglia (dopaminergic agents, zolpidem) to
nonspecific thalamic nuclei. The paradoxical alerting effect of zolpidem may be due to a
preferential inhibition of globus pallidus neurons, which project to the thalamus and are
potently inhibited by zolpidem (220, 1135). The strong wake-promoting effects of the

dopaminergic system and the weaker arousal effects of adenosine A2A antagonists in normal
humans/animals may also be explained by such interactions of the basal ganglia and
intralaminar thalamus.
Coma in humans is rarely associated with damage to the final node of the ventral pathway,
the BF, presumably because its blood supply arises from multiple cerebral arteries so it is
less susceptible to stroke. However, recent studies in animals suggest that extensive cell-
specific lesions of the BF can also result in a comalike state (397, 611).
B. Insomnia
Insomnia, defined as insufficient quantity or quality of sleep, is the most prevalent sleep
disorder. Approximately 50% of adults complain of occasional insomnia, and 10–15% of
chronic insomnia, persisting for at least 1mo (892). Insomnia can involve difficulty falling
asleep, staying asleep, or poor quality of sleep. Consequences of insomnia including daytime
sleepiness, lack of energy, and cognitive impairment (835). Insomnia may even precipitate
or accompany the development of psychiatric disorders (913). Insomnia is classified into
two types: comorbid, with other psychological and/or physical pathologies; and primary,
existing independent of other conditions (931).
1. Animal models of insomnia—Clinical and animal studies have employed a variety of

sleep disruption techniques to mimic the symptoms of various types of insomnia (835).
Other animal models investigate the neural mechanisms causing insomnia (1061). Stress-
related models include classical fear conditioning with foot shock, cage change, or
disturbing stimuli such as noise, unpleasant odors, cold, and pain (987, 1061). Some forms
of insomnia may be due to hyperarousal (121, 929). Thus insomnia may also be induced
pharmacologically in animals through manipulations of the vigilance-state circuitry
described in earlier sections, e.g., through serotonergic synthesis inhibition by
parachlorophenylalanine (PCPA) (899), adenosine receptor antagonism with caffeine (384),
or enhancement of histaminergic (1044), dopaminergic (129), or orexinergic tone (1024,
1073). Genetic models that involve manipulation of circadian clock genes may also be
regarded as insomnia models (see sect. VI). A rare autosomal dominant genetic disorder,
fatal familial insomnia, involves a gene mutation of the prion protein gene prnp 878).
Transgenic mice with a mutation of the prnp gene exhibit very fragmented sleep, as well as
an exaggerated response to sleep deprivation (313, 1294) correlating with damage to the
thalamic branch of the ARAS.
2. Possible neural circuits mediating insomnia—Recent preclinical investigations

have begun to unravel the neural mechanisms by which cognitive, emotional, and sleep
neural circuitry may interact to generate insomnia (186, 1116). For example, the sleep-
promoting VLPO as well as the wake-promoting orexinergic zone of the lateral
hypothalamus receive projections from mnemonic and emotion-related regions such as the
infralimbic cortex, lateral septum, bed nucleus of stria terminalis, amygdala (central
nucleus), and ventral subiculum (222, 1102, 1466). In an insomnia model involving cage
change as a stressor, Fos protein was expressed in arousal, autonomic, and surprisingly, also
in sleep-promoting regions, suggesting coactivation of arousal and sleep systems (186).
Consequently, it was suggested that, in contrast to development of sleep-promoting
compounds, attenuation of arousal systems may be a more effective approach to treat
insomnia.
3. Imaging of insomnia—Functional imaging studies in humans have described brain

regions with altered activity in insomnia (303, 304, 929). SPECT and PET studies have
revealed that, during transition into NREM sleep in the insomniac, the normal reduction of

glucose consumption is attenuated in the anterior cingulate cortex, the medial prefrontal
cortex (mPFC), and limbic/arousal systems. Furthermore, during wakefulness, decreased
glucose metabolism was evident in the cortex, thalamus, hypothalamus, and reticular
formation relative to controls (303, 304, 929).
4. Insomnia treatment—Pharmacological treatment of insomnia usually involves sleep

aids acting as agonists of the α1 subunit of the GABA receptor, such as benzodiazepines
and the “Z” drugs (zolpidem, zalpelon, zopiclone) (329) which potentiate the action of
sleep-promoting GABAergic neurons. Newer compounds to promote sleep that do not
primarily involve manipulation of GABAergic systems have been recently introduced, such
as the melatonin receptor agonist ramelteon (964); ritanserin, an antagonist of both 5-HT2A
and 5-HT2C receptors (1372); and antidepressants such as trazadone (848) and agomelatine,
a unique compound that acts as both a serotonergic 5-HT2C antagonist and melatonin
receptor agonist (879). A variety of other compounds used to treat insomnia antagonize
histaminergic (676) and orexinergic wake-promoting nuclei. In preliminary studies, dual
orexin receptor antagonists, almorexant and MK4305, were shown to enhance both NREM
and REM sleep and reduce wakefulness in animals, healthy humans, and insomniacs (140,
505).
C. Sleep Apnea
In sleep apnea, the patient stops breathing (the apneic moment) during sleep, leading to
blood oxygen desaturation (hypoxia), as well as an elevation of carbon dioxide levels

(hypercarbia, also known as hypercapnia). Sleep apneas are divided into three categories:
central, obstructive, and complex (a combination of obstructive and central sleep apneas).
Central sleep apnea involves dysfunction of the central respiratory control centers in the
brain (1401). Obstructive sleep apnea (OSA) affects nearly 7% of the general population
(1468) and is characterized by episodic cessation in breathing during sleep due to closure of
the airway, of at least 10 s in length, and usually accompanied by hypoxia and hypercarbia
(301, 1401). The apneic moment is usually terminated by a slight arousal, as well as an
increase in sympathetic tone, as airway patency is reestablished. OSA diagnostic criteria
include a rate of 5 or more apneic episodes per hour, and the most severe cases may
experience upwards of 70–80 moments per hour. The sleep profile of an OSA patient
includes sleep fragmentation and decreased prevalence of both deep stage NREM and REM
sleep.
1. Mechanism of apnea—A reduction of activity in motoneurons innervating the upper

airway during sleep is the cause of sleep apnea, occurring during both NREM and REM
sleep. As described in section IV, a reduction in the activity of motoneurons occurs during
NREM sleep and progresses to complete silence during tonic periods of REM sleep so that
the upper airway is more susceptible to collapse during inhalation in susceptible individuals
(369, 614, 760, 852, 948, 1189). Respiratory motoneurons follow a similar pattern, with
expiratory pharyngeal and upper airway (hypoglossal, XII) motoneurons being the most
strongly suppressed whilst phrenic motoneurons that drive the diaphragm are the least
affected (398). Following the apneic moment, the upper airway reflex occurs, during which
dilator muscles activate, reestablishing the patency of the airway (1401).
2. Cognitive consequences of apnea-induced sleep disruption—The abnormal

sleep profile of OSA patients leads to daytime sleepiness, which is often comorbid with
impaired cognitive function (626). Deficits in executive function among apneic patients
have been assumed to be related to prefrontal lobe dysfunction caused by intermittent
hypoxia (IH) (88). Consistent with this idea, rats exposed to IH exhibited spatial learning
and memory impairments (437). However, sleep disruption itself can affect both “lower”

level processes, such as arousal, as well as “higher” cognitive processes, such as memory
and executive function (835). Thus the extent of behavioral impairment in OSA patients
correlates with both the degree of hypoxemia and with the degree of fragmentation (87).
Animal models mimicking the SF that occurs during OSA (see sect. V) revealed increased
sleepiness and cognitive decrements in attention and working memory-tasks (844, 1273) as
well as impaired hippocampal LTP (1273). Thus one cannot assume that the deficits in
higher cognitive function observed in apneic patients are due solely, or even primarily, to
hypoxemia during sleep. In fact, a functional imaging study suggested that working memory
deficits exhibited in patients with sleep apnea may be due to the sleep fragmentation, not
nocturnal hypoxia (1288).
3. Pathological features of OSA—Apneic episodes during OSA are accompanied by

abnormal blood gas levels of oxygen (hypoxia) and carbon dioxide (hypercarbia). Animal
models of intermittent hypoxia revealed cognitive deficits, oxidative stress, an increase of
gene products related to apoptosis, and a decreased number or functional activity of
catecholaminergic and cholinergic BF neurons (301, 835). However, whether apoptosis
actually occurs is controversial (301). Clinical and animal studies have determined that
exposure to intermittent hypoxia promotes reactive oxygen species, and in turn oxidative
stress (301, 693). Reactive oxygen species formation has been shown to lead to
physiological pathology, including cardiovascular morbidity, sympathetic activation, and
hypertension. Accordingly, OSA has been confirmed to be a risk factor for stroke,
atherosclerosis, heart attack, and hypertension (301, 1156).
4. Brain imaging of OSA patients—Investigations of brain anatomical abnormalities in

