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arousal system that originates from brainstem neuronal
groups principally containing serotonin (dorsal raphé
nuclei), noradrenaline (locus coeruleus), histamine (tuber-
omammillary nucleus), and dopamine (ventral periaque-
ductal grey). Orexin neurons from the perifornical region
of the hypothalamus and cholinergic neurons from the
basal forebrain also contribute to this ascending arousal
system. 10 Overall, multiple neuronal systems contribute to
cortical arousal and wakefulness. These neuronal systems
are also positioned to influence respiratory neurons and
motoneurons via their anatomical projections to the pons,
medulla, and spinal cord (see Fig. 21-2 ).
mation is used to mimic this process experimentally in
animal studies, that is, the “carbachol model of REM
sleep.” 17 , 18 A significant component of the motor sup-
pression of REM sleep is mediated by descending path-
ways involving activation of medullary reticular formation
relay neurons 19 that are inhibitory to spinal motoneurons
via release of glycine. 20
Despite the strong experimental support for the inter-
action of pontine monoaminergic and cholinergic neurons
as being primarily responsible for the initiation and main-
tenance of REM sleep, recent evidence has implicated a
glutamatergic-GABAergic mechanism. 21 , 22 One of the key
differences between the aminergic-cholinergic and the
glutamatergic-GABAergic hypotheses of REM sleep gen-
eration is that the motor atonia is produced by different
pathways, that is, the latter framework does not require
a relay in the medullary reticular formation. 22 Rather, in
the glutamatergic-GABAergic mechanism of REM sleep
induction, the REM sleep-active pontine neurons are
thought to lead to suppression of spinal motoneuron
activity via long glutamatergic projections to the ventral
horn of the spinal cord, which then activate local gly-
cinergic interneurons to inhibit motor activity. 22 Such a
mechanism is likely involved in the strong inhibition of
spinal intercostal motoneurons in REM sleep, but whether
collaterals from these specific long descending glutama-
tergic projections also synapse onto glycinergic inhibitory
interneurons in the hypoglossal motor pool is not
established. 16
In summary, a number of neural systems show changes
in activity across sleep-wake states and project to respira-
tory neurons and motoneurons. Given that motoneurons
are the final common output pathway for the influence of
the central nervous system on motor activity, this chapter
will initially focus on the control of respiratory motoneu-
rons across sleep-wake states before addressing the control
of the central respiratory neurons that ultimately drive
breathing via those motoneurons.
NREM Sleep
Sleep is actively generated by neurons in the ventrolateral
preoptic area, anterior hypothalamus, and basal forebrain
(see Fig. 21-2 ). 10 These neurons become active in NREM
sleep, an effect influenced by the thermal stimulus that
accompanies the circadian-mediated decline in body tem-
perature at normal bedtime. 11 This circadian-mediated
decline in body temperature is mediated by a change in the
set-point of hypothalamic temperature-regulating neurons,
which initially leads to a relative “warm stimulus” as body
temperature is at first higher than the new set-point, that
is, before heat loss occurs. This warm stimulus activates
NREM sleep-active hypothalamic neurons and so pro-
motes sleep onset. This effect of internal body temperature
on sleep is distinct from the influences of ambient envi-
ronmental temperature on sleep regulation. Activation of
ventrolateral preoptic neurons leads to a direct suppression
of cortical arousal, this via ascending inhibitory cortical
projections. Ventrolateral preoptic neurons also promote
sleep by descending inhibition of the aforementioned
brainstem arousal neurons via release of gamma-aminobu-
tyric acid (GABA) and galanin. 11 , 12 This effect of GABA
explains the sedative-hypnotic effects of barbiturates, ben-
zodiazepines, and imidazopyridine compounds that
enhance GABA-mediated neuronal inhibition via interac-
tions with binding sites on the GABA A receptor. 13 GABA A
receptors are also strongly implicated in respiratory control
and are present throughout the respiratory network, 14
excessive stimulation of which can promote respiratory
depression. 15
In summary, sleep onset is triggered by increased GABA-
ergic neuronal activity, and this is accompanied by a massed
and coordinated withdrawal of activity of brainstem arousal
neurons comprising serotonergic, noradrenergic, hista-
minergic and cholinergic neurons. Given the widespread
projections of these sleep state-dependent neuronal
groups, these changes in neuronal activity in sleep are also
positioned to influence respiratory neurons and motoneu-
rons (see Fig. 21-2 ). 16
A characteristic and defining feature of mammalian motor
activity is that postural muscle tone is highest in wakeful-
ness, decreased in NREM sleep, and minimal in REM
sleep, with the hypotonia of REM sleep punctuated by
occasional muscle twitches that are associated with vigor-
ous eye movements and phasic REM sleep events. 20
Whether respiratory muscle activity is affected in the same
way as postural muscle activity across sleep-wake states is
somewhat complicated by the interaction of the primary
influence of sleep state (e.g., producing suppression of
muscle tone) and any subsequent respiratory response
(e.g., to compensate for any hypoventilation). On balance,
however, the overall stereotyped pattern of suppression of
postural muscle activity across sleep-wake states also typi-
cally occurs in respiratory muscles, with the degree of sleep
state-dependent modulation being most readily apparent
in those muscles that combine respiratory and nonrespira-
tory (e.g., postural and behavioral) functions such as the
intercostal and pharyngeal muscles. 23 In these respiratory
muscles, decreases in activity typically occur immediately
REM Sleep
Decreased serotonergic and noradrenergic activity pre-
ceding and during REM sleep withdraws inhibition of
the laterodorsal and pedunculopontine tegmental
nuclei. 10 , 12 This effect leads to increased acetylcholine
release into the pontine reticular formation to trigger
REM sleep. 17 , 18 Exogenous application of cholinergic
agonists or acetylcholinesterase inhibitors (to increase
endogenous acetylcholine) into the pontine reticular for-
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