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Basic Mechanisms of Sleep-Wake States

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Figures

Neural systems promoting slow wave sleep. This schematic depiction of a paramedian, sagittal section of the cat brain represents neuronal systems implicated in the facilitation, generation, and maintenance of slow wave sleep. Outlined areas represent the regions in the brainstem (raphe and solitary tract nuclei) and forebrain (anterior hypothalamus, preoptic area, and basal forebrain) where large lesions are associated with a chronic decrease or loss of slow wave sleep. Points marked with "5" (slow wave sleep) indicate regions where low-frequency electrical stimulation produces cortical synchrony and behavioral sleep, as well as where particular neurons manifest a higher rate of spontaneous activity (or typical burst-pause pattern of activity) during slow wave sleep compared with waking (including the solitary tract nucleus, nonspecific thalamic nuclei, anterior hypothalamus-preoptic area, and basal forebrain). Diumond-shaped symbols represent neurons of the solitary tract nucleus (of unknown neurotransmitter content) implicated in slow wave sleep regulation, which project (dotted lines) forward into the viscerallimbic forebrain. Stars represent serotonin-containing neurons of the brainstem raphe nuclei, which may facilitate the onset of slow wave sleep and which project forward into the rostral tegmentum, thalamus, subthalamus, hypothalamus, and basal forebrain and also from the midbrain directly to the cerebral cortex and hippocampus. Triungles represent gamma-aminobutyric acid (CABAFsynthesizing neurons located in multiple regions. In the reticular formation, local CABAergic neurons may inhibit surrounding neurons of the ascending reticular activating system. Of the CABAergic neurons in the anterior hypothalamus-preoptic area and basal forebrain-septum, some may also inhibit nearby cholinergic activating neurons, some project (solid lines) caudally to the posterior hypothalamus and brainstem to inhibit neurons of the arousal system, and some (solid lines) project to the cerebral cortex and hippocampus to dampen cortical activation directly (see Fig. 11-1). CABAergic neurons are also located in the thalamic reticular nucleus, where they play an important role in generating spindles and slow waves of slow wave sleep. Not shown are other neuronal systems or factors implicated in slow wave sleep, including adenosine. Multiple peptides, such as the opiates, somatostatin or cortistatin, and growth hormone-releasing factor, may be involved in slow wave sleep generation and are often colocalized with one of the other primary neurotransmitters, particularly CABA. The neuronal systems implicated in the maintenance of slow wave sleep may be involved in primary processes of sensory inhibition and analgesia, behavioral inhibition, and parasympathetic and neuroendocrine (notably growth hormone) responses and regulation, by which they may also facilitate the onset and maintenance of slow wave sleep. ac, anterior commissure; CB, cerebellum; cc, corpus callosum; Hi, hippocampus; OB, olfactory bulb; oc, optic chiasm; Ser, serotonin.
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11
Basic
Mechanisms
of
Sleep Wake States
Barbara
E.
]ones
ABSTRACT
A
state of wakefulness is maintained by neurons in the brain-
stem reticular formation, which in turn excite neurons in the
nonspecific thalamocortical projection system along a dorsal
pathway and in the posterior hypothalamus and basal fore-
brain along a ventral pathway. The thalamocortical, hypothal-
amocortical, and basalocortical projections serve to activate
the cerebral cortex in turn in a long-lasting and widespread
manner, stimulating fast activity on the electroencephalogram
(EEG). The major population of neurons comprising the
ascending reticular activating system use glutamate
as
a neuro-
transmitter. Other contributing pontomesencephalic tegmental
neurons use acetylcholine. In addition, locus coeruleus neurons
containing norepinephrine project diffusely from the brain-
stem to the entire forebrain, including the cerebral cortex, and
thereby serve to stimulate and maintain cortical activation.
Similarly, posterior hypothalamic neurons containing hista-
mine and others containing orexin (hypocretin) project
diffusely to the forebrain and cortex. Whereas the thalarno-
cortical projection system uses glutamate
as
a neurotransmitter,
the basalocortical system primarily uses acetylcholine. In
addition to the smaller neurotransmitter molecules, neurons
in these activating systems also contain and often colocalize
peptides, including substance vasoactive intestinal peptide,
and neurotensin, that serve to enhance
or
prolong their
excitatory actions.
For sleep, a shift from sympathetic to parasympathetic
regulation occurs, and activating systems are dampened.
Neurons in the solitary tract nuclei and in the anterior hypo-
thalamus and preoptic area, constituting parasympathetic
control centers, are particularly important in these processes.
Serotonergic raphe neurons may also facilitate the onset of
sleep. Inhibition of activating systems is effected by particular
gamma-aminobutyric acid-ergic (GABAergic) neurons, which
are selectively active during slow wave sleep. Dampening the
brainstem, hypothalamic, and basal forebrain activating
systems leads to disfacilitation and hyperpolarization of thala-
mocortical systems, which consequently shift their mode of
operation from fast, tonic discharge to slow, bursting discharge,
reflected
as
spindles and slow wave activity
on
the EEG.
Certain peptides, such
as
somatostatin and cortistatin, are
colocalized with GABA
in
particular neurons and may
enhance and prolong the inhibition of the activating systems
in the initiation and maintenance of slow wave sleep.
Since the 1930s, the basic mechanisms of sleep-wake states
have been studied by an interdisciplinary approach to eluci-
date the neurophysiologic, neuroanatomic, and neurochemi-
cal substrates. Through this search, what was initially
136
considered to be a unitary process of sleep emerged
as
a dual
process comprising
two
distinct states, slow wave sleep and
paradoxical or rapid eye movement
(EM)
sleep. Although
normally dependent on the prior occurrence of slow wave
sleep, paradoxical sleep is generated by different neural
systems than slow wave sleep. In the following historical
consideration of basic mechanisms, the term
sleep
refers in
a general manner to total sleep when discussing research
before 1960 and more specifically to slow wave sleep when
reviewing more contemporary research. In the treatment of
recent research on the basic mechanisms of sleepwake states,
this chapter deals with the particular mechanisms of slow
wave sleep, whereas other chapters focus on the specific
mechanisms of paradoxical sleep. The chapter is organized in
a historical progression with parallel subdivisions according to
the different techniques and approaches applied at different
periods.
NEURONAL SYSTEMS IMPLICATED
The Activating System
Identification of an Activating System
in the Brainstem
In the early 1900% many physiologists, including, notably,
Kleitman, believed that wakefulness and consciousness were
maintained by ongoing sensory input to the brain.' Bremer
showed that in the
cerveau
isole,
or cerebrum isolated from the
spinal cord and brainstem by a transection at the mesodien-
cephalic junction, wahng signs were absent and sleep signs
predominant,
as
marked by slow waves on the cerebral cortex
and miosis
of
the pupils.2 The absence of waking parameters
was interpreted at the time as being due to the interruption
of
sensory inputs from the body and head to the forebrain. In
the 1940s, Moruzzi and Magoun questioned this interpreta-
tion and suggested instead that it was not interruption of the
sensory input to the cerebrum that eliminated wakefulness
but interruption
of
input from the brainstem's netlike core
of
neurons, the reticular formation. Indeed, they showed that
electrical stimulation of the reticular formation, and not of the
sensory pathways, produced long-lasting and widespread
cortical activation marked by the replacement of cortical slou-
waves with fast activity3 (Fig. 11-11, Second, they showed that
lesions of the reticular formation, but not of the sensory path-
ways, produced a
loss
of
cortical activation that was replaced
by cortical slow waves and behavioral immobility indicative
of
coma.4 Lesions with the most marked and enduring effect
were located in the oral pontine and midbrain reticular
formation and the posterior hypothalamus and subthalamus.
IN SLEEP-WAKE STATE GENERATION
Basic
Mechanisms
of
Sleep-Wake States
137
Figure
11-1.
Neural systems generating wakefulness. This schematic depiction of
a
lateral, sagittal section of the
cat
brain represents neuronal
systems implicated in the generation and maintenance of wakefulness. Outlined areas represent the region in the brainstem (oral pontine and
midbrain reticular formation) and caudal diencephalon (posterior hypothalamus, subthalamus, and ventral thalamus) and in the basal forebrain
where large lesions are associated with a decrease
or
loss
of cortical activation and behavioral activity indicative of wakefulness. Whereas lesions
of the central midbrain tegmentum primarily affect cortical activation, lesions of the ventral midbrain tegmentum predominantly alter behavioral
arousal. Points marked with
‘W
(waking) indicate regions where high-frequency electrical stimulation produces cortical activation and arousal,
as
well
as
where neurons manifest
a
higher rate
of
spontaneous activity during wakefulness than during slow wave sleep (including the medullary,
oral pontine, and midbrain reticular formation; the midline and intralaminar thalamic nuclei; the subthalamus and posterior hypothalamus; and
the basal forebrain).
Diamond-shaped symbols
represent the neurons of the reticular formation, and
dotted lines
indicate their major ascending
projections into the forebrain, which proceed along
two
major routes. The dorsal route terminates in the nonspecific thalamic nuclei, which in
turn project in
a
widespread manner to the cerebral cortex (not shown).
The
ventral route passes through and terminates in the subthalamus
and posterior hypothalamus and continues into the basal forebrain and septum, where neurons in turn project in
a
widespread manner to the
cerebral cortex and hippocampus.
Squares
represent catecholaminergic neurons of the locus coeruleus (dorsal pons), which contain norepi-
nephrine, and of the substantia nigra and ventral tegmental area (ventral midbrain), which contain dopamine. The noradrenergic neurons are
mainly implicated in processes
of
cortical activation and project
(dashed lines)
directly and diffusely to the cerebral cortex,
as
well
as
to the sub-
cortical way stations. The dopaminergic neurons are predominantly implicated in processes of behavioral arousal and responsiveness and project
(not shown) heavily into the basal ganglia (including caudate) and frontal cortex.
Solid circles
represent acetylcholine-containing neurons of the
brainstem reticular formation (including the laterodorsal and pedunculopontine tegmental nuclei in the dorsal pons and midbrain) and basal
forebrain (substantia innominata, diagonal band nuclei, and septum).
The
brainstem cholinergic neurons project
(solid lines)
to subcortical way
stations, including, most importantly, the thalamus, where they
excite
the nonspecific thalamocortical projection system. The cholinergic basal
forebrain neurons project
(solid lines)
in
a
widespread manner to the cerebral cortex and hippocampus to stimulate cortical activation directly.