OSA patients have provided some evidence of structural injury. MRI studies have reported
gray matter morphological abnormalities in the frontal, anterior cingulate, and parietal
cortices, mammillary bodies, temporal lobe, hippocampus, and cerebellum (678, 769). Most
recently, diffusion tensor imaging revealed extensive abnormalities in white matter,
including the corpus callosum, cingulum bundle, fornix, cerebellar peduncle, as well as
within structures such as the deep cerebellar nuclei and the cingulate, prefrontal, and parietal
cortices (770). Thus neural damage may occur in OSA. However, such findings were not
replicated by other investigators (937), a discrepancy that may be due to differences in
analysis methodology and subject variation (770).
5. Apnea treatment—Effective treatments for apnea include the CPAP (continuous

positive airway pressure) device, dental devices, weight loss, and surgery (672).
Pharmacological interventions to treat OSA increase the activity of the upper airway dilator
muscles, as well as the ventilatory drive, e.g., noradrenergic and serotonergic agents,
progestogens, and bronchodilators. Some patients experience the majority of apneic
moments during REM sleep. Therefore, treatment with serotonergic agents that suppress
REM sleep may be useful (1349). The stimulant modafinil has been prescribed to address
the daytime hypersomnia experienced by the OSA patient (616).
6. Sudden infant death syndrome—Although not strictly an apneic syndrome, sudden

infant death syndrome (SIDS) may be considered under the umbrella term of sleep-
disordered breathing. SIDS deaths are usually caused by hypotension and bradycardia, due
to an abnormal response to respiratory challenge (634). SIDS involves aberrant brain stem
control of cardiorespiratory mechanisms by the developing brain. In one study, attenuated
muscarinic cholinergic receptor binding of the arcuate nucleus, which is involved in
cardiorespiratory mechanisms, was documented in SIDS cases (632). Also, serotonergic
abnormalities in SIDS cases were recently shown (633), including deficient receptor binding
and decreased tissue levels of both serotonin and the serotonergic synthetic enzyme

tryptophan hydroxylase (318). Due to such abnormalities, the infant may have an attenuated
response to respiratory challenges such as hypoxia or hypercapnia. An unusually high
reoccurrence rate of SIDS has been documented within families, suggesting genetic
susceptibility (634).
D. Metabolic Syndrome
Metabolic syndrome (MetS) consists of a combination of symptoms (low high-density
lipoprotein cholesterol levels, abdominal obesity, elevated triglycerides, hypertension,
insulin resistance/glucose intolerance) which increase the likelihood of developing
cardiovascular disease (330). If at least three of these five criteria are present, the patient is
considered to be suffering from MetS (330). Epidemiological studies indicate that poor sleep
is associated with MetS symptoms (1200), although the direction of causality in patients
with MetS remains to be determined; thus sleep disturbances may cause MetS symptoms or
vice versa. Conversely, treatment of sleep disorders may help alleviate glucose and energy
metabolism abnormalities (1200). An association of MetS with sleep is perhaps not
surprising considering that one function of sleep appears to be regulation of energy
metabolism (see sect. III).
Behavioral alterations of sleep are also associated with increased risk for MetS (1333). Shift
work enhances the risk for a number of MetS symptoms by increasing oxidative stress
(1158). Short or long sleep duration is associated with increased likelihood of MetS
symptoms (405), with the incidence doubling in those that slept less than 6 h a night.
Disturbed circadian/diurnal regulation of sleep also leads to MetS in animals. Homozygous
Clock mutant mice with attenuated diurnal rhythms of feeding ate more, gained more
weight, and had increased peripheral metabolic hormones such as insulin and leptin and
abnormalities in hypothalamic hormones which regulate food intake (1313). Knockout of
other circadian regulatory genes causes similar metabolic defects (41).
E. Narcolepsy
Narcolepsy is defined by a tetrad of symptoms: excessive daytime sleepiness, cataplexy,
hypnagogic hallucinations, and sleep paralysis (1467). Narcolepsy affects all three stages of
sleep and wakefulness, with a prevalence of ~1 in 2,000 individuals and an onset in early
adulthood (1127, 1261). As originally described by Westphal (1400) and Gelineau (408) at
the end of the 19th century, in this disorder there is a pronounced fragmentation of
wakefulness, disrupted night-time sleep and intrusion of REM signs into wakefulness.
Particularly striking and disabling are involuntary sleep attacks and episodes of (REM-like)
muscle atonia induced by emotional arousal (cataplexy) with preservation of consciousness
resulting from both abnormal control of REM control mechanisms (see below) and
alterations in emotional processing (202, 303, 1309). Additional REM-like symptoms are
hypnagogic hallucinations (hallucinations occurring around sleep onset or awakening) and
sleep paralysis (inability to move following awakening from REM sleep).
Narcolepsy is caused by loss of orexin neurons or orexin receptors. Following the seminal
discoveries of the gene defect responsible for a heritable form of narcolepsy in dogs
(alteration of orexin type 2 receptor) (727) and narcolepsy-like symptoms in orexin
knockout mice (214), this disease is now known to be caused by a loss of orexin/hypocretin
neurons, orexin peptides, or their receptors. A marked reduction in the CSF levels of these
peptides is found in living narcoleptic patients, whereas post mortem brains of human
narcoleptics show a loss of orexin neurons (924, 999, 1284). A mutation in the preproorexin
gene was found in a rare early-onset case of narcolepsy (999). Orexin neurons can also be
damaged following stroke (1129) or traumatic brain injury (82), leading to excessive
daytime sleepiness. Animal studies (217) show a narcoleptic phenotype following 1)

knockout of orexin peptides or orexin receptors (214, 640, 870, 1415), 2) nonspecific lesion
of the lateral hypothalamic area where orexin neurons are concentrated (414), and 3) genetic
modification introducing a toxic transgene (ataxin-3) specifically in the orexin neurons (96,
479). However, the complete narcoleptic phenotype including cataplexy is not observed
following short-term pharmacological blockade of orexin receptors (140) or RNAi-mediated
knockdown of orexin peptides (221), suggesting that a more prolonged loss of orexin
signaling is required to observe the full narcoleptic phenotype. This idea is consistent with
studies which revealed neurodegenerative changes (1178), alterations of emotional arousal,
and upregulations of cholinergic and dopaminergic systems involved in REM sleep control
in narcolepsy (923).
1. Mechanisms underlying cataplexy—The multiple mechanisms by which orexins

promote consolidated wakefulness and suppress REM sleep were discussed in sections II
and IV, respectively. Early pharmacological studies in narcoleptic dogs suggested increased
activity of cholinergic REM-on and decreased activity of aminergic REM-off systems is
important for causing cataplexy. Infusions of cholinergic agonists in the pontine reticular
formation caused cataplexy in normal dogs and exacerbated symptoms in narcoleptic dogs
(1055, 1056). Furthermore, enhanced acetylcholine release was detected in the pons during
cataplexy (1054). Recent data report an association of the choline kinase β (CHKB) gene
involved in acetylcholine synthesis with susceptibility to narcolepsy (864). Enhanced
cholinergic enzyme levels were detected in brain stem cholinergic neurons in orexin
knockout mice (594). Electrophysiological studies in narcoleptic dogs revealed a cessation

