Download Control of Wake and Sleep States

Control of Wake and Sleep States
George Bokinsky, MD
Brown, Ritchie E. et al “Control of Sleep and
Wakefulness” Physiol. Rev. 2012;92:1087-1187.
Electrographic Signs of Wakefulness
• Low voltage fast activity (LVFA) are
summed synaptic currents from apical
dendrites of pyramidal neurons
• Beta (15-30Hz) and Gamma (30-120
Hz) rhythms
• Alpha rhythms (8-14 Hz)
• Theta rhythms (4-8 Hz)
Brain Stem Reticular and Basal Forebrain
Activating Systems
• Dual systems ultimately projecting to
the neocortex via intermediate
connections
• Dorsal pathway of the ARAS
• Ventral pathway of the ARAS
• Default cortical network.
Dorsal and Ventral Pathways of Ascending Reticular Activating System
Dorsal Ascending Reticular Activating System
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Initial Components: Glutamatergic neurons in midbrain, pons, and
medullary reticular formations. Cholinergic neurons in pedunculopontine and latero-dorsal tegmental nuclei (PPT/LDT).
Intermediate Connections: Non-specific thalamic nuclei leading to fast
cortical rhythms. Sensory relay neurons in thalamus. Brain stem
cholinergic neurons also innervate dopaminergic and GABA-ergic
neurons of midbrain ventral tegmental.
Final destinations: neocortex as a whole as LVFA EEG, sensory
cortex as local short responses, nucleus accumbens and pre-frontal
cortex.
P.S.: Changes in reticular and thalamic function preceed changes in
cortical EEG in humans during anaesthesia and sleep. Thalamic
lesions may not affect cortical activation.
Ventral Ascending Reticular Activating System
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Initial Components: Glutamatergic neurons of parabrachial nucleus
(PB), Noradrenergic neurons from Locus Coeruleus (LC),
Serotonergic neurons from dorsal and medial raphe (DR), and
Dopaminergic periaqueductal gray (PAG) neurons.
Intermediate Connections: Glutamatergic, Histaminergic, and
Orexinergic neurons of posterior/lateral hypothamamus → Caudal
basal forebrain (BF) cholinergic, GABA-ergic, and glutamatergic
neurons, and, finally,
Neocortex with a branch to the rostral BF theta rhythm generator.
P.S. Large lesions of parabrachial (PB) nucleus which supplies brain
stem glutamatergic input to BF lead to coma.
Direct input to neocortex and nonspecific thalamic nuclei also arise
from brain stem noradrenergic and serotoninergic neurons