Contributing in an important manner to the brainstem arousal systems are neurons in the posterior hypothalamus containing histamine and
orexin, which project (not shown) diffusely through the brain and directly to the cerebral cortex (not shown). Glutamate-synthesizing neurons
(diamonds)
comprise the projection neurons of the reticular formation, thalamus, and cerebral cortex and are thus critical
at
all
levels in processes
of cortical activation and wakefulness. Multiple peptides (not shown), such
as
substance
P,
corticotropin-releasing factor, thyrotropin-releasing
factor, vasoactive intestinal polypeptide, and neurotensin, may stimulate wakefulness or cortical activation and are often colocalized with one of
the other primary neurotransmitters, such
as
acetylcholine
or
glutamate. The neuronal systems implicated in the maintenance of wakefulness
may be involved in primary processes of sensory transmission and attention, motor response and activity, and orthosympathetic and neuroen-
docrine (particularly adrenocorticotropic hormone and thyrotropin) responses and regulation, by which they may also enhance and prolong
vigilance and arousal.
ac,
anterior commissure; Ach, acetylcholine;
CB,
cerebellum;
cc,
corpus callosum; DA, dopamine; Clu, glutamate; H, his-
tamine; Hi, hippocampus; NE, norepinephrine;
06,
olfactory bulb; ot, optic tract; Orx, orexin;
SC,
spinal cord.
where ascending pathways reach into the f~rebrain~.~
(Fig. 1 1-1). Electrophysiologic and neuroanatomic studies
showed that the neurons of the reticular formation receive
collateral input from visceral, somatic, and special sensory
systems and project in turn by a dorsal pathway to the thala-
mus and a ventral pathway to the basal forebrain. From thal-
amus and basal forebrain, impulses are in turn relayed to the
cerebral cortex in a widespread
marine?'
(Fig. 11-11. This
system was called the
ascending
reticular
activating
system
and
deemed
to
be necessary and sufficient
for
tonic maintenance
of cortical activation and behavioral arousal of wakefulness.
In the 1800s, clinical cases
of
somnolence
or
coma were
found to be due
to
lesions
of
the midbrain and posterior dien-
cephal~n.~-~ Based on cases
of
“encephalitis lethaqgca” in the
early 1900s, von Economo proposed that a “sleepregulating
center”
was
present in the midbrain and diencephalon and
was
composed of antagonistic wahng and sleeping parts.’O
On the basis of the location
of
lesions in cases characterized
138
Sleep
Mechanisms
by somnolence, he posited that the wahng part was localized
in the rostra1 midbrain tegmentum and caudal diencephalon.
Since those observations, many clinical cases of somnolence,
stupor, and coma resulting in a
loss
of consciousness have
been reported with lesions in the oral pontine and midbrain
tegmentum
or
posterior hypothalamus and subthalamus.
l.12
With smaller and more localized lesions in the midbrain
and caudal diencephalon, dissociation between the cortical
activation and behavioral arousal of wakefulness was sub-
sequently noted in both experimental animal and human
cases of somnolence and coma. In animals, lesions of the central
midbrain tegmentum were found to produce a deficiency in
cortical activation without preventing behavioral responsive-
ness to sensory ~timulation.’~ On the other hand, lesions
of the ventral tegmentum and hypothalamus were found to
produce a state of behavioral quiescence and unresponsive-
ness without
a
loss
of cortical activation
or
alerting. Similar
clinical symptoms had previously been noted in humans
and were referred to as “ahnesia” and “akinetic mutism.””
It
thus appeared that
two
parallel systems controlled cortical
activation and behavioral arousal.
Activating Systems in the Forebrain
Investigation in the
1960s
and
1970s
indicated that in the
chronic course, the brainstem reticular formation was not
absolutely necessary for wakefulness because cortical activa-
tion could eventually recover given sufficient time after lesions
or transections through the brainstem.
14*15
In fact, when
lesions were effected gradually in stages, the same total lesions
of the midbrain reticular formation that produced long-lasting
coma when performed in one operation, were followed by
total recovery.
l6
This recovery could be explained by a certain
amount
of
regeneration and plasticity that are now
known
to
occur in the central nervous system. However, the recovery
could also be interpreted as due to activity
of
other activating
systems located in the forebrain. Indeed, based on recovery of
electroencephalographic fast activity in the chronic
ceweau
isole
cat,
it
was concluded that cortical activation can be
independently generated by the forebrain.
l5
Electrophysiologic and lesion studies showed that the
activating influence of the reticular formation is transmitted to
the cerebral cortex by a dorsal relay through the thalamus and
a ventral, extrathalamic relay through the basal forebrain. In
the thalamus, electrical stimulation
of
the midline and
intralaminar nuclei, which form the nonspecific thalamocortical
projection system, could produce fast activity across the
entire cerebral cortex5 (Fig.
11-11,
Ablation
of
the thalamus in
animals led to a loss of cortical activation, which did however
re~0ver.l~ Cortical fast activity could still be elicited after
thalamic lesions by stimulation of the midbrain reticular
formation, indicating that the extrathalamic route and relay to
the cortex could be ~ufficient.~ Identified by neuroanatomic
techniques in the
1970s,’*
this relay to the cortex originates
from neurons located in the posterior hypothalamus and
basal forebrain (substantia innominata
or
nucleus basalis
of Meynert), which project in a widespread manner to the
entire cortical mantle. Electrical stimulation through these
regions could produce widespread cortical activation5
(Fig.
11-11,
The posterior hypothalamus was also thought to
be important as a wahng center because of
its
regulation of
the sympathetic division of the autonomic nervous system.
1y,20
Lesions destroying nerve cell bodies and not nerve fibers of
the posterior hypothalamus by neurotoxins have been shown
to decrease wakefulness,2 confirming the importance
of
hypothalamic neurons and not just fibers ascending from the
brainstem for this state. Lesions of cells in the basal forebrain,
which project
to
the cortex, have also been found to be
associated with a loss of cortical activation
of
wakefulr~ess~~.~~
(Fig.
11-1).
Thus, the essential activating system had to be
enlarged to include, in addition to the reticular formation, the
posterior hypothalamus-subthalamus and basal forebrain,
which receive ascending input from the reticular formation
and project in turn to the cerebral These forebrain
systems in the ventral extrathalamic relay also appear to be
able to maintain cortical activation of the forebrain in the
long-term absence of input from the brainstem reticular
formation and thus function independently as activating
systems.
Single-Unit Recording
of
Wake-Active
Neurons
Most neurons in the brain were found to discharge at higher
rates during wakefulness than during slow wave sleep.25 In the
midbrain reticular formation, most cells were found to have a
high rate
of
tonic discharge in association with cortical fast
activity during waking and to decrease their rate of discharge
before the onset of cortical
slow
wave activity and slow wave
sleep26 (Fig.
11-1).
These reticular neurons excite in turn neu-
rons
of
the nonspecific thalamocortical projection system. The
thalamic neurons also manifest a high rate
of
tonic discharge
with cortical activation and wakefulness. Through their wide-
spread projections to the cortex, they activate cortical neu-
rons, which fire at high sustained rates with fast cortical
activity. Neurons lying in the ventral, extrathalamic pathway
in the posterior hypothalamus and basal forebrain have also
been found to have a higher rate of firing during wakefulness
than during slow wave (Fig.
11-1).
Sleep-Generating Systems
lden tification
of
a
Sleep-Generating System
in the Brainstem
In the
1940s
and
1950s,
many physiologists believed that
sleep was the result of fatigue and decrease in activity
of
the
reticular activating system, thus representing a passive deacti-
vation
of
the forebrain.
l4
However, transections through
particular levels of the brain resulted in diminished sleep.
Transections of the brainstem behind the oral pontine
tegmentum resulted in a total insomnia,2y indicating that
important sleep-generating structures were located in the
lower brainstem with the capacity to antagonize the ascending
reticular activating system in the upper brainstem.
In clinical cases, slow wave sleep was reported to be dimin-
ished or absent with lesions in the lower pons or medulla.’0
These cases show a predominance of alpha activity on the
electroencephalogram (EEG), typical of wahng, even though
behavioral alertness and responsiveness are lacking in what
has been referred to as an “alpha coma.”
Low-frequency electrical stimulation of the medullary
reticular formation, particularly the dorsal medullary reticular
formation and the solitary tract nucleus, produced cortical slow
wave-activity awake animals3 (Fig.
1
1-21.
Conversely, lesions
Basic Mechanisms
of
Sleep-Wake States
139
Figure
11-2.
Neural systems promoting slow wave sleep. This schematic depiction of
a
paramedian, sagittal section of the
cat
brain represents
neuronal systems implicated in the facilitation, generation, and maintenance of slow wave sleep. Outlined areas represent the regions in the
brainstem (raphe and solitary tract nuclei) and forebrain (anterior hypothalamus, preoptic area, and basal forebrain) where large lesions are asso-
ciated with
a
chronic decrease or loss of slow wave sleep. Points marked with
"5"
(slow wave sleep) indicate regions where low-frequency
elec-
trical stimulation produces cortical synchrony and behavioral sleep,
as
well
as
where particular neurons manifest
a
higher rate of spontaneous
activity (or typical burst-pause pattern of activity) during slow wave sleep compared with waking (including the solitary tract nucleus, nonspe-
cific thalamic nuclei, anterior hypothalamus-preoptic area, and basal forebrain).
Diumond-shaped symbols
represent neurons of the solitary tract
nucleus (of unknown neurotransmitter content) implicated in slow wave sleep regulation, which project
(dotted lines)
forward into the visceral-
limbic forebrain.
Stars
represent serotonin-containing neurons of the brainstem raphe nuclei, which may
facilitate
the onset of slow wave sleep
and which project forward into the rostral tegmentum, thalamus, subthalamus, hypothalamus, and basal forebrain and also from the midbrain
directly to the cerebral cortex and hippocampus.