of firing of REM-off LC norepinephrine neurons (1435) and an increase in firing of muscle
atonia related neurons in the medial medulla (1176, 1177) preceding and during cataplexy.
Behavioral arrest reminiscent of cataplexy was observed following intense activation of the
locus coeruleus with optogenetic techniques (196). More recent recording studies confirmed
the cessation of firing of LC neurons and demonstrated its selectivity, since histaminergic
neurons do not change their firing and DRN serotonin neurons show only a reduction and
not a complete cessation of activity (564, 1436). Thus neuronal activity in cataplexy does
not exactly parallel that observed during REM sleep, a finding confirmed by recordings of
neuronal activity in the lateral pontine tegmentum REM control area (1283).
2. Narcolepsy treatment—Current treatment of narcoleptic symptoms normally involves

the use of stimulants acting on the dopaminergic systems (e.g., modafinil) to alleviate
excessive daytime sleepiness and antidepressants (especially those promoting increased
noradrenergic tone) for suppression of REM-like phenomena such as cataplexy (923). γ-
Hydroxybutyrate (GHB, sodium oxybate) is prescribed to improve nighttime sleep in
narcoleptics (151). GHB is a metabolite of GABA that modulates sleep via activation of
GABAB receptors (1369). Pharmacological agonists of the orexin receptors and histamine
H3 receptor antagonists/inverse agonists (increasing histaminergic tone) are under

development for the treatment of narcolepsy (395, 723, 854). Transplantation of orexin
neurons (42) and orexin gene therapy (733, 734) are also being explored in preclinical
animal studies. A dual orexin receptor antagonist has recently been promoted as a potential
sleep aid (140), although development of narcoleptic symptoms could be a potential side
effect of such compounds (no cataplectic events have been observed as yet).
3. Evidence that narcolepsy is an autoimmune disorder—Narcolepsy has long

been considered an autoimmune disorder (728) due to its late onset, its association with the
human leukocyte antigen (LHA) class II allele DQB1*0602 (728, 1259), and more recently
due to the observed loss of orexin neurons in the hypothalamus in most human cases of the
disease (1261). However, direct connections to the immune system have been hard to
demonstrate. The strongest evidence comes from very recent findings of a linkage to a

polymorphism in the T-cell receptor alpha gene (475) encoding the major receptor for HLA
peptide presentation, findings of autoantibodies against the Tribbles Homolog 2 (TRIB2)
gene product which is produced in orexin neurons (270, 613, 1304), and findings of anti-
streptococcal antibodies (39) in a proportion of patients in the early stages of the disease.
Although tantalizing, whether these markers are related to the cause, the progression, or are
incidental to the disease process remains to be determined (721).
F. Other Sleep Muscle Tone-Related Disorders

1. REM sleep behavior disorder—REM sleep behavior disorder (RBD) is a human
manifestation of the syndrome originally observed in cats (583) following large lesions of
the brain stem reticular formation including sites involved in muscle atonia (893)(sect. IV).
Sporadic cases can also be observed in cats and dogs without experimenter-induced lesions
(493, 494). This disorder was first formally described in humans in a landmark study by
Schenck, Mahowald and colleagues in 1986 (1131) and has a reported prevalence of 0.5%
(779). RBD involves uncontrolled movements and muscular expression of dream sequences
leading to sleep fragmentation and injury to patients and their sleeping partners (1134). In
the sleep laboratory such activity is correlated with enhanced EMG activity during sleep,
whereas other aspects of REM sleep are normal. It is more common in people aged over 50
years old and affects more men than women. Acute RBD can be induced by various
medications (e.g., antidepressants acting to increase serotonergic or noradrenergic tone)
(401, 982, 1418), whereas the cause of the chronic form is unknown. The acute form of
RBD is managed by withdrawal of the offending medication, whereas the chronic form can
be well managed symptomatically by clonazepam (first choice) or melatonin treatment prior
to bedtime (401, 779).
Importantly, RBD has been shown to precede and predict the later development of
neurodegenerative diseases known as synucleinopathies (115, 400) including Parkinson’s
disease (117, 399, 1132), dementia with Lewy bodies disease (116, 1314, 1315), and
multiple system atrophy (547, 1291). These studies suggest that a neurodegenerative process
in the generation of idiopathic RBD, presumably occurring in the brain stem REM muscle
atonia generation zones in the dorsolateral pons and medulla. RBD may be an important
marker allowing early-stage preventative treatments of synucleinopathies since RBD often
occurs many years earlier than the other conditions (400, 547, 1132, 1270, 1291). In fact,
post mortem studies in idiopathic RBD have revealed damage to the LC-SubC area (1314,
1315). MRI scans revealed a discrete infarct in the upper pons in several cases (267, 627),
although not all studies have found such abnormalities. Surgery involving damage to the
upper pons can also result in RBD (1025). A recent advance in RBD research is the
identification of an animal model which recapitulates many of the features of RBD (148).
This model consists of transgenic mice that have deficits in inhibitory glycinergic and
GABAergic neurotransmission due to the expression of a mutant glycine receptor α1
subunit, consistent with the substantial evidence for a role of these neurotransmitters in
controlling muscle atonia during REM sleep (see sect. IV).
2. Restless legs syndrome—Restless legs syndrome (RLS) is a compelling urge to

move limbs, particularly the legs, in the evening, due to unpleasant sensations, such as
tingling, which can be relieved by movement. RLS is a very common in older subjects,
particularly in western countries such as the United States, where ~9% of adults are affected
(946). RLS can lead to severe insomnia and subsequent daytime hypersomnia (335).
A) Pathogenesis of Rls: Recent investigations implicate iron deficiency and abnormalities

of dopaminergic systems as possible root causes of RLS (21). Iron is a cofactor for tyrosine
hydroxylase, required for synthesis of dopamine; thus iron deficiency may lead to

dopaminergic dysfunction. CSF iron levels are low in a minority of RLS patients (327, 868),
and iron supplementation decreased symptoms of RLS in some cases (328). Studies of post
mortem brain tissue revealed reduced iron content (257), confirmed by neuroimaging
techniques such as MRI (326). Furthermore, the severity of RLS symptoms correlates with
low levels of ferritin, an intracellular protein that binds iron (327, 673, 868), as well as high
levels of transferrin, a plasma glycoprotein involved in iron transport (327, 868).
Experimentally induced iron deficiency in animal studies produced an increase of
wakefulness during the inactive (light) period (294). This model, although incomplete,
paralleled the circadian aspect of RLS, whereby symptoms mostly occur during the early
part of the inactive/rest period (952). Genetic studies have identified polymorphisms in three
loci encoding developmental factors as predisposing to RLS (1204, 1420) and in particular
to periodic limb movements during sleep (see next section).
B) Treatment and Animal Models of Rls: Dopaminergic agonists alleviate RLS symptoms
(497), and blocking dopaminergic transmission worsens symptoms (887, 1419).
Dopaminergic cell-specific lesioning of the A11 region, by means of the toxin 6-
hydroxydopamine, produced an increase in sleep latencies, as well as less sleeplike
behaviors (951). Excitotoxic (NMDA) lesions of another dopaminergic region, at the ventral
mesopontine junction, produced an increase of wakefulness, as well as periodic leg
movements during NREM sleep, similar to that seen in the RLS patient (682). A
combination of A11 lesions and an iron-deficient diet led to a significant increase in
locomotor activity, which was elevated compared with either manipulation (lesion or diet)
alone (1030). Furthermore, symptoms were improved following treatment with D2/D3
agonists (such as ropinirole), as well as worsened with a D2 antagonist (haloperidol). D3
receptors, specifically in the dorsal horn (246, 712, 1142), may play a role in RLS
symptomatology (247). D3 antagonists and D3-receptor knockout mice both exhibited
increased locomotor activity, and D3 antagonist treatment leads to a decrease of total sleep
(2, 71). Therefore, dopaminergic systems may be abnormally affected in RLS patients,
particularly the A11 dopaminergic cell group and its efferent projections to the spinal cord
(1187).
3. Periodic limb movements—RLS is usually accompanied by stereotyped periodic

limb movements (PLM) during sleep, which are involuntary repetitive extensions of the
toes, feet, and occasionally the knee and hip. Interestingly, two genetic studies of RLS
identified a locus, BTBD9, which also predispose individuals to PLM (1204, 1420). PLM
may also be evident in narcolepsy (886), apnea (392), and RBD (688).
4. Other disorders of motor control during sleep—Inappropriate activation of motor

programs during sleep also occurs in bruxism (grinding of teeth during sleep), sleepwalking
(occurring during NREM sleep), nocturnal sleep-related eating disorder (NSRED), and
sexsomnia (automated sexual behavior during sleep).
G. Posttraumatic Stress Disorder

The diagnostic criteria for posttraumatic stress disorder (PTSD) include hyperarousal and
disturbed sleep including sleep-onset insomnia, inability to stay asleep, excessive daytime
sleepiness, and traumatic nightmares (1183). Approximately 8% of the adult population
suffers from PTSD (617) caused by exposure to either emotional or physical trauma.
NREM-related symptoms include an increased latency to fall asleep, as well as a decrease of
overall NREM amounts (429, 847). The majority of studies also report REM-related
symptoms, including decreased REM episode length, increased episode number, and an
increased number of arousals from REM sleep (847, 1078).

