Figure 1–3. The ventrolateral preoptic nucleus (VLPO), shown in purple, inhibits the components of the ascending arousal
system during sleep. VLPO neurons contain both gamma-aminobutyric acid (GABA) and an inhibitory peptide, galanin, and
send axons to most of the cell groups that compose the ascending arousal system. This unique relationship allows the VLPO
neurons effectively to turn off the arousal systems during sleep. Loss of VLPO neurons results in profound insomnia. 5-
HT, serotonin; ACh, acetylcholine; DA, dopamine; Gal, ; His, histamine; LC, locus coeruleus; LDT, laterodorsal tegmental
nuclei; NA, noradrenaline; ORX, orexin; PeF, ; PPT, pedunculopontine; TMN, tuberomammillary nucleus; vPAG, ventral
periaqueductal gray matter. (From Saper, CB, Scammell, TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms.
Nature 437:1257–1263, 2005. By permission of Nature Publishing Group.)
Figure 1–4. A diagram of the flip-flop relationship between the ventrolateral preoptic nucleus (VLPO), which promotes
sleep, and several monoaminergic cell groups that contribute to the arousal system, including the locus coeruleus (LC), the
tuberomammillary nucleus (TMN), and raphe nuclei. During wakefulness (a), the orexin neurons (ORX) are active, stimu-
lating the monoamine nuclei, which both cause arousal and inhibit the VLPO to prevent sleep. During sleep (b), the
VLPO and extended VLPO (eVLPO) inhibit the monoamine groups and the orexin neurons, thus preventing arousal. This
mutually inhibitory relationship ensures that transitions between wake and sleep are rapid and complete. (From Saper, CB,
Scammell, TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 437:1257–1263, 2005. By permission
of Nature Publishing Group.)
23
individual is profoundly unresponsive to exter-
nal stimuli.
A second flip-flop switch in the pons for
switching from NREM to REM sleep (and back
again) has recently been identified in the rostral
pons. Many GABAergic neurons in the extended
part of the ventrolateral preoptic nucleus are
specifically active during REM sleep, suggest-
ing that they inhibit a population of REM-off
neurons.
88
In addition, the orexin neurons in
the lateral hypothalamus are excitatory, but their
firing inhibits REM sleep, suggesting that they
may activate REM-off neurons, as patients or
animals with narcolepsy who lack orexin neu-
rons transition into REM sleep exceptionally
quickly.
70,89
By searching for the intersection of
these two pathways, a population of neurons
was defined in the rostral pons, including the
ventrolateral periaqueductal gray matter and the
lateral pontine tegmentum at the level where
they are adjacent to the dorsal raphe nucleus.
These sites contain many GABAergic neurons,
and lesions of this region increase REM sleep,
confirming a REM-off influence.
53
GABAergic
neurons in the REM-off area innervate an ad-
jacent region including the sublaterodorsal nu-
cleus and pre-coeruleus region that contain
REM-active neurons. This REM-on region con-
tains two types of neurons. GABAergic neurons,
mainly in the sublaterodorsal nucleus, project
back to the REM-off area. This produces a flip-
flop switch relationship accounting for the ten-
dency for transitions into and out of REM sleep
to be relatively abrupt. A second population of
neurons is glutamatergic. Glutamatergic REM-
on neurons in the sublaterodorsal nucleus pro-
ject to the brainstem and spinal cord, where
they are thought to be responsible for the motor
manifestations of REM sleep, including atonia
and perhaps the rapid eye movements that are
the hallmarks of the state. Glutamatergic REM-
on neurons in the coeruleus region target the
basal forebrain where they appear to be critical
for maintaining EEG phenomena associated
with REM sleep.
Cholinergic and monoaminergic influences
may have a modulatory effect on REM sleep by
playing upon this flip-flop switch mechanism.
Although lesions of these systems do not have
a major effect on REM sleep, overactivity may
have quite dramatic effects. For example, injec-
tions of cholinomimetic agents into the region
containing the REM switch can trigger pro-
longed bouts of a REM-like state in animals.
90
Whether this is due to activating REM-on neu-
rons or inhibiting REM-off neurons (or both)
is not known. On the other hand, patients who
take antidepressants that are either serotonin
or norepinephrine reuptake inhibitors (or both)
have very little REM sleep. This effect may be
due to the excess monoamines activating the
REM-off neurons or inhibiting the REM-on
Figure 1–5. The control elements for rapid eye movement (REM) sleep also form a flip-flop switch. Gamma-aminobutyric
acid (GABA)-ergic REM-off neurons in the ventrolateral periaqueductal gray matter (vlPAG) and the lateral pontine teg-
mentum (LPT) inhibit the REM-on neurons in the sublaterodorsal (SLD) and the precoeruleus (PC) areas, whereas GABA-
ergic SLD neurons inhibit the vlPAG and the LPT. This mutual inhibition forms a second flip-flop switch that regulates
transitions into and out of REM sleep, which also are generally rapid and complete. Other modulatory systems, such as the
extended ventrolateral preoptic nucleus (Ex VLPO) and the melanin-concentrating hormone (MCH) and orexin neurons in
the hypothalamus, regulate REM sleep by their inputs to this switch. Similarly, the monoaminergic dorsal raphe nucleus
(DRN) and locus coeruleus (LC) inhibit REM sleep by activating the REM-off neurons, and cholinergic neurons in the
pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT) activate REM sleep by inhibiting neurons in the REM-
off region. Neurons in the SLD cause motor atonia during REM sleep by excitatory inputs to inhibitory interneurons in the
ventromedial medulla (VMM) and the spinal cord (SC), which inhibit alpha motor neurons. Neurons in the PC contact the
medial septum (MS) and basal forebrain (BF), which drive the electroencephalogram (EEG) phenomena associated with
REM sleep. (Modified from Lu, Sherman, Devor, et al.,
53
by permission.)
24
Plum and Posner’s Diagnosis of Stupor and Coma