Triungles
represent gamma-aminobutyric
acid
(CABAFsynthesizing neurons located in multi-
ple regions. In the reticular formation, local CABAergic neurons may inhibit surrounding neurons of the ascending reticular activating system. Of
the
CABAergic neurons in the anterior hypothalamus-preoptic area and basal forebrain-septum, some may also inhibit nearby cholinergic
acti-
vating neurons, some project
(solid lines)
caudally to the posterior hypothalamus and brainstem to inhibit neurons of the arousal system, and
some
(solid lines)
project to the cerebral cortex and hippocampus to dampen cortical activation directly
(see
Fig.
11-1).
CABAergic neurons
are
also located in the thalamic reticular nucleus, where they play an important role in generating spindles and slow waves of slow wave sleep. Not
shown are other neuronal systems or factors implicated in slow wave sleep, including adenosine. Multiple peptides, such
as
the opiates, somato-
statin or cortistatin, and growth hormone-releasing factor, may be involved in slow wave sleep generation and are often colocalized with one of
the other primary neurotransmitters, particularly CABA. The neuronal systems implicated in the maintenance of slow wave sleep may be involved
in primary processes of sensory inhibition and analgesia, behavioral inhibition, and parasympathetic and neuroendocrine (notably growth
hormone) responses and regulation, by which they may also facilitate the onset and maintenance of slow wave sleep.
ac,
anterior commissure;
CB,
cerebellum;
cc,
corpus callosum; Hi, hippocampus;
OB,
olfactory bulb; oc, optic chiasm; Ser, serotonin.
of these structures produced fast activity in the
EEG
of sleeping
animals.32 Collectively, these results indicated the presence of
neurons in the dorsal medullary reticular formation and the
nucleus of the solitary tract that could generate sleep. Their
action
was
hypothesized to be exerted by inhibition of the
rostrally located neurons of the ascending reticular activating
system, although a direct synchronogenic influence on forebrain
systems
was
also considered possible.
The solitary tract nucleus receives afferent fibers from the
glossopharyngeal and vagus (9th and 10th cranial) nerves,
which carry afferent input from baroreceptors and chemo-
receptors of the thoracic and abdominal viscera. Efferent
projections from the solitary tract nucleus and dorsal
medullary reticular formation ascend to the level of the rostral
pons and midbrain, where many terminate in the parabrachial
nuclei.33 The parabrachial nuclei project rostrally to the
thalamus, hypothalamus, preoptic area, amygdala, and orbito-
frontal cortex, regions commonly belongmg to the visceral-limbic
forebrain. The solitary tract nucleus also projects forward
although lightly
to
all
of these forebrain structures, except the
(Fig.
11-2).
From these neuroanatomic data,
it
appeared that the action of the solitary tract nucleus may not be
uniquely through inhibition of the reticular activating system,
but
also
through
action on limbic forebrain structures that had
also
been implicated
in
sleep generation.
Sleep-Generating Systems in the Forebrain
From the original studies of Bremer with the
ceweau
isole'
preparation,2
it
had been
known
that synchronogenic struc-
tures could also be located
in
the forebrain because cortical
slow wave activity occurs continuously in this preparation in
140
Sleep
Mechanisms
absence of brainstem influences. In acute experimental stud-
ies applying electrical stimulation, slow cortical activity could
be driven or recruited by low-frequency stimulation of the
midline thalamus.35 In chronic preparations, thalamic stimu-
lation was shown to induce natural sleep,
as
defined by behav-
ioral
as
well
as
electroencephalographic criteria (Fig
11-2),
findings that led to the conclusion that the thalamus
is
the “head ganglion of sleep.”36 Such a conclusion has been
supported by clinical cases of “fatal familial insomnia,” which
are associated with selective degeneration of thalamic
nuclei.37 However, experimental lesion studies in animals have
shown that although the thalamus may be necessary for the
production of cortical spindles,
it
is
not necessary for the
generation of cortical slow waves and behavioral sleep, which
persist after
its
complete ablation.17
In the early
19OOs,
von Economo had noted that in some
cases of “encephalitis lethargica,” insomnia was the promi-
nent symptom, and in such cases the lesions were centered in
the anterior hypothalamus.1° He thus posited that a sleep
center was located in the anterior hypothalamus, which would
be in opposition to,
as
well
as
normally in balance with, the
waking center in the posterior hypothalamus. The existence of
a sleep facilitatory region in the anterior hypothalamus and
preoptic area was subsequently confirmed by lesion studies in
animals.20 It was also demonstrated that electrical stimula-
tion of this area could elicit behavioral suppression and auto-
nomic changes that normally accompany sleep.
l9
Electrical
stimulation of the basal forebrain and preoptic area was
shown to lead to drowsiness followed by natural behavioral
and electroencephalographic sleep38 (Fig.
1
1-21.
Conversely,
large lesions of these areas led to an elimination or decrease in
sleep and a disruption of the sleep cycle3g (Fig.
11-2).
The
anterior hypothalamus, preoptic area, and basal forebrain
were thus clearly shown to be important, together with the
lower brainstem, for the generation of sleep.
However,
it
was subsequently shown that these structures
were not sufficient for slow wave sleep and that the cerebral
cortex and basal ganglia could also contribute to sleep onset
and maintenance.* Animals without neocortex and striatum
(thus called diencephalic cats), but with sleep-inducing struc-
tures of both the lower brainstem and the anterior dien-
cephalon intact, did not show a normal sleep cycle but instead
a large decrease in slow wave sleep. Although some damage to
basal forebrain structures may have occurred in these prepa-
rations to explain the decrease in sleep, the results nonethe-
less suggested that the cerebral cortex and basal ganglia may
also have a role in sleep induction
or
maintenance, perhaps by
influence on the activating system of the caudal diencephalon
and rostra1 brainstem. Electrical stimulation of the
orbitofrontal cortex and caudate had been shown to produce
cortical synchrony and behavioral sleep.41 Bilateral lesions of
the frontal cortex resulted in a permanent moderate reduction
of
sleep, whereas lesions of the caudate nuclei led to a
temporary decrease in sleep.42 Other lesion studies indicated
that the orbitofrontal cortex
is
particularly important in the
generation of slow wave activity and behavioral sleep.43
Evidence thus suggested that neurons in the orbitofrontal
cortex, together with those in basal forebrain, preoptic area,
and anterior hypothalamus constitute a forebrain sleepinducing
system.
From neuroanatomic and neurophysiologic studies, several
principles were to emerge concerning the links of forebrain
sleep-inducing systems with the limbic system and the inter-
action of this larger system with the brainstem activating
system. From early neuroanatomic studies, neurons in the
preoptic area and anterior hypothalamus were known to be
interconnected with limbic forebrain structures, including,
notably, the septum, amygdala, and orbitofrontal cortex, and
also to send descending projections to the medial limbic mid-
brain region“ (Fig.
11-2).
This descending projection went to
the central gray and raphe nuclei but also terminated laterally
in the midbrain reticular formati~n.~~?~~ Electrical stimulation
of the basal forebrain was shown to disrupt ongoing activity in
midbrain reticular neurons, showing that sleep-generating
neurons in the forebrain may act by antagonizing neurons of
the ascending reticular activating system.* Connections of
the forebrain limbic regions with lower brainstem autonomic
centers are also present. Neurons in the anterior hypothala-
mus project directly to the solitary tract nucleus and adjacent
region in the medulla, also sending fibers through,
as
well as
to, the parabrachial nuclei in the pons.47 The orbitofrontal
cortex also projects directly to the solitary tract nucleus, in
addition to supplying an important input to the preoptic area,
anterior hypothalamus, and parabrachial nuclei.48 These fore-
brain and lower brainstem structures form by their intercon-
nections a system that plays an important role in autonomic
regulation in addition to having the capacity to influence
sleep. The importance of visceral regulatory mechanisms to
sleep regulation was originally proposed years ago by Hess
and Nauta, who both emphasized the anatomic overlap
between centers involved in regulation of the autonomic
nervous system and those involved in the sleepwake cycle.19
An overlap
exists
between sleep and parasympathetic centers
in the anterior hypothalamus-preoptic area, where stimula-
tion elicits both behavioral and electroencephalographic signs
of sleep and in parallel evokes a decrease in blood pressure
and heart rate and causes pupillary miosis. Caudally, an over-
lap
exists
between waking and orthosympathetic centers
in
the posterior hypothalamus and midbrain reticular formation,
where stimulation elicits behavioral arousal and cortical
activation and in parallel stimulates an increase in blood
pressure and heart rate and causes pupillary mydriasis.
Single-Unit Recording
of
Sleep-Active Neurons
Neurons that increase their rate of firing during slow wave
sleep are in the minority in the brain and particularly in the
brain~tem.~~.~~ In the region of the solitary tract nucleus, how-
ever, a number of neurons have been found to be more active
during slow wave sleep than during waking50 (Fig.
11-2).
Such sleep-related cells are invariably intermingled with
cells in the same area that show a higher rate
of
spontaneous
activity during wakefulness.
Neurons that increase their overall rate of discharge during
slow wave sleep compared with walung were found in the ante-
rior hypothalamus and preoptic area,
as
well
as
in the amyg-
dala49
(Fig.
11-2).
Most recently, sleepactive neurons have been
found to
be
concentrated in the ventrolated preoptic area,
where they were
first
located by their expression of c-Fos,
as
an
indication of neural activity, in association with sleep recov-
er~.~~.~~ Sleepactive neurons were
also
found distributed
among
wake-active cells in the basal forebrain (including the substantia
innominata and dlagonal band nuclei; Fig.
1
l-2).27
Basic Mechanisms
of
Sleep-Wake States
141
It
originally came as a surprise to the early physiologists to
find that neurons in the cerebral cortex are very active during
slow wave sleep, given that they discharge in periodic bursts
of spikes.53 However, because of long pauses between the
bursts, this pattern of discharge
is
actually associated with a
decrease in average spike rate during slow wave sleep relative
to walung, thus allowing a relative rest for the cortical neurons
during slow wave sleep. The bursting activity occurs first in
association with spindles that are generated in the thalamus
by neurons of the thalamic reticular nucleus.54
As
shown by
Steriade and colleagues, the thalamic reticular neurons have
intrinsic properties that allow them to burst at the frequency
of thalamocortical sleep spindles
(-12
to
14
Hz) and to pace
the thalamocortical projection neurons that they innervate.