1. Nightmares in PTSD—The chief subjective sleep complaint reported by PTSD

patients is an increased prevalence of frightening dreams/nightmares (1329), suggesting a
pathological enhancement of the normal activation of brain areas involved in emotion during
REM sleep (sect. IV). In particular, increased activation of the amygdala and its connections
with the hippocampus and prefrontal cortex may be important (719). The amygdala is a key
player in the formation of fearful memories, and amygdala activity is abnormally elevated in
PTSD patients following exposure to visual trauma-related stimuli (538). PTSD is also
associated with endocrinological alterations that may contribute to disturbed sleep, including
an attenuation of catecholamine plasma levels and an elevation of corticotrophin-releasing
factor (CRF) levels (917).
2. Medication for PTSD—Numerous medications have been prescribed to decrease the

hyperarousal associated with PTSD, with varying degrees of improvement of sleep
disturbances (389). Treatments include benzodiazepines, monoamine oxidase inhibitors,
selective serotonin reuptake inhibitors, atypical antidepressants (such as nefazadone and
trazodone), beta blockers (such as propranolol), and α-adrenergic antagonists (prazosin).
Norepinephrine plays a key role in the brain’s response to stress and anxiety and in the
suppression of REM sleep (sect. IV). Activation of α1 norepinephrine receptors is involved
in the REM suppressing effect of norepinephrine (644, 782, 990, 1079). Therefore,
manipulations of this receptor may lead to improvement of sleep-related PTSD disturbance.
Administration of the α1 receptor antagonist prazosin to PTSD patients increased total sleep
amounts, normalized the REM sleep profile, and decreased traumatic nightmares (674,
1049). Another system that may be targeted in the future is the orexin system. Recent work
in a rat model demonstrated a role for the orexin system in panic anxiety (565).
H. Depression
There are several intriguing links between depression and sleep (1208, 1228). Both
monopolar and bipolar depression are associated with sleep disturbances, and acute sleep
deprivation has a potent and rapid antidepressant action in severely depressed individuals.
Furthermore, commonly used antidepressants that enhance serotonergic and noradrenergic
tone strongly inhibit the expression of REM sleep (sect. IV). Conversely, light deprivation
produces damage to monoamine neurons and a depressive behavioral phenotype in rats
(433). Major (monopolar) depression is associated with sleep fragmentation, decreases in
NREM sleep intensity, and promotion of REM sleep (173, 1208, 1228). EEG delta power, a
measure of sleep intensity (sect. III), is reduced in depressed patients (124). REM alterations
most commonly observed are a decrease in REM latency, sometimes resulting in sleep-onset
REM periods, a prolonged duration of the first REM period, and increased phasic REM
events. Consistent with the reciprocal-interaction theory of REM sleep control (sect. IV),
pharmacological challenge experiments with cholinergic or serotonergic agents suggested an

increased sensitivity of cholinergic systems and/or decreased activity of aminergic systems
may cause these REM abnormalities (426 – 428, 1228).
VIII. CONCLUSIONS
The past century witnessed an enormous explosion in our knowledge of the brain
mechanisms that control wakefulness and sleep. Ethological and genetic studies have
revealed the presence of NREM sleep-like states even in invertebrates such as Drosophila
and have revealed that homologous genes/proteins control rest/sleep in flies, fish, mice, and
humans. Multiple interacting neurotransmitter systems making up the ARAS arouse the
brain and produce wakefulness in response to physiological challenges as diverse as
increases in blood CO2decreases in ambient temperature, and the presence of rewarding
stimuli. Increases in arousal are observed as an increase in low-amplitude fast EEG rhythms

important for synchronization of neuronal assemblies involved in attention, working

memory, and conscious awareness. Conversely, NREM sleep is associated with high-
amplitude slow waves produced by the combination of a circadian inhibition of ARAS
neurons mediated by GABAergic neurons in the preoptic hypothalamus and basal forebrain
and by the action of a plethora of homeostatic sleep factors acting locally in the cortex or
basal forebrain. Multiple interacting lines of evidence support a role for NREM sleep in the
control of energy metabolism and synaptic plasticity/memory formation. REM sleep is
induced by the increased firing of glutamatergic and cholinergic neurons in the dorsolateral
pons, resulting in muscle atonia coupled with both tonic and phasic activation of the cortex.
Phasic activation of visual cortex and limbic regions during REM sleep, coupled with
deactivation of prefrontal cortex, is responsible for the bizarre imagery of dreams and may
reflect a role for REM sleep in emotional regulation and/or memory consolidation in the
adult or establishment of neural circuitry in the developing animal. Sleep deprivation leads
to an inhibition of arousal mechanisms at subcortical and cortical sites, leading to
impairments in cognitive function, which in turn can result in accidents at home and in the
workplace. Deficits in arousal mechanisms and highfrequency rhythms are observed in sleep
disorders and conditions such as coma, schizophrenia, Alzheimer’s disease, and epilepsy.
Consistent with a role for sleep in energy metabolism, sleep deprivation is a major
contributor to metabolic syndrome, a leading public health issue. Furthermore, dysregulation
of sleep is a feature of depression, PTSD, and a variety of sleep disorders related to muscle
control. Thus studies of the mechanisms controlling sleep and wakefulness can reasonably
be expected to lay the groundwork for therapies to treat a multitude of afflictions affecting
mankind.
Acknowledgments
We thank the two anonymous reviewers for their time and helpful critiques which helped to improve the
manuscript.
GRANTS
This work was supported by Department of Veterans Affairs Medical Research Service Awards (to R. W.
McCarley, R. Basheer, and R. E. Strecker) and by National Institutes of Health Grants R01 MH-039683 (to R. W.
McCarley), R21 MH-094803 (to R.E. Brown), and P01 HL-095491 (to R. W. McCarley and R. E. Strecker).
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FIGURE 1.
Electroencephalographic (EEG) recordings in the human and rat capture differences
between vigilance states (wakefulness, NREM sleep, and REM sleep). Wakefulness in both
species is characterized by low-amplitude/high-frequency activity. Note that high-frequency
beta and gamma activity is not easily visible at this slow timescale. In the human, NREM
sleep begins in stage 1, the prevalent EEG frequency begins to slow, with strong alpha
activity at posterior sites and theta activity at anterior sites. In NREM sleep stages 2/3, both
sleep spindles (7–14 Hz) and K-complexes are seen, as the EEG amplitude increases and
frequency further slows. In NREM sleep stage 4, also known as slow wave sleep, strong
delta (0.5–4 Hz) activity is evident, accompanied by a large increase in amplitude. During
REM sleep, the EEG returns to a profile similar to wakefulness, with low-amplitude and
high-frequency activity. In the rodent, NREM sleep is usually not parsed into separate
stages. NREM sleep exhibits a significant increase of delta range activity, as well as an
increase in amplitude. REM sleep is defined by the strong synchronous theta range (7–9 Hz)
activity, probably generated in the hippocampus. Human EEG recordings are adapted from
Purves et al. (1028). Note the voltage scales are not matched between species.

FIGURE 2.
Location of brain nuclei controlling the sleep-wake cycle (see sects. II–IV) in sagittal (A)
and coronal (B) schematics of the rat brain. Location of sections in B are represented as
vertical dashed lines in A. Medulla oblongata: DPGi, dorsal aspect of the
paragigantocellular reticular nucleus; GiV, ventral gigantocellular nucleus. Pons/midbrain:
DR, dorsal raphe nucleus; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; LPB,
lateral parabrachial nucleus; LPT, lateral pontine tegmental region; MPB, medial
parabrachial nucleus; MR, median raphe nucleus; PB, parabrachial nucleus; PnC, nucleus
pontine caudalis; PnO, nucleus pontine oralis; PPT, pedunculopontine tegmental nucleus;
SubCA, subcoeruleus nucleus, alpha; SubCD, subcoeruleus nucleus, dorsal; SubCV,

subcoeruleus nucleus, ventral; SN, substantia nigra; vlPAG, ventrolateral aspect of the
periaqueductal gray; VTA, ventral tegmental area; VTG, ventral tegmental nucleus of
Gudden. Hypothalamus: DMH, dorsomedial nucleus of the hypothalamus; LH, lateral
hypothalamus; MM, medial mammillary nucleus; MnPO, median preoptic nucleus; MPO,
medial preoptic nucleus; PeF, perifornical region of the hypothalamus; PH, posterior
hypothalamus; PO, preoptic region (including VLPO); SCN, suprachiasmatic nucleus;
SUM, supramammillary nucleus; TMN, tuberomammillary nucleus; VLPO, ventrolateral
preoptic nucleus. Forebrain: BF, basal forebrain (including HDB, horizontal limb of the
diagonal band; MCPO, magnocellular preoptic nucleus; SI, substantia innominata; VP,
ventral pallidum); AMY, amygdala; CPu, caudate putamen; GP, globus pallidus. Thalamus:
CM, thalamic centromedial nucleus; LGN, lateral geniculate nucleus; PV, thalamic
paraventricular nucleus; RE, nucleus reuniens; RT, thalamic reticular nucleus VL, thalamic
ventrolateral nucleus; VM, thalamic ventromedial nucleus; VMPO, ventromedial preoptic
nucleus. Hippocampus: CA1, CA1 region of the hippocampus; CA3, CA3 region of the
hippocampus; DG, dentate gyrus of the hippocampus. Neocortex: AC, anterior cingulate
cortex; IL, infralimbic cortex; PrL, prelimbic cortex. [Adapted from Paxinos and Watson
(989), with permission from Elsevier.]

FIGURE 3.
Simplified model of cortical circuitry generating gamma oscillations. Cortical circuits
consist primarily of excitatory pyramidal neurons and inhibitory GABAergic interneurons.
Inhibitory drive generated by interneurons plays an important role in the generation of
oscillatory output. Fast spiking interneurons containing parvalbumin (PV) that synapse onto
the cell bodies of pyramidal neurons are particularly important in generating gamma
oscillations. Recurrent glutamatergic synapses onto GABAergic interneurons provide
excitatory drive to the fast spiking interneurons. Both chemical and electrical synapses
between PV-positive interneurons enhance synchrony and the coupling of gamma rhythms
to theta rhythms.

FIGURE 4.
A simplified structural model of hippocampal theta rhythm control. Tonic neuronal activity
of the reticular formation, largely originating in the nucleus pontine oralis (PnO), excites the
supramammillary nucleus (SUM) by means of glutamatergic projections. Pontine tonic
activity is converted to rhythmic firing in SUM, indicated by the wave symbol.
Glutamatergic SUM output then excites GABAergic and cholinergic neurons of the medial
septum/vertical limb of the diagonal band (MS/vDB), which serves as the pacemaker of the
hippocampal theta rhythm.

FIGURE 5.
Dorsal and ventral pathways of the ascending reticular activating system (ARAS). The
dorsal pathway (blue) originates in pontine and midbrain reticular formation, most
prominently cholinergic (LDT/PPT) and glutamatergic neurons which project to the
“nonspecific” intralaminar and midline thalamic nuclei which diffusely innervate many
areas of the cerebral cortex as well as thalamic relay neurons with more selective projections
patterns. The ventral pathway also originates in pontine/midbrain regions and projects to the
lateral hypothalamic (LH) and tuberomammillary (TMN) nuclei of the hypothalamus, as
well as the basal forebrain (BF). Output of LH and TMN also ascend to BF, which in turn
projects to the cortex. Noradrenergic neurons of the locus coeruleus (LC) and serotonergic
neurons in the dorsal raphe (DR) contribute to both pathways and send direct projections to
the cortex as do histamine neurons of the TMN and orexinergic neurons in the LH. LDT,
laterodorsal tegmental nucleus; PPT, pedunculopontine nucleus. [Adapted from Paxinos and
Watson (989), with permission from Elsevier.]

FIGURE 6.
Functional interactions between wake-promoting neuromodulatory systems projecting to the
cortex. Wake-promoting neuromodulatory systems are interconnected mainly in a mutually
excitatory network. Cholinergic (ACh) basal forebrain, orexinergic (OX) lateral
hypothalamic, serotonergic (5–HT) raphe, noradrenergic (NA) locus coeruleus, and
histaminergic (HA) tuberomammillary neurons all interact to promote wakefulness. Thus, if
one region is experimentally lesioned, other systems remain and maintain cortical activation
and wakefulness. The main exceptions to this pattern are inhibitory serotonergic and
norepinephrine projections to cholinergic and orexin neurons. Cortically projecting
glutamatergic and GABAergic systems are also important in cortical activation and
wakefulness (see text). Note: adrenergic projections to the histamine neurons act by
disinhibition (inhibition of GABAergic synaptic inputs), whereas other effects shown are
postsynaptic. Receptors involved are as follows: α1, alpha adrenergic type 1; α2, alpha
adrenergic type 2; H1, histaminergic type 1; M3, muscarinic cholinergic; OxR1, orexin
receptor type 1; OxR2, orexin receptor type 2.

FIGURE 7.
The “flip-flop” switch model of transitions between sleep and wakefulness (1117). The
wake state is stabilized by lateral hypothalamic (LH) excitatory orexinergic input to wake-
related nuclei, including GABAergic/ histaminergic neurons of the tuberomammillary
nucleus (TMN), serotonergic neurons of the dorsal raphe nucleus (DR), and noradrenergic
neurons of the locus coeruleus (LC). During sleep, GABAergic/galaninergic ventrolateral
preoptic (VLPO) neurons inhibit wake-promoting nuclei, including LH. Transitions between
wake and sleep are due to mutual inhibition between these sleep- and wake-related nuclei.
(Adapted from Saper et al. Nature 437: 1257–1263, 2005, with permission from MacMillan
Publishers Ltd.

FIGURE 8.
Investigations of the role of adenosine (AD) as a neuromodulatory sleep factor. A:
extracellular AD concentrations in the feline basal forebrain (BF) for 10-min consecutive
samples from an individual animal, showing elevated levels during wakefulness. Labels
indicate behavioral state: W, wakefulness; S, slow wave (NREM) sleep; R, REM sleep.
[Adapted from Porkka-Heiskanen et al. (1018). Reprinted with permission from AAAS.] B:
AD concentrations in the feline BF rise during 6 h of sleep deprivation (SD) and decrease
towards baseline levels during 3 h of spontaneous recovery sleep. [Adapted from Porkka-
Heiskanen et al. (1018). Reprinted with permission from AAAS.] C: AD and nitric oxide
(NOx, red) concentrations in the rat BF rise during 11 h of SD. The rise of NOx during SD

precedes the rise of AD. AD levels are significantly elevated by hour 2 of SD and remain
elevated until recovery sleep, when levels fall towards baseline levels. Levels are
normalized to baseline levels in the 2 h preceding SD. [Adapted from Kalinchuk et al. (591),
with permission from John Wiley and Sons.] D: AD and NOx levels in the rat frontal cortex
also rise during SD. Again, the rise of NOx during SD precedes the rise of AD. The rise of
AD is significant by hour 6 of SD and is delayed compared with the rise seen in BF, as
shown in C. Levels are normalized to baseline levels in the 2 h preceding SD. [Adapted
from Kalinchuk et al. (591), with permission from John Wiley and Sons.] E: graphic
depiction of the intracellular signaling pathway of the AD A1 receptor in BF observed
following sleep deprivation in rats. Steps of the pathway: 1) AD binds to the A1 receptor; 2)
activation of PLC pathway, releasing inositol 1,4,5-trisphosphate (IP3); 3) IP3 receptor-
mediated intracellular calcium mobilization and activation of protein kinase C; 4)
phosphorylation of Iκ-B and release of nuclear factor-κB (NF-κB) dimer; 5) nuclear
translocation of NF-κB dimer; 6) promoter DNA binding of NF-κB and transcriptional
activation of target genes including A1 receptor; 7) protein synthesis (A1 receptor synthesis).
This signaling cascade appears to be confined to cholinergic neurons of BF. (Adapted from
Basheer et al. Neuroscience 104: 731–739, 2001, with permission from Elsevier.