Through intrinsic properties of the thalamic relay neurons and
of
cortical projection neurons, other slow oscillations
(0.1
to
4
Hz), including delta waves, that characterize slow wave
sleep activity are also carried through the thalamocorticotha-
larnic network.j5 This slow activity is also transmitted from
the cortex in corticofugal projections to striatum, basal fore-
brain, brainstem, and spinal cord,
as
well
as
to the thalamus,
to play the important role in enforcing slow wave sleep
through the central nervous system that was originally evident
in lesion st~dies.'~
CHEMICALS IMPLICATED
IN
SLEEP-WAKE STATES
In the early
1900s,
Pieron demonstrated that transfer of cere-
brospinal fluid (CSF) from sleep-deprived animals to unde-
prived animals caused the undeprived animals to sleep,
indicating that a chemical factor accumulated in the brain
during walung to generate sleep.j6 Later, in the
1950s
and
1960s,
it
was discovered that the chemicals serving
as
neuro-
transmitters in the peripheral nervous system were present in
the brain and that drugs acting on these chemicals had
profound effects on sleepwake states. After localization of
these neurotransmitters by histochemical techniques, Jouvet
proposed that sleep and waking may be generated by specific
neurotransmitters contained in specific neuronal systems.
57
Monoamines and acetylcholine were found in neurons in the
brainstem that have widespread projections through the
brain, suggesting that these neurons were important compo-
nents of sleepwake regulating systems. Other small amino
acid neurotransmitters and large peptide neuroactive sub-
stances are also found in widely projecting systems
as
well
as
locally projecting neurons. These varied chemicals have been
found to be released at short, medium, or long distances from
their targets and to have fast, medium,
or
long duration
actions on their targets. Thus, chemicals of different molecular
size may function
as
neurotransmitters, neuromodulators,
or
neurohormones to participate collectively in the generation of
the sleep-wake cycle.
Chemicals Implicated in Waking
Neurotransmitters or Neuromodulators
and Wakefulness
CATECHOLAMINES
These chemicals were first shown to be involved in arousal
and wakefulness in the
1950s
and
1960~~~
Reserpine, which
depletes monoamines, produced a state of inactivity and
tranquilization that could be reversed by administration of the
catecholamine precursor
L-dihydroxyphenylalanine
(L-dopa).
The precursor administered alone also stimulated a strong
and long-lasting arousal and comcal activation. Amphetamine,
which was shown to act by releasing the catecholamines,
dopamine and norepinephrine, produces an intense behav-
ioral arousal and prolonged vigilance associated with cortical
activation. Another stimulant, cocaine, was found to act by
blocking reuptake and thus inactivation of catecholamines.
Drugs that prevent the enzymatic catabolism of catecholamines
by monoamine oxidase cause an intense and prolonged
arousal. Similarly, those that inhibit catechol-o-methyltrans-
ferase, another catabolic enzyme, stimulate and prolong
behavioral arousal and cortical activation alone and to height-
ened levels when combined with L-dopa.j8 Conversely, wake-
fulness is decreased after inhibition of catecholamine
synthesis by blocking either tyrosine hydroxylase
or
dopamine-be ta-hydroxylase.
Catecholamine perikarya located in the brainstem in
regions of the oral pontine and mesencephalic tegmentum are
important for the maintenance of wakef~lness~~ (Fig.
11-11.
The dopamine- and norepinephrine-containing neurons have
distinctly different distributions and projections, suggesting
different functional roles. Dopamine-containing neurons are
localized in the substantia nigra and ventral tegmental area in
the midbrain (Fig.
11-1)
and are also scattered through the
posterior hypothalamus and subthalamus. The dopaminergic
neurons of the substantia nigra project forward through the
lateral hypothalamus into the neostriatum, to which they pro-
vide a dense innervation.60 Together with those of the ventral
tegmental area, these dopaminergic neurons also innervate
the basal forebrain, nucleus accumbens, septum, amygdala,
and frontal cortex. By these efferent projections, the midbrain
dopaminergic neurons may modulate activity in motor and
limbic systems. The norepinephrine-containing neurons are
found in the pontine tegmentum (Fig.
11-1)
and medullary
reticular formation.61 The largest cluster of noradrenergic neu-
rons, giving rise to ascending projections,
is
in the locus
coeruleus nucleus in the dorsolateral pontine tegmentum.
Noradrenergic neurons of the locus coeruleus project in a dif-
fuse manner to the entire forebrain, along pathways and ter-
minal areas that overlap to a certain extent with those of the
reticular formation but that most uniquely also include all
areas of the cerebral cortd2 (Fig
11-11.
Other noradrenergic
or
adrenergic neurons are scattered through the ventrolateral
pontine and medullary reticular formation. Collectively, the
noradrenergic and adrenergic brainstem neurons provide
innervation to the entire forebrain, brainstem, and spinal cord
and thus can directly modulate activity throughout the central
nervous system, including the cerebral cortex.
Lesions of the dopamine-containing perikarya in the ven-
tral tegmental area and substantia nigra in the cat produced a
state of behavioral unresponsiveness and immobility
or
akine-
sia57.63 (Fig.
11-1).
With lesions limited to the ventral mid-
brain tegmentum, this behaviorally comatose state was not
necessarily associated with a decrease in cortical activation
of
wakefulness. On the other hand, lesions of the central mid-
brain tegmentum, where the ascending noradrenergic fibers
pass, produced a severe decrease in cortical activation
of
wakefulness (Fig.
11-1).
In these animals, behavioral
responses to stimulation could be elicited along with cortical
142
Sleep
Mechanisms
activation; however, behavioral somnolence associated with
moderately slow electroencephalographic activity was in evi-
dence most of the time when the animals were not stimulated.
In summary, dopaminergic neurons of the substantia nigra
and ventral tegmental area, which project to the striatum and
frontal cortex, play an important role in behavioral arousal,
whereas noradrenergic neurons of the locus coeruleus and
brainstem, which project diffusely to the forebrain, including
the cortex, play an integral role in cortical activation.
Clinical studies provide evidence for the involvement of
these chemicals in conditions of akinesia and coma. Cases of
akinesia and akinetic mutism often involve lesions of the ven-
tral midbrain tegmentum or ventral posterior hypothalamus,
where dopaminergic perikarya and pathways are respectively
located.
l1
Similarly, advanced cases of parlunsonism associ-
ated with severe akinesia involve extensive degeneration of
dopaminergic neurons in the midbrain and depletion
of
dopamine in the ~triatum.~~ Such alunesia can be improved by
treatment with L-dopa. Comas marked by a
loss
of
cortical
activation occur with lesions
of
the mesencephalic reticular
formation, through which the ascending noradrenergic path-
ways course.65 Improvement
of
comatose states due to cere-
bral lesions has also been reported after administration of the
catecholamine precursor r-dopa.66
Spontaneous recovery from destruction of catecholaminer-
gic neurons has been documented in animals. The recovery of
motor function, however, after substantia nigra lesions was
shown to depend on intact dopaminergic neurons, which are
capable of compensation, plasticity, and regenerati~n.~~ In
such cases, functional recovery can occur
if
more than
5%
of
the dopaminergic nigrostriatal projection is left intact by the
lesion. With such plasticity, severe long-term deficits may be
rare and difficult to detect. Indeed, selective lesions of cate-
cholaminergic neurons produced with 6-hydroxydopamine
were found to have small to minimal, transient effects on
spontaneous motor activity and cortical activation of wakeful-
ness.68 Moreover, localized lesions
of
the noradrenergic locus
coeruleus neurons in the oral pontine tegmentum did not
produce the
loss
of
wakefulness
or
cortical activation
of
the
same severity as that associated with midbrain lesions of
ascending pathways.69 On the other hand, reversible cooling
of
the locus coeruleus has been found to produce sleep in a
waking animal, and electrical stimulation has been found to
produce arousal in a sleeping animal.70 These results indicate
that collectively, catecholaminergic neurons normally enhance
and prolong wakefulness, but may not be essential for behav-
ioral arousal and cortical activation because they represent
components of larger and thus redundant neuronal systems.
Single-unit recording and neurotransmitter release studies
have substantiated the role
of
catecholaminergic neurons in
arousal processes (Fig.
1
1-1).
Presumed dopaminergic neurons
in the substantia nigra and ventral tegmental area have a low
basal rate of discharge that is similar across sleepwake states,
although they do increase their discharge and tend to fire in
bursts of action potentials in association with significant
sensory stimulation, purposive movement, or behavioral
arousal.71 Presumed noradrenergic locus coeruleus neurons
are most active during attentive, highly aroused, or stressful
waking situations and otherwise show a regular, slow rate
progressively decrease their rate of discharge during slow wave
sleep and virtually cease firing during paradoxical sleep.
of spontaneous activity during quiet wahng.25172-74 The
Y
Release of dopamine and norepinephrine is greatest during
the walung state and, moreover, greatest in association with
behavioral aro~sal.~*,~~
Catecholamines do not act on ionotropic receptors, which
open ion channels directly, but instead
on
metabotropic
receptors, which act indirectly on ion channels through second
messenger pathways, and are thus more typical of neuromod-
ulators with long-lasting indirect actions than classic neuro-
transmitters with rapid direct actions.
In
the thalamus and
cortex, stimulation of adrenergic receptors results in a depo-
larization and excitation of the projection neurons and a
switch from the burst discharge mode underlying slow wave
sleep to a tonic discharge mode underlying waking.77 The
drug modafinil, which enhances and prolongs wakefulness in
humans and animals without eliciting the behalloral excitation
associated with amphetamine, was found to act on postsy-
naptic adrenergic receptors without stimulating catecholamine
release like am~hetamine.~",~~ These pharmacologic results
further substantiate the notion that norepinephrine and
adrenergic receptors appear to be particularly important in
stimulating and maintaining activating processes in thalamo-
cortical systems, whereas dopaminergic systems are potent in
stimulating behavioral arousal. Through widespread
or
diffuse
projections and slow modulatory actions
on
other systems,
catecholamine-containing neurons may collectively stimulate,
enhance,
or
prolong a waking, attentive, and aroused state
ACETVLCHOLINE
This chemical was
known
to be important for vigilance and
cortical activation during waking from pharmacologic evidence
in the
1950s
and
1960~.~~.""
Atropine or belladonna, which
acts by bloclung muscarinic cholinergic receptors, decreases
vigilance. This deficit was shown in animals to be due to the
appearance of cortical slow wave activity
on
the cerebral cortex
that persisted even during spontaneous movement in what
was thus described as the dissociation of
EEG
and behavior.