FIGURE 9.
Sleep and energy metabolism. The interaction between state-dependent changes in ATP,
AMPK, and AMPK-regulated anabolic and catabolic pathways is shown. Wakefulness and
sleep deprivation are both characterized by increased neuronal activity and increased
consumption of ATP. A higher AMP/ATP ratio results in and leads to increased
phosphorylated-AMPK (P-AMPK), promoting catabolic processes. Sleep states are
characterized by increased NREM delta activity, low neuronal activity, and a rise in ATP
levels. The resulting lower AMP/ATP ratio leads to decreased phosphorylated AMPK,
promoting anabolic processes, such as synthesis of proteins, glycogen, and fatty acids.
[Adapted from Dworak et al. (323).]

FIGURE 10.
Pontine tegmental membrane depolarization and action potential activity increases prior to
and during REM sleep. A: first trace is nuchal (neck) EMG in the cat, showing a lack of
muscle tone during REM sleep; second trace is frontal cortex EEG, showing low-amplitude
activity during REM sleep; third trace is lateral geniculate nucleus (LGN) neuronal activity,
revealing PGO waves immediately preceding and during REM sleep; fourth trace is
extraocular muscle EOG, showing eye movement during REM sleep; and fifth trace is the
membrane potential record for one pontine tegmental neuron (MP). B: oscilloscope
photographs depict the changes of action potential frequency that accompany MP
depolarization. Arrows in the MP trace of A correspond to the eight oscilloscope
photographs of B showing tonic neuronal firing during transition into REM sleep, the REM

sleep episode, and transition out of REM sleep. REM, REM sleep; NREM, NREM sleep; T,
transition; W, wake; Wm, wake with movement. [Adapted from Ito et al. (550).]

FIGURE 11.
Descending circuitry responsible for muscle atonia during REM sleep. During REM sleep,
descending pontine subcoeruleus (SubC) glutamatergic projections excite diffusely
organized glycinergic neurons of the bulbar reticular formation, including the medullary
ventral gigantocellular nucleus (GiV). GABAergic/glycinergic output from the GiV inhibits
spinal motoneurons, producing muscle atonia. An alternative pathway consists of a direct
SubC glutamatergic projection to the spinal cord, directly synapsing on inhibitory
interneurons of the ventral horn. When activated, these interneurons inhibit the spinal cord
motor neurons, again producing muscle atonia. Red lines denote excitation; black,
inhibition. [Adapted from Pakinos and Watson (989), with permission from Elsevier.]

FIGURE 12.
The original (A) and modified (B) reciprocal interaction models of REM sleep control,
originally proposed by McCarley and Hobson (819). A: the original reciprocal interaction
model demonstrates increased REM activity as positive feedback of REM-on neuronal
populations occurs. This activity leads to excitation of REM-off neuronal populations, which
then inhibit REM-on activity. REM-off activity is self-inhibiting, and eventually wanes,
releasing REM-on neurons as REM sleep again occurs. [Adapted from McCarley and
Hobson (819). Reprinted with permission from AAAS.] B: LDT/PPT REM-on activity
excites pontine reticular formation (PRF) glutamatergic REM-on cells, promoting REM
sleep. LDT/PPT REM-on neurons also excite GABAergic interneurons adjacent to REM-off

neurons, inhibiting REM-off neuronal activity. REM-on output also inhibits GABAergic
REM-off interneurons, which in turn inhibit REM-on PRF neurons. As REM sleep
progresses, REM-on cells begin to excite REM-off cells, leading to REM sleep cessation.
Dorsal raphe (DR) and locus coeruleus (LC) REM-off neurons inhibit laterodorsal/
pedunculopontine tegmental nuclei (LDT/PPT) REM-on neurons during waking and NREM
sleep. Self-inhibition of these REM-off neurons leads to disinhibition of REM-on neurons,
again allowing REM sleep. (Adapted from McCarley. Sleep Med 8: 302–330, 2007, with
permission from Elsevier.)

FIGURE 13.
Pontine generation of REM sleep phenomena. Interaction between the pontine/
mesencephalic reticular formation (PRF Glutamatergic) and cholinergic laterodorsal/
pedunculopontine tegmental nuclei (LDT/PPT ACh) produces ascending and descending

activation, resulting in REM sleep phenomena, including PGO waves, rapid eye movements,
muscle atonia, hippocampal theta oscillations, and cortical activation. GiV, ventral
gigantocellular nucleus; HDB, horizontal limb of the diagonal band; MCPO, magnocellular
preoptic nucleus; MRF, medullary reticular formation; MS/vDB, medial septum/vertical
limb of the diagonal band; PRF, pontine reticular formation; SI, substantia innominata.

Table 1
Inactivation of brain regions/neurotransmitter systems and effects on sleep-wake behavior
Brain Area/System Targeted Inactivation Technique Effect on Sleep-Wake and EEG
Brain stem
Midbrain/pontine reticular formation Transections in cat (136–138, 580, 730, Loss of cortical activation during waking and REM
1393). sleep.
Cerveau isole mesencephalic transaction Loss of forebrain signs of REM sleep.

immediately caudal to the third nerve
nuclei (effects contrast with encephale
isole intact sleep-wake with transaction at
C1 level of spinal cord).
Brain stem damage in human patients Coma.

(980).
Transection at caudal pontine or prebulbar Loss of REM sleep and of the ability of pontine
level (1341, 1393). carbachol to elicit tonic and phasic REM
components.
Electrolytic lesions in cat (730). Loss of cortical activation (not observed when
lateral sensory pathways were interrupted). Coma
like state.
Neurotoxic lesions ibotenic acid lesions in Temporary increase in EEG slow waves but no
cat (302) or rat (758). long-term effects (cat). One week coma like state
for combined PH/MPRF lesions. Recovery

occurred. No effect (rat).
Dorsolateral pons including the dorsal Electrolytic (387, 388, 495, 498, 569, 893, Very large lesions:
subcoeruleus (=sublaterodorsal nucleus or 900, 1111, 1121, 1122).
peri-locus coeruleus alpha) or dorsal
pontine nucleus oralis (PnO)
Neurotoxic kainic acid (577, 1122, 1394), Loss of REM sleep correlated with loss of
ibotenic acid (758), NMDA (682, 683), cholinergic neurons.
hypocretin 2-saporin (100), quisqualic
acid (606).
Acute brain stem encephalitis with Large lesions including the SubC and surrounding
isolated inflammatory lesion in areas:
dorsomedial pontine tegmentum
(including DRN, MR, PnO, LC, SubC,
LDT, PPT) (810).
Pharmacological tetrodotoxin (1111, REM sleep behavior disorder (RBD) in humans,

1114). oneiric (dream-like) behavior in animals.
Idiopathic degeneration in humans (400, Smaller discrete lesions (focusing on SLD/SubC

1133). area):
REM without atonia in animals, increased limb
movements during sleep.
GABA or muscimol (183, 1112, 1440, Wakefulness↑, NREM↓, REM sleep↓.

1441)
Norepinephrine (262), noradrenergic α2 Decreased REM and/or REM without atonia.

agonist clonidine (1300), or dopamine
acting on α2 receptors(263).
Noradrenergic β antagonist, propanolol REM↑ due to increased number of REM episodes.

(1301).
Inhibition of adenylyl cyclase (799). REM sleep↑ (increased frequency of episodes).
Peribrachial pons (surrounding brachium Cooling, electrolytic or neurotoxic lesion Loss of pontine component of PGO waves (P-
conjunctivum): includes PPT/LDT, in P-wave generation zone (277, 278, 604, waves). Reduced expression of learning related
cuneiform nucleus, subcoeruleus (FTG in 690, 691, 814, 1100). genes and proteins following active avoidance
cat), medial and lateral parabrachial training. Reduced frequency of hippocampal theta
nucleus. and reduced synchronization between
hippocampus and amygdala.


M2 receptor antagonist, methoctramine Block of enhanced PGO-wave activity and REM-
sleep like state induced by carbachol in the cat.
(283).
Serotonin (279) Inhibition of P-waves when injected into P-wave

generator in dorsal subcoeruleus.
Medial parabrachial nucleus Neurotoxic: ibotenic acid (758). Wake 21%↓
Precoeruleus Neurotoxic: ibotenic acid (758). Loss of theta rhythm during REM
Ventral medulla (gigantocellular and Neurotoxic quisqualic acid in cat (514) or Muscle tone↑ during NREM and REM sleep.
magnocellular tegmental fields) neonatal rat (606). Increased movements during REM sleep.
Reduction in REM sleep and atonia duration
during first postlesion week followed by recovery
in weeks 2 and 3. Amount of remaining REM sleep
correlated positively with ratio of remaining
cholinergic or GABA neurons to serotonergic
neurons.
Transection at ponto-medullary junction in Abolition of muscle atonia produced by electrical
decerebrate cat (1179) or injection of stimulation of medial medulla.
lidocaine into pontine reticular formation
(652).
Brain stem cholinergic (PPT) Ibotenic acid (758). Wake 30%↓
Locus coeruleus (LC) Electrolytic lesion (576). No effect on REM sleep generation.
Scopolamine, minipump perfusion (1168). REM sleep↓ during the daytime (inactive period)
in the rat.
GABAA agonist muscimol (959, 1303); Increased REM sleep with muscimol (due to
increase in number of REM bouts) Possibly due to
preferential inhibition of local GABAergic
neurons.
GABAB receptor agonist baclofen into Decreased REM sleep and memory consolidation
PPT/DpMe (370). with baclofen.
α2 Agonist, clonidine, α1 antagonist REM sleep↑.

prazosin or β antagonist (958).
Adenylyl cyclase or protein kinase A REM sleep ↓ (due to decrease in number of

inhibition (67, 282). episodes).
Serotonin (279, 1113). No effect on PGO waves.
Brain stem cholinergic (LDT) Ibotenic acid (758). LDT: increased fragmentation but no effect on
amount of sleep.
Neurotoxic lesion: kainic acid (1394),

ibotenic acid (758), dopamine-β-
hydroxylase saporin (100).
Cooling (201) REM sleep ↑
RNAi knockdown of orexin 1 receptor REM sleep during dark period↑

(219).
Microdialysis of α2 agonist clonidine Decreased activity of LC neurons. Waking ↓,

(1096). NREM sleep ↑.
DSP-4 lesion (238, 244, 881). Reduced immediate-early and synaptic plasticity
related gene expression.
Either no change in baseline sleep-wake (238, 244)
or increase in REM (881).
Dorsal raphe nucleus (DRN) Electrolytic lesion (1451). No effect.
Neurotoxic lesion: ibotenic acid (758), No effect on amounts of sleep-wake.

5,7-dihydroxytryptamine (757).
GABAA receptor agonist, muscimol (926). REM sleep ↑.
Median raphe (MR) Electrolytic:(1451) Hippocampal theta rhythm ↑.


Pharmacological glutamatergic
antagonists (629); GABAA agonist,
muscimol (630), 5-HT1A receptor agonists

(1364).
Dopamine- vPAG/DRN 6-OHDA or ibotenic acid (757). Marked decrease in waking (>20%), concomitant
increase in sleep.
Ventrolateral periaqueductal gray (vlPAG) Electrolytic lesion in encephale isole cats Cortical activation preserved.
(730).
Neurotoxic lesion: orexin 2-Saporin (612, REM sleep ↑ in both normal and orexin KO
758) animals.
Pharmacological muscimol in the cat Increased REM bouts and REM bout duration
(1120), rat (1118), and guinea pig (1336). during dark period.
Lateral pontine tegmentum (LPT) = deep Electrolytic lesion in encephale isole cats Cortical activation preserved.
mesencephalic nucleus (DpMe) (730).
Neurotoxic lesion orexin 2-saporin in the REM sleep ↑. Increased REM bouts during light
rat (758) and mouse (612). period and occasional bouts of cataplexy.
Pharmacological muscimol in the cat

(1120), rat (1118), and guniea pig (1336).
Superior colliculus/pretectum Aspiration (857) Abolition of lights off-induced increase in REM

sleep.
Hypothalamus
Preoptic area/anterior hypothalamus Viral insult in humans (1378). Prolonged (>3 wk) and large suppression of sleep
(both NREM and REM).
Electrolytic lesions in the cat (761, 840,
911) and neonatal rat (873).
Neurotoxic lesions in the cat: ibotenic

(1105) or kainic acid (1255).
Lateral preoptic area/bed nucleus of the Neurotoxic lesions in the rat. Ibotenic acid Reduction in number of erections during REM
stria terminalis (BNST) (1138) or NMDA (1201). sleep (1138). NREM sleep ↓ (1201).
Ventrolateral preoptic area (VLPO, core) Neurotoxic (rats). ibotenic acid (756). NREM 50–60%↓, REM sleep 59%↓, EEG delta
power 60–70% ↓lasting at least 3 wk. Extent of
lesion correlated with loss of NREM sleep. Sleep-
wake fragmentation.
GABA/galanin-positive neurons
Extended VLPO (dorsomedial) Neurotoxic (rat). ibotenic acid (756). REM sleep 35% ↓, NREM sleep,15%↓, 25% loss
of delta mainly during light period. Extent of
lesion correlated with loss of REM sleep.
Ventromedial preoptic area Neurotoxic (rat). ibotenic acid (756), No effect on sleep-wake (756). Reduced NREM
NMDA (563, 1201). and REM sleep (563, 1201). Disrupted body
temperature regulation.
Median preoptic area Pharmacological: muscimol perfusion Prolonged waking state

(1251)
Suprachiasmatic nucleus (SCN) Electrolytic: rat (1439). Loss of circadian rhythms. Reduced REM sleep
during the rest (light) phase.
Dorsomedial hypothalamus (DMH) Neurotoxic: ibotenic acid (52, 224). Loss of circadian rhythms of sleep-wakefulness.
Posterior/lateral hypothalamus (PH/LH) Viral insult (1378) Hypersomnolence in human patients following
influenza pandemic.
Orexin/hypocretin (perifornical Damage to PH/LH including perifornical Narcolepsy.

hypothalamus; PFH) hypothalamus due to tumor (43) or stroke
(1129).
Electrolytic/transection: (730, 840, 911, Reduction or abolition of cortical activation.

1046) Hypersomnolence for several days followed by
recovery (cat).


Neurotoxic: PH/LH: no long-term effects (cat)
LH: hypocretin 2-saporin (411, 413) TMN area: minor changes.
Orexin KO or orexin receptor Narcolepsy with cataplexy in mice. Unchanged 24

doubleknockouts (29, 214, 598, 640). h wake amount but sleep-wake fragmentation,
cataplexy, loss of circadian control of REM sleep.
Reduced voluntary motor activity (wheel running).
Orexin receptor 2 mutations (727). Inherited narcolepsy in dogs.
Loss (degeneration) of >90% of orexin Idiopathic narcolepsy-cataplexy in humans.

neurons and reduced CSF orexin (999,
1284).
Partial (33%) loss of orexin neurons Idiopathic narcolepsy without cataplexy in

(1285). humans.
Mutation in preproorexin (999). Early onset narcolepsy in humans.
Orexin postnatal genetic (ataxin-3) lesion Narcolepsy with cataplexy in mice and rats.
(96, 479)
Knockdown of orexin in PFH with siRNA REM sleep during dark period in rats↑.
(221).
Orexin receptor 1 KO mice (640). Mild effects on sleep-wake. No cataplexy or sleep-

onset REM episodes.
Orexin receptor 2 KO mice (1415). Milder form of narcolepsy-cataplexy (less

cataplexy or sleep onset REM episodes).
Orexin receptor (1 and 2) antagonist Increased sleep, especially REM sleep in rat, dogs,
(140). and humans. No cataplexy.
Melanin concentrating hormone (MCH) MCH knockout mice (5). NREM and REM sleep ↓.
Perifornical hypothalamus MCH 1 receptor antagonist (12)
Histamine (tuberomammillary nucleus) Reduced CSF histamine in narcolepsy and Excessive daytime sleepiness in humans.
idiopathic hypersomnia (597).
HDC (synthetic enzyme) knockout mice No change in 24 h wake amount. Increased