Conversely, neostigmine, which inhibits the catabolic enzyme
acetylcholinesterase and thus prolongs the postsynaptic
action
of
acetylcholine, enhances vigilance in association with
prolonged cortical activation. The cholinergic agonists, mus-
carine and nicotine, enhance
or
prolong vigilance and cortical
fast activity. Acetylcholine thus appears to play an important
role in cortical activation, independent
of
walung behavior,
and thus potentially during both waking and paradoxical
sleep.s1-s2
Two major groups of cholinergic neurons give rise to fore-
brain and cortical
projection^^'^"^
(Fig.
11-1).
One is located
in the oral pontine-caudal mesencephalic reticular formation
(in the laterodorsal and pedunculopontine tegmental nuclei)
and gives rise to projections into the forebrain, particularly to
the midline and intralaminar thalamic nuclei, but also to a
lesser degree to the lateral hypothalamus and basal forebrain.
Another
is
made up of cholinergic neurons located in the
basal forebrain (nucleus basalis, substantia innominata,
nuclei of the diagonal band, and septum), which project in a
widespread manner to the entire cortical mantle. The latter
cells appear to serve as the ventral, extrathalamic relay from
the brainstem reticular formation to the cerebral cortex.
Although the pontomesencephalic cholinergic neurons
serve as a component of the ascending reticular activating
system, their destruction does not eliminate cortical activation
of waking, but eliminates paradoxical sleep."' Lesions of the
Basic Mechanisms
of
Sleep-Wake States
143
cholinergic neurons of the basal forebrain produce alterations
in cortical activity that are similar to those seen after atropine
administration, that
is,
slowing of cortical activity and loss of
vigilan~e~~.~~ (Fig. 11-1). Such lesions also alter slow wave
~leep.~~,~~ The latter effects could be due to destruction of
codistributed sleep-active cells, which probably do not con-
tain acetylcholine. Pharmacologic inhibition
or
inactivation of
the cholinergic cells by local microinjections
of
chemical
agents clearly diminishes the high-frequency (30 to
60
Hz
gamma) cortical activity that characterizes cortical activation
as
evident in aroused, attentive awake states and in paradoxi-
cal sleep.85 These results confirm that the cholinergic neurons
of the basal forebrain are very important for cortical activation.
Alzheimer's disease, which is associated with a loss of
cholinergic innervation of the cerebral cortex and degenera-
tion of cholinergic neurons of the basal forebrain,
is
charac-
terized by a diffuse slowing of cortical a~tivity.~~,~~ In later
stages of the disease, sleep
is
also greatly perturbed, marked
by a loss of spindles and slow waves
as
well
as
a decrease in
REM
sleep (see Chapter 71). Such general disruption of the
EEG
and sleep cycle probably reflects the diffuse degeneration
and neurofibrillary changes of multiple cell populations
through the brainstem and basal forebrain
as
well
as
~~rtex.~~*~
Presumed cholinergic pontomesencephalic neurons dis-
charge at higher rates during waking than during slow wave
sleep (and often at an even higher rate during paradoxical
sleep),
as
reflected by increased release of acetylcholine from
the thalamu~~~,~~ (Fig. 11-1). Cholinergic basal forebrain
neurons are also most active during waking (and paradoxical
sleep) compared with slow wave sleep,
as
reflected by high
levels of acetylcholine release from the c~rteXa~,~~ (Fig. 11-11.
Acetylcholine acts on muscarinic and nicotinic receptors in
the central nervous system. Muscarinic receptors are
metabotropic, associated through second messenger systems
with slow and prolonged postsynaptic actions that are pre-
dominantly excitatory, although also in some cases inhibitory.
Nicotinic receptors are ionotropic, directly linked to ion
channels that permit fast postsynaptic excitatory actions. The
excitation of pyramidal cells by acetylcholine results in a shift
in their mode of firing from a burst discharge associated
with cortical slow waves to a tonic discharge associated with
cortical fast activity.77 Cholinergic brainstem and basal fore-
brain neurons may thus exert a tonic facilitatory influence on
transmission and activity in both the thalamus and cortex
to promote thalamocortical transmission and fast cortical
activity during wakefulness and paradoxical sleep.
HISTAMINE
This chemical has long been assumed to play
a
role in walang
given the well-known sedative effects of the early antihista-
minergic drugs93 (see Chapter
37).
Histamine administered
directly into the cerebral ventricles has an arousing effect.94
Histamine-containing neurons are located in the tuberomam-
millary nuclei and surrounding area of the posterior hypo-
thalamus,95 where lesions had been shown to be associated
with coma
or
a decrease in wakefulness (Fig.
11-1).
Like locus
coeruleus neurons, histaminergic neurons give rise to diffuse
projections through the brain, including the entire cerebral cor-
tex. Neurotoxic lesions, selective to cell
bodies
and sparing fibers
of passage, of the posterior hypothalamus have been shown to
produce a decrease in wakefulness and increase
in
both slow
wave sleep and paradoxical sleep.21 Putative histaminergic
neurons have also been shown to be most active in association
with the cortical activation of wakefulness and turn off during
paradoxical sleep.96 Histamine acts on metabotropic receptors,
which are generally excitatory and produce a depolarization
and resulting tonic discharge
in
thalamic and cortical projec-
tion neurons,
as
typically associated with walang, fast cortical
activity." Like norepinephrine, histamine would thus pro-
mote cortical activation during wakefulness.
CLUTAMATE
The major excitatory neurotransmitter in the brain, glutamate
plays a fundamental role in neural activity of the waking
brain.81 Glutamate agonists produce seizures. Some glutamate
receptor antagonists (e.g., ketamine) are used as sedatives
or
anesthetic^.^^
Glutamate
is
found in high concentrations in
the large neurons of the brainstem reticular formation and
likely serves
as
the primary neurotransmitter of the ascending
reticular activating systemz4 (Fig. 11-1). It
is
also contained in
the projection neurons of the thalamus and cerebral
Glutamate is released from the cerebral cortex in greatest
quantities in association with cortical activation of sponta-
neous wakefulness
or
that evoked by stimulation of the
midbrain reticular formation.99 Glutamate acts on different
postsynaptic receptors, including both ionotropic (kainate,
a-amino-3-hydroxy-5-meth~o~le4-propionic
acid
[AMPAI,
and N-methybaspartate [NMDAI) and metabotropic (trans-
aminocyclopentane-1 ,Idicarboxylic acid [t-ACPD]) receptors
that are generally excitatory but are associated with different
durations of excitation and induced patterns of discharge.
Stimulation of the different receptors is commonly associated
with increased discharge of thalamic and cortical neurons."
However, stimulation of NMDA receptors can induce a burst
discharge that has been implicated in the burst discharge of
pyramidal cells during slow wave sleep.loO Thus, glutamate,
contained in the reticular formation neurons of the brainstem
activating system and in most of the projection neurons in the
forebrain,
is
critical for cortical activation and a waking,
responsive state. In addition, particular glutamate receptors
may also be activated during slow wave sleep in association
with a burst mode
of
discharge.
Cerebrospinal Fluid-Borne Factors,
Peptides, and Wakefulness
Wake-promoting factors
are suspected of being present in the
CSF because wakefulness and activity have been produced in
recipient animals after extraction
of
CSF from waking host
animals.101.102
It
has long been suspected that such factors
would be peptides, although other chemicals, such
as
the
catecholamines, have been shown to accumulate in the CSF
and to vary according to a circadian rhythm.
Peptides
have been tested for wake-
or
sleep-promoting
effects by intraventricular administration. This route of
administration may
or
may not mimic physiologic routes of
action
or
reach physiologic sites
of
action for these factors.
Peptides are often colocalized with other smaller molecule
neurotransmitters, although they may be differentially released
from the same nerve terminals
as
a function of different levels
of neuronal activity. Neuroactive pepndes act on metabotropic
receptors to produce relatively long-duration presynaptic
or
postsynaptic effects, some of which serve only to modulate
the effects of other neurotransmitters
or
neuromodulators.
144
Sleep
Mechanisms
Several peptides, when introduced into the CSF
or
directly
into the brain, enhance cortical activation, waking, and, in
some cases, paradoxical sleep. These include
substance
E
vasoactive intestinal peptide
(VIP), and
neurotensin.103,'04
These
different peptides are contained in neurons distributed in
different regions through the brainstem and forebrain and are
thought to act on neurons at a distance from their release
sites. In many cases, they may act on
or
together with cate-
cholaminergic
or
cholinergic neurons in the brainstem
or
fore-
brain. Peptides that stimulate release of pituitary hormones are
also contained in neurons that project to other regions
of
the
brain and may thus influence waking and arousal, including
corticotropin-releasing factor
and
thyrotropin-releasing factor.
After intraventricular administration, cortico tropin-releasing
factor stimulates behavioral arousal associated with prolonged
cortical activation.
lo5
These releasing factors may thus act
centrally to alter state and behavior in a manner synergistic
with the peripheral effects of their targeted hormones.
Orexin
or
hypocretin
was recently discovered as the peptide
that
is
deficient in narcolepsy and would thus play an impor-
tant role in maintaining waking.lo6J07 The neurons that
contain orexin are located in the posterior hypothalamus in
the region where classic lesions were
shown
to be associated
with decreases in waking
or
induction of coma, and more
recent neurotoxic lesions were associated with increases in
slow wave sleep and paradoxical sleep2' (Fig.
11-1).
They give
rise to diffuse projections to the brain and spinal cord and can
excite neurons in thalamocortical and basalocortical systems
as well as other hypothalamic and brainstem arousal systems
to stimulate cortical activation and behavioral arousal.
lo8-l12
Orexin neurons could correspond to wake-active and
REM
sleepoff cells that have been recorded in the perifornical
region
of
the posterior hypothalarnu~."~ Given their degener-
ation in narcolep~y,"~ orexinergic neurons are considered to
play
a
critical role in maintaining waking and preventing
sleep, including paradoxical sleep. They may form an impor-
tant component of the orthosympathetic system of the poste-
rior hypothalamus because they may also stimulate energy
metabolisml" through activation of the sympathetic and
hypothalamic-pituitary-adrenal
axis,
as would be important in
association with waking activity.