(29, 978). fragmentation. Decreased θ-power during waking
increased δ during sleep. Increased REM during
light period. Decreased sleep latency in novel
environment.
α-FMH (histamine decarboxylase Wake ↓ (cat, mice). No effect on 24 h values (rat).

inhibitor) in cat (724), mice (978), and rat
(551, 1152).
Systemic H1R antagonists crossing the Reduced wakefulness and alertness ↓ (human, cat).
blood-brain barrier: human (1402), cat No change (mice), decreased fragmentation.
(724), mice (528).
H1R knockout mice (528) No change in 24 h wake amount or diurnal

rhythms of sleep-wake. Decreased fragmentation.
Systemic H3R (autoreceptor) agonist in cat Cat: wake ↓ NREM sleep↑

(725), rat (686, 885)
Rat: no effect.
Mammillary body (MB) Pharmacological inhibition: local Abolition of hippocampal theta in urethane-
anesthetic procaine (639). anesthetized animals. Reduced frequency (1 Hz
less) of hippocampal theta in awake animals.
Supramammillary nucleus (SuM)/posterior Pharmacological inhibition local Abolition of hippocampal theta in urethane-
hypothalamus anesthetic procaine (639). anesthetized rats. Reduced frequency (1 Hz less) of
hippocampal theta in awake rats.
Basal forebrain
Rostral basal forebrain (MS, vDB) Electrolytic lesions rabbits (30, 1090). Hippocampal theta rhythm reduced (neurotoxic) or
abolished (electrolytic).


Neurotoxic lesions: rat: kainic acid No other change in sleep-wake.
(preferential loss of noncholinergic
neurons) (1463), Orexin-saporin (415).
Rostral BF cholinergic Pharmacological: AP5 (NMDA receptor Reduced power of hippocampal theta.
antagonist) (104); muscimol (106);
procaine(945).
Neurotoxic lesion IgG192 saporin or Reduced amplitude of hippocampal theta rhythm

orexin-saporin (80, 415, 600, 697, 1463). and theta-gamma coupling. No change in sleep-
wake.
Rostral BF GABAergic (mainly PV-Pos) Pharmacological inhibition of H-current Reduced hippocampal theta (1446) or minor
with ZD7288 in rat (1343, 1446). effects (1343).
Caudal basal forebrain (SI, HDB, MCPO) Neurotoxic ibotenic acid or quisqualate No effect on 24 h sleep-wake. Increased delta
(177, 611, 1064). power in all states. Reduced recovery sleep and
delta power after ±SD.
Caudal BF cholinergic Pharmacological procaine (190), Increased sleep, delta wave activity.
adenosine (1247).
IgG192-saporin (94, 102, 103, 592, 611). No or minor effects on baseline sleep-wake.
Reduced EEG gamma. Reduced recovery sleep and
delta power after sleep deprivation (611).
Caudal BF, TMN, LC Triple lesions using saporin-conjugated No changes in daily amounts of wake. More sleep
neurotoxins (101). during light-to dark transition period. More stable
sleep architecture.
Forebrain
Thalamus Electrolytic: monkey (1046). No effect on sleep-wake or EEG except abolition
of high-voltage spindles (sharp-wave/ripples).
Neurotoxic ibotenic acid in rat (177, 397).
Basal ganglia Ibotenic acid lesion (1029). Rostral striatum:
Wake 15 %↓
Sleep fragmentation, slowing of EEG during

waking (theta→delta).
Globus pall.: wake 46 % ↑ Increased

fragmentation.
Slowing of EEG.
NAcc core: wake 27 % ↑ NREM bout duration ↓.
Slowing of EEG.
STN: minor changes.

SNr: minor changes.
Substantia nigra Hypocretin-2 saporin (412). Insomnia.
SN/VTA NMDA lesion (683). No decrease in wakefulness.
Neurotransmitters/neuromodulators
(Systemic or icv effects)
Acetylcholine Systemic muscarinic antagonists (177, Increase in EEG delta waves. Increased high-
555, 744). voltage spindles (sharp waves/ ripples). Block of
PGO waves.
M2/M4 double knockouts (434). No effect on sleep-wake
M3 receptor knockouts (434). REM 22% ↓
Rats reared on a diet lacking choline Reduced NREM and REM sleep
(1256).
Serotonin Depletion of serotonin (363, 555, 582, Increased PGO waves in all states of sleep-wake.
1080).


Norepinephrine Dopamine-β-hydroxylase knockout mice Either no change in baseline sleep-wake or
(539, 956). decrease in REM. Shorter sleep latency after mild
stress.

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Physiol Rev. 2012 July ; 92(3): 1087–1187. doi:10.1152/physrev.00032.2011.

CONTROL OF SLEEP AND WAKEFULNESS

A. Characteristics of Sleep-Wake States

electrodes record the electroencephalogram (EEG), electrodes placed on or in skeletal

B. Control of Sleep Timing and Intensity

C. Effects of Sleep Loss on Cognition

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

1. Gamma/beta rhythms (15–120 Hz)—Low-amplitude gamma (30–120 Hz) and beta

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

Fast-spiking interneurons containing PV generate gamma rhythms. Evidence supports the

neocortical interneurons in vivo (via genetic introduction of bacterial light-activated ion

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

A) Thalamocortical Mechanisms Generating Alpha Rhythms: The mechanisms

3. Theta rhythms (4–8 Hz)—Theta-rhythms occur prominently during waking associated

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

B. Brain Stem Reticular and Basal Forebrain Activating Systems

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

default network differ from those affecting other cortical areas.

C. Neurotransmitter Systems Promoting Wakefulness

1. Acetylcholine—The cholinergic system promotes high-frequency oscillatory activity

BF cholinergic neurons projecting to the neocortex promote LVFA. Caudal BF neurons

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

B) Brain Stem Cholinergic Projections to the Thalamus: While BF cholinergic neurons

C) Effects of Cholinergic Lesions: While electrical or pharmacological stimulation of

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

especially gamma-activity, was strongly reduced with extensive lesions of caudal

resulting from disruption of serotonin signaling was due to a disruption of thermoregulation,

A) Mechanisms by which Serotonin Promotes Wakefulness: Serotonin promotes waking

B) State-Dependent firing of Serotonin Neurons: Most serotonin neurons fire in a slow,

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

resulting in a 60–80% depletion of forebrain serotonin, blocked the effects of MR electrical

3. Norepinephrine—Norepinephrine neurons are generally thought of as part of the

Studies utilizing neurotoxic or electrolytic lesions of the LC or norepinephrine system

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

potentiation implicate noradrenergic β-receptors in promotion of synaptic plasticity (519,

4. Histamine—Histamine neurons were first implicated in wake promotion due to the

Modest decreases/increases in waking have been observed following pharmacological

5. Orexins/hypocretins—Orexins/hypocretins were discovered relatively recently by two

A) Orexins Promote Wakefulness: Early work showed that intracerebroventricular

B) Orexin Neurons Increase Waking in Response to Low Food Availability: One

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

E) Inhibition of Orexin Neurons During Sleep: The spontaneous activity of orexin

F) Downstream Effectors of Orexin Promotion of Wakefulness: How do the orexins

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

6. Neuropeptide S—Like the orexins, neuropeptide S (NPS) is a recently discovered

7. Dopamine—Pharmacological agents increasing dopaminergic tone such as

B) Ventral Periaqueductal Gray Dopamine Neurons: Dopaminergic neurons in the

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

8. GABA—GABAergic neurons and glutamatergic neurons (reviewed below) are very

Physiol Rev. Author manuscript; available in PMC 2013 July 01.

9. Glutamate—The vast majority (>90%) of glutamatergic projections to the cortex arise

amygdala, VTA, laterodorsal tegmentum, and hypothalamus (540) provide minor

A) Thalamic Intralaminar and Relay Neurons: The thalamus is an important component

10. Effector systems of neurotransmitters promoting wakefulness—The effector

Physiol Rev. Author manuscript; available in PMC 2013 July 01.