Wake-Promoting Blood-Borne Factors
Epinephrine,
which
is
normally released
in
the blood by the adre-
nal medulla, was shown by intravenous administration in early
pharmacologic
studies
to produce cortical activation in a sleeping
animal preparati~n.~~ Results of multiple
studies
also
suggested
that peripherally circulating norepinephrine released by sympa-
thetic discharge could act centrally through the reticular activat-
ing system to produce cortical activation and wakefulness.
It
was
only later learned that epinephrine and norepinephrine do not
cross
the blood-brain barrier. However, epinephrine and other
blood-borne substances could act on the specialized circumven-
mcular organs that lie outside the blood-brain bamer and in
regions thought to be important in the sleepwake cycle and in
autonomic and neuroendocrine regulation, such
as
the area
postrema
in
the medulla and the median eminence and organum
vasculosum in the hypothalamus.
Histamine,
which is produced in peripheral tissues, was
shown to produce an arousing effect in rabbits when admin-
istered intraven~usly.~~ Furthermore, higher concentrations of
histamine have been measured in the blood of aroused versus
sleeping rabbits, which suggests its participation
as
a neuro-
humoral factor in the regulation of wakefulness and arousal.
Like epinephrine, it must have
its
effect through regions
of
the
brain that are outside the blood-brain barrier.
The action of peripheral chemical factors, which may also
include pituitary hormones such
as
corticotropin
and
thyrotropin,
may permit the reinforcement
or
alteration of centrally gener-
ated states. In addition, steroid hormones, such as the gluco-
corticoids secreted by the adrenal cortex, readily enter the
brain and act directly through specific receptors on multiple
neurons, by which they may also enhance arousal. Plasma
cortisol
has a very marked circadian rhythm, as measured in
humans, reaching a nadir during slow wave sleep in the night
and then increasing in the early morning hours before sunrise
and awakening, likely reflecting
a
hormonal preparatory
mechanism for the waking state.l16
Chemicals Implicated
in
Slow
Wave Sleep
Neurotransmitters
or
Neuromodulators
and Slow Wave Sleep
SEROTONIN
Serotonin (5-hydroxytryptamine [5-HT]) appeared in early
pharmacologic studies to play a role in sleepwake states
opposite to that
of
catecholamines because the tranquilization
produced by depletion
of
monoamines with reserpine was
not reversed by subsequent administration of the immediate
serotonin precursor (5-hydroxytryptophan),
as
it
was
by
the
immediate catecholamine precursor (r-dopa).j' Monoamine
oxidase inhibitors, which primarily block serotonin catabo-
lism, were shown to enhance and prolong slow wave sleep.
Conversely, inhibition of serotonin synthesis by blocking
tryptophan hydroxylase led to insomnia, which could be
reversed by administration of small amounts of the immediate
serotonin precursor.
Serotonergic neurons are located in nuclei on the midline
or "raphe" through the medulla, pons, and midbrain of the
brainstem,j9 suggesting they could comprise part of the brain-
stem slow wave sleep systernjj (Fig. 11-21, Serotonin raphe
neurons provide a diffuse innervation to the brain and spinal
cord, the rostrally located (dorsal and central superior) raphe
nuclei projecting mainly forward into the forebrain (including
the thalamus, hypothalamus, basal forebrain, and all cortical
areas), and the caudally located (magnus, pallidus, and obscu-
rus)
nuclei projecting mainly caudally into the spinal cord.
'I7
Total lesions of the raphe serotonin nuclei produced a total
insomnia in the cat5' (Fig. 11-2). Partial lesions involving the
medullary, pontine, or midbrain raphe nuclei were associated
with variable decreases in sleep, with the amount of sleep
being proportional to the percentage of serotonin remaining
in the brain. These results suggested that serotonin raphe
neurons constitute an integral component of a brainstem sleep-
generating system that lies in the midline midbrain, pontine,
and medullary raphe nuclei,
as
well as in the dorsolateral
medullary region of the solitary tract nucleus (see earlier).
Clinical cases of insomnia have been found to be associated
with lesions located in the region of the caudal midbrain and
pontine tegmentum and particularly involving the midline
raphe nuclei at these
level^.^^^^^^"^
In one case of extreme
Basic Mechanisms
of
Sleep-Wake States
145
insomnia (or "agrypnie" in a patient with
choriefibrillarie
de
Mowan),
administration of the immediate serotonin precursor
was found to restore natural slow wave ~1eep.l'~
Recovery from the insomnia produced by raphe lesions
has
since been found to occur in
animals,
particularly after lesions
produced by serotonin-selective neurotoxins.
lZo
Similarly, recov-
ery from the insomnia produced by pharmacologic depletion of
serotonin was demonstrated in prolonged chronic studies. It thus
appeared that serotonin was not necessary for slow wave sleep.
Further demonstrating the lack of a critical role of seroton-
ergic neurons in the maintenance of sleep, single-unit record-
ings subsequently revealed that presumed serotonergic raphe
neurons actually decreased their rate of firing with the onset
and for the duration of slow wave sleep and ceased firing in
paradoxical sleep.
lZ1
These single-unit data were supported by
results from biochemical studies of serotonin release, which
was found to be lower during slow wave sleep and also para-
doxical sleep than during wakefulness.'2z On the basis of
these results,
it
was
concluded that serotonergic neurons did
not play an essential role in sleep maintenance.
Yet, given the overwhelming evidence indicating that sero-
tonin could normally facilitate sleep onset, it appeared that
serotonergic neurons must exert an influence during waking
that could facilitate sleep onset. Experiments applying elecmcal
stimulation to raphe nuclei had in fact shown that although
sleep is not produced by such stimulation, behavioral inhibi-
tion and sensory modulation
or
analgesia are prod~ced.'~~J~~
Serotonin could thus act by attenuating other systems that
normally stimulate cortical activation and arousal. In this
regard, serotonin has been shown to have an inhibitory action
on cholinergic neurons in both the pontomesencephalic
tegmentum and basal f~rebrain.'~~.'~~ Microinjections of sero-
tonin into the basal forebrain lead to decreases in cortical
high-frequency (gamma) electroencephalographic activity,
suggesting that serotonin may attenuate cortical activation
and be associated with either a quiet waking state
or
initiation
of slow wave sleep.lZ7
It
has also been hypothesized that sero-
tonin neurons may be responsible for the synthesis and accu-
mulation of sleep factors during waking in neurons of the
anterior hypothalamus.
128
In summary, serotonin may prepare
the brain and organism for slow wave sleep during waking
by attenuating activating systems and possibly stimulating
accumulation of other sleep factors.
Serotonin acts on multiple receptors, which include second
messenger-linked receptors but also ionotropic receptors, and
which thus range from long acting to fast acting with inhibitory
as
well
as
excitatory effects on different postsynaptic cells. The
pharmacologic effects of selective serotonin receptor agonists
or
antagonists on electroencephalographic activity and sleep have
not been clearly interpretable,
as
is
perhaps not surprising given
the variety of receptors on diverse projection neurons
as
well
as
intemeuronal cell populations. It
is
significant, nonetheless,
that the ionotropic excitatory postsynaptic receptor (5-HT3)
is
found mainly on gamma-aminobutyric acid-ergic (GABAergic)
interneurons in the cortex and forebrainlZ9 and that the major
inhibitory postsynaptic receptor (5-HT1.J
is
found on many
projection neurons and notably on the cholinewc basal fore-
brain neurons that are hyperpolarized and inhibited by sero-
tonin through this receptor.lZ6 In summary, serotonin may thus
act through concerted activation of multiple
different
receptors
on different cell types to attenuate cortical activation and thus
facilitate the initiation of slow wave sleep.
ADENOSINE
This nucleoside has long been thought to play a role in slow
wave sleep because caffeine (methylxanthine), which acts
as
a
stimulant, blocks adenosine receptors.
130
It has been shown
that adenosine analogues can increase slow wave sleep
and cortical slow wave activity and that this increase can be
prevented by administration of ~affeine.'~'
Adenosine
is
found in high concentrations in particular
neurons from which it may be released
as
a neurotrans-
mitter,'32 but
is
also present in the extracellular space
as
a
degradation product of adenosine triphosphate (ATP), which
is
packaged and released by many synaptic vesicles, including
those containing acetylcholine. Adenosine
is
also transported
out of cells when production of adenosine monophosphate
is
increased during the formation of ATP from
two
molecules of
adenosine diphosphate,
as
occurs
as
a consequence of energy
demand.'33 Although extracellular concentrations of adeno-
sine in the brain are higher during waking than during slow
wave sleep, these concentrations appear to increase progres-
sively with prolonged waking and to decrease progressively
with subsequent sleep, such
as
to suggest a cumulative extra-
cellular increase in what could be a fatigue-like and sleep-
inducing factor in the
Adenosine acts
as
a neuromodulator through second
messenger-linked postsynaptic receptors to inhibit neuronal
discharge, and also through other receptors to block neuro-
transmitter release from nerve terminals. It thus suppresses
transmission at excitatory synapses in the brain and periph-
ery. It inhibits cholinergic neurons in the brainstem and basal
forebrain.
136
In the thalamus and cortex, adenosine hyperpo-
larizes projection neurons and can facilitate the burst
discharge that underlies the slow wave activity of slow wave
~1eep.l~' Adenosine could thus function in the brain,
as
it
has
been shown to do in the body,
as
a factor that accumulates
with continuous activity and acts to protect cells from damage
that could result from excess activity.'33 In the brain,
its
action
could be associated with the specialized burst discharge in
thalamocortical circuits that underlies slow wave sleep.
138
GAMMA-AMINOBUTYRIC ACID
GABA, an amino acid which
is
the major inhibitory neuro-
transmitter in the brain, has long been thought to have a role
in sleep. Many sedative and hypnotic agents,
as
well
as
anes-
thetics, act by enhancing the postsynaptic action of GABA
through binding to
GABA
receptors'39 (see Chapter
36).
In
clinical cases of so-called idiopathic recumng stupor, an
endogenous benzodiazepine-like factor (endozepine) was
identified in the CSF and found to be present in elevated
levels in association with stuporous episodes that could be
reversed with a benzodiazepine antagonist.'%
GABA-synthesizing neurons (containing the synthetic
enzyme glutamic acid decarboxylase) are distributed through
the brainstem and forebrain and comprise both interneurons
and projection neurons14' (Fig.
11-2).
In the brainstem retic-
ular formation, relatively small GABAergic neurons are inter-
mingled with larger glutamatergic projection neurons and
would
thus
appear to have the capacity through local projec-
tions to inhibit the glutamatergic neurons of the ascending
reticular activating system.24 The neurons of the thalamic
reticular nucleus that generate thalamocortical spindles
contain GABA and simultaneously inhibit while pacing
146
Sleep
Mechanisms
thalamocortical relay neurons by inhibitory postsynaptic
potentials.
142
This inhibition of the thalamus, the afferent
gateway to the cerebral cortex,
is
fundamental to slow wave
sleep and the
loss
of consciousness that accompanies it.
143
GABAergic neurons are distributed through the anterior hypo-
thalamus-preoptic area and basal forebrain and some give rise
to descending projections to the posterior hypothalamus,
where they can inhibit neurons of the activating ~ystem.'~~,'~~
A
particular cluster of GABAergic neurons that were found to
be active (as evidenced by c-Fos expression) during sleep pro-
ject on histaminergic neurons in the posterior hypothala-
mus.521146 GABA release in the posterior hypothalamus has
been found to be significantly higher during slow wave sleep
than during walung or paradoxical sleep.'47 There are also
GABAergic neurons in the subthalamus, hypothalamus, and
basal forebrain that give rise to long ascending projections to
the cortex'48-149 (Fig.
11-2).
Some of these GABAergic neu-
rons may correspond to long-projecting sleep-active cells
recorded in these
region^.*^,'^^
The release of GABA from the
cortex was highest in association with cortical slow waves of
natural sleep.99 GABAergic intemeurons and projection neu-
rons, however, are certainly active during waking in all regions
of the brain and can also be important in pacing fast activity
as well as slow activity in the cortex. It would thus be most
likely that particular GABAergic cells may be active during
sleep or that particular GABAergic receptors may be activated
during sleep. Moreover, larger amounts of GABA could be
released with the bursting mode of discharge by GABAergic
reticularis and other neurons to reach more receptors on more
neurons in the thalamus and other regions during slow wave
sleep.
GABA acts on
two
types of receptors, GABAA, which
is
linked directly to the (chloride) ion channel (and
is
modulated
by benzodiazepines and pentobarbital), and GABAB, which
acts through second messenger systems to modulate different
(potassium and calcium) ion channels. Although both recep-
tors are generally associated with inhibition, the action of the
GABAA
is
very rapid, whereas that of the GABAB
is
slow and
prolonged and includes attenuation of neurotransmitter
release
as
well as neuronal spiking. In the thalamocortical
system, GABAA and GABAB receptors participate in the hyper-
polarization associated with spindling and slow waves.151J52
GABAA agonists can enhance spindling and slow wave activity
along with sleep in humans.'53 The enhancement of slow
wave activity and sleep produced by gamma-hydroxybutyrate
in humans may well be mediated through GABAB recep-
tors.
154~155
In summary, GABAergic transmission
is
fundamen-
tally involved in the induction and maintenance of slow wave
sleep, first by inhibition of activating systems and second by
initiating, pacing, and sustaining the thalamocortical burst
discharge that underlies spindling and slow wave activity. This
involvement must entail, however, selective activity of particu-
lar GABAergic neurons
or
distinct patterns of discharge of
GABAergic neurons and resulting selective or prolonged
activation of particular GABAergic receptors located on those
neurons that serve to maintain waking and consciousness.
Cerebrospinal Fluid-Borne Factors,
Peptides, and
Slow
Wave Sleep
Sleep-inducing factors
have been shown to be present
in
the
CSF
or
brain in multiple animal experiments.10',102'28
CSF
or
brain extract removed from a sleep-deprived animal or from
an animal in the sleep-intense part of the cycle promotes sleep
when
it
is
injected into the ventricles of another animal, even
during the awake, active period of the day. Identification of
the sleep-promoting factors, however, has proven to be diffi-
cult and remains controversial.
Peptides,
which are synthesized, stored, and released
from neurons of the central nervous system, can act as
sleep-promoting factors in particular neuronal systems
or
throughout the brain by diffusion through the CSF. Attempted
isolation of factors from the CSF has not yet yielded any one
substance or peptide, although many candidates have been
proposed and tested as sleep factors, with ambiguous results.
Testing of known peptides by intraventricular administration
has revealed several (discussed in the following) that have an
effect on sleep.
Opiate
peptides have long been suspected
of influencing sleepwake states, in view of the sensory
anesthesia, behavioral stupor, and associated electroen-
cephalographic synchrony produced by the synthetic opiate
analogue morphine.'56 Administered by intraventricular route,
opiate peptides also produce anesthesia, akinesia, and elec-
troencephalographic hyper~ynchrony,'~~ but they
do
not
appear to induce or increase physiologic slow wave sleep.
158
This negative effect may simply be due to the fact that opiate
peptides normally act within specific neuronal circuits and
not by release and diffusion through the
CSF.
The endogenous
opiate peptides, including enkephalin, endorphin, and dynor-
phin, have all been shown to have a role in sensory modula-
tion and analgesia'59 that could be important in the onset and
maintenance of sleep. These peptides could thus be involved
in attenuation of systems that normally stimulate arousal and
waking.
Enkephalin
is
contained in neurons that are widely
distributed through the brain, including the cerebral cortex,
and in neurons within regions involved in slow wave sleep,
including the solitary tract nucleus, the preoptic area, and the
raphe, where it
is
colocalized with serotonin.
160
Enkephalin-
containing fibers innervate the locus coeruleus noradrenergic
neurons; opiates inhibit these neurons and produce a
decrease in walung and enhancement of natural slow wave
sleep when delivered locally. Derived from proopiomel-
anocortin,
beta-endorphin
is
contained in neurons located in
the arcuate region of the hypothalamus that give rise to wide-
spread projections that are particularly dense in the periven-
tricular regions of the hypothalamus and preoptic area.162
Other beta-endorphin cells are located in the nucleus of the
solitary tract.
Somatostatin,
administered intraventricularly, produces
analgesia, akmesia, and
a
depression of electroencephalo-
graphic activity.15' Although distributed in multiple systems
in the brain, somatostatin-containing neurons are located in
the solitary tract nucleus and raphe nuclei.
163
Furthermore,
somatostatin
is
colocalized with GABA in certain neuronal
systems, including, notably, neurons
of
the thalamic reticular
nucleus and a proportion of cortical inteme~rons.'~~ Like
GABA, somatostatin has been found to have primarily
inhibitory effects on central neurons.16' Like other peptides,
it
acts on second messenger-linked receptors that are inhibitory
to neuronal discharge and also to neurotransmitter release
from nerve terminals.
Cortistatin,
which
is
structurally similar
to somatostatin and found in the cerebral cortex, was also
found to suppress neuronal activity and to antagonize the
effects
of
acetylcholine on cortical neurons. In addition, this
Basic Mechanisms
of
Sleep-Wake States
147
peptide was found to induce cortical slow waves.165 Because
peptides are often colocalized with other smaller neurotrans-
mitters, and somatostatin and cortistatin appear to be com-
monly colocalized with GABA,'-
it
is possible that they may
be coreleased with the smaller inhibitory neurotransmitter.
Moreover, peptides may be released particularly in association
with the bursting discharge of neurons,167 which would occur
in the thalamocortical system during slow wave sleep, where
and when somatostatin
or
cortistatin could be coreleased with
GABA and thus further sustain conditions for slow wave
activity.
Galanin
is
another peptide that is colocalized
with
other neurotransmitters and notably GABA in the ventro-
lateral preoptic area in putative sleep-promoting neurons.146
Growth hormone-releasing factor,
which is produced by
neurons in the hypothalamus168 and stimulates the release of
growth hormone by the pituitary, also appears to have slow
wave sleepinducing properties by acting on neurons in the
anterior hypothalamus-preoptic area.lo5
Its
release would
accordingly facilitate slow wave sleep at the same time that
it
would stimulate the surge in growth hormone release from the
pituitary that occurs during slow wave sleep in the early part
of the night in humans.
It
should be noted that in these
specific systems in the hypothalamus, somatostatin acts to
suppress growth hormone release and can also thereby
decrease slow wave ~1eep.l~~
Other substances, including serotonin, that are not peptides
and have sleep-inducing effects are found in the CSF.
Prostaglandin DZ,
which
is
synthesized in brain (predomi-
nantly by glia) with a circadian fluctuation that is parallel to
the sleepwake cycle, has been shown to induce sleep in ani-
mals when it is administered in small amounts into the third
~entric1e.l~~ Cytohnes, most particularly
interleukins,
that are
now
known
to be synthesized in the brain (predominantly by
glia) also produce sleep and enhance slow wave activity when
injected into the ~entric1es.l~~
A
brain lipid
orfatty
acid amide
was isolated from CSF of sleepdeprived cats that induced
physiologic sleep when injected into the ventricles of
rats.
172~173
This substance, called
oleamide,
is similar to the
anandamides, which are endocannibinoid compounds, and
may act through cannibinoid receptors. Oleamide may also
act on GABAAreceptors.
It
thus appears that in addition to
neuropeptides that are released by specific neurons, other
substances, which may be synthesized by glia
as
well as
neurons and released by nonexocytotic mechanisms from
these cells, may participate in facilitating slow wave sleep.
Whether such substances accumulate in the CSF and thereby
diffuse through the entire brain to exert their effects, remains
to
be established.
Blood-Borne factors and Slow Wave Sleep
Presumably produced by platelets,
serotonin
in the blood
could act in specialized regions of the brain located outside
the blood-brain barrier to facilitate the onset of sleep. This
possibility
is
suggested by the finding that local application of
serotonin in the area postrema produced slow wave ~1eep.l~~
Insulin
has been shown to have marked slow wave
sleepinducing effects when
it
is
administered intravenously
in animals.175
It
is suggested that the accumulation of insulin
during the active, hyperphagic walung periods would lead to
the subsequent induction
of
sleep. Insulin receptors have
been found in the brain in circumventricular organs located
outside the blood-brain barrier and in nearby nuclei, notably
in the basal hypothalamus and solitary tract, paravagal
region.
176
Because the intraventricular administration of
insulin has also been shown to induce sleep,
it
is suggested
that its sleep-inducing action would be directly on the brain.
Chokcystokinin
is
a hormone that
is
released in the gut after
food ingestion and suppresses further food intake. This
so-called satiety hormone also promotes rest and may induce
slow wave sleep.177 Another
gut
hormone,
bombesin,
also
released after food ingestion, increases slow wave sleep when
it
is
administered peripherally.178 These peripheral hormones
that are in part responsible for postprandial satiety may thus
also contribute to postprandial induction of rest and sleep,
either by indirect action through vagal afferents to the solitary
tract nucleus
or
by direct action on circumventricular organs
located outside the blood-brain barrier.
Muramyl peptides
also originate in the gut from intestinal
bacteria and have been shown to have sleep-inducing proper-
ties.17' Like other bacteria and viruses, they also stimulate
synthesis and release of cytohnes, particularly
interleukins,
that promote slow wave ~1eep.l~' Thus, sleep may be facili-
tated through hormones and other peptides that are released
from the gut
or
from
the immune system in response to exoge-
nous substances.
Delta sleep-inducing peptide
was identified in the blood of
rabbits during slow wave sleep produced by low-frequency
thalamic stirnulati~n.'~~ It was shown to induce sleep when
injected into the blood
or
CSF of recipient rabbits. Although
conflicting reports regarding the sleep-inducing effects of delta
sleep-inducing peptide in various species have appeared, con-
firmation of an increase in slow wave sleep has been obtained
in mice after intraperitoneal administration of delta sleep-
inducing peptide, an increase comparable with that obtained
after intraperitoneal administration of sleep-promoting
substance isolated from brain tissue.
I8O
Whether a similar
peripheral and central peptide exists, where the peripheral
substances are produced, and how they reach relevant recep-
tors in the brain remain to be elucidated.
It
would thus appear that
as
in the regulation of waking,
blood-borne substances can have an influence on the central
sleep-generating systems, in part through the circumventricu-
lar organs by which they all have access to the brain. Included
in these factors would accordingly also be certain pituitary
hormones, such
as
growth hormone
and
prolactin,
which are
released maximally during slow wave sleep and may also influ-
ence sleep.L77
CONCLUSIONS
Neurophysiologic and Neuroanatomic
Results
The neuronal systems that govern the cyclic alternation
between waking and sleep are contained in the isodendritic
core of the brain that extends from the medulla through the
brainstem and hypothalamus up into the basal forebrain.
No
structure in this core
is
uniquely
or
monolithically involved in
the control of one state. Instead, different neurons in the same
structure
or
field of cells are important for sleep versus wak-
ing. Despite such an intermingling of sleep-active and wake-
active neurons, a differential concentration of such cells may
exist in different regions. Thus,
it
appears that neurons mainly
148
Sleep
Mechanisms
involved in maintaining activation are concentrated in the oral
pontine and midbrain central tegmentum and posterior
hypothalamus, whereas cells that exert an important sleep-
promoting influence are concentrated in the midline brain-
stem and dorsolateral medullary reticular formation and the
anterior hypothalamus-preoptic area, with possible intermin-
gling of the
two
in the basal forebrain. Just
as
cells with
different activity profiles and primary functional involvements
are codismbuted in such fields, cells with different projections,
including ascending versus descending, are intermingled in
the same fields and may thus respectively modulate forebrain
and spinal activities during the sleepwake cycle.
N
eu roc hem
ica
I
Resu
I
ts
Just
as
cells with different activities and projections are inter-
digitated in the reticular core,
so
cells containing different
neuroactive chemicals are intermingled through the same
regions. It
is
thus possible that the specificity
of
action derives
from the neurotransmitter released
as
well
as
from the activity
and projections of the neurons. Although such a behavioral
specificity may not apply to the small amino acid neurotrans-
mitters that are contained and act in multiple local-circuit
neurons, it may apply to the amine (more appropriately
called) neuromodulators, including catecholamines, acetyl-
choline, histamine, and serotonin, which are contained in
restricted neuronal aggregates located in the reticular core and
have widespread projections to the forebrain and spinal cord.
Such systems may simultaneously bias
or
modify the mode
of activity of entire populations of neurons in the central
nervous system. Moreover, molecules of larger peptides may
also function
as
neuromodulators
or
even neurohormones
that may be responsible for even longer-lasting alterations in
neuronal function that would underlie the sleepwake states
and cycle. However, to date, no single chemical neurotrans-
mitter, neuromodulator,
or
neurohormone has been identified
that is necessary or sufficient for the generation and mainte-
nance of sleep
or
waking. Instead, multiple factors and
systems are involved in the onset and maintenance of these
states.
Overview
of
Slee p-Wa ke Mechanisms
Wakefulness
is
initiated and reinforced by particular visceral,
somatic, and special sensory input, which
is
transmitted fairly
directly to special cortical areas but also, and more important
for wakefulness, through collaterals to the brainstem reticular
formation, extending from the medulla to the midbrain, in
which visceral, somatic, auditory, vestibular, and visual sensory
collaterals proliferate. This system overlaps extensively with
systems in the brainstem and caudal hypothalamus that regu-
late the sympathetic nervous system. Activation
is
transmitted
into the forebrain and cortex through the nonspecific thala-
mocortical projection system and through the subthalamus,
hypothalamus, and basal forebrain, where cortically project-
ing cells are also located. Olfactory sensory input may also
influence activation by collateral transmission through the
basal forebrain neurons. In
this
isodendritic core, particular
neurons that are distributed through the brainstem, hypothal-
amus,
and
basal forebrain are activated more
or
less during
waking, depending on sensory input from internal and exter-
nal milieus; however, they appear to remain tonically active at
some level during this state, irrespective of sensory input,
according to an autochthonous rhythm. This activating
system
is
essential for the maintenance of wakefulness and
cortical activation indicative of that state. In this system of
cells are located catecholaminergic and cholinergic neurons
that are tonically active during wakefulness and that, through
particularly long and widespread forebrain projections, may
modulate the activity of the subcomcal and cortical neurons
and circuits to facilitate tonic fast discharge in thalamocortical
systems. Histamine-containing neurons and orexin-containing
neurons located in the posterior hypothalamus also con-
tribute through long projections to this modulation. The pre-
dominant neurotransmitter of neurons of the reticular
activating system,
as
well
as
thalamic and cortical projection
neurons,
is
glutamate, the excitatory amino acid that
is
essential for activity in these systems. Certain neuropeptides
contained in neurons with relatively long and widespread
projections and also colocalized with smaller neurotrans-
mitters, such
as
substance
F
vasoactive intestinal peptide,
neurotensin, comcotropin-releasing hormone, and thyrotropin-
releasing hormone, may enhance and prolong such actions to
promote activation. Certain factors camed in the blood,
including epinephrine, histamine, and certain peptides, can
serve to reinforce the central state of arousal.
kded by a decrease in certain types of sensory input
and facilitated
by
an increase in other types of somatic and
visceral sensory input, such
as
warmth and satiation, sleep-
inducing neurons become active and promote cortical slow
wave activity by dampening the cyclic activity of reticular acti-
vating neurons and directly modulating activity in the fore-
brain. Sleep-inducing neurons are concentrated in the lower
brainstem reticular formation and solitary tract nucleus and in
the rostra1 hypothalamus, preoptic area, and basal forebrain,
extensively overlapping with autonomic, particularly parqm-
pathetic, regulatory systems. Cortical slow wave activity
evolves from a change in the pattern of discharge of cortical
and thalamic neurons from tonic and fast to bursting at a slow
rate with intervening pauses. Serotonin-containing neurons of
the raphe may be important in dampening certain sensory
input and attenuating cortical activation in the initiation of
slow wave sleep. Adenosine may be a factor that accumulates
during waking and could promote slow-bursting discharge in
thalamocortical systems. Critical for spindling and slow waves
is
the activity of WAergic neurons located in the thalamic
reticular nucleus. GABAergic neurons in many other regions,
including the reticular formation, hypothalamus, and basal
forebrain, also may be important for inhibiting neurons
involved in cortical activation. GABAergic neurons located in
the hypothalamus and basal forebrain that project to the
cortex may be important for initiating and maintaining slow
wave activity. Multiple neuropeptide-containing neurons are
located in the brainstem and hypothalamic-basal forebrain
regions and may, through release of peptide onto other
neurons
or
into the CSF, alter activity and transmission
through the forebrain. The peptides somatostatin and
com-
statin are colocalized with GABA in neurons in the thalamus
and cortex. The sleep-promoting substances of the
CSF
remain to be identified; however, several
known
substances,
including the opiates, cortistatin, and oleamide, have been
shown to have certain sleep-inducing properties when intro-
duced into the
CSE
Peripheral factors, such
as
serotonin,
insulin, gut hormones, cytokines, and sleep peptides, may
also influence the sleepwake cycle and facilitate sleep.
Basic Mechanisms
of
Sleep-Wake States
149
In summary, many of the chemical and neuronal substrates
of
the sleepwake states have been identified
and
character-
ized
according to their activity
and
transmission.
Many
other
chemical neuroactive substances await discovery and,
as
components of multifarious systems,
hold
promise to play
important roles in the generation
of
waking
and sleep.
<
:li
11
icul
Ptw
1.1
Sleep and wakefulness are controlled by diverse neuronal
systems containing diverse chemicals in the brain. Thus,
lesions can result in either somnolence or insomnia
depending on their location.
Loss
of wakefulness, marked
by loss of cortical activation or behavioral arousal, can
occur with lesions in the oral pontine and midbrain
tegmentum, involving the glutamatergic neurons
of
the
reticular formation, noradrenergic locus coeruleus neurons,
cholinergic pontomesencephalic tegmental neurons, or
dopaminergic ventral tegmental neurons; lesions in the
posterior hypothalamus, involving histominergic or orexin-
ergic neurons; or lesions in the basal forebrain, involving
cholinergic basalis neurons.
Loss
of natural sleep can occur
with lesions located in the lower brainstem orpreoptic area
in the forebrain, involving particularly CABAergic neurons.
Acknowledgments
The author thanks members
of
the laboratory, including
Lynda Mainville for technical assistance and Elida
Arriza
for
help with illustrations. The author’s research
has
been funded
by the Canadian Institutes of Health Research (CIHIQ and
US.
National Institutes
of
Health (NIH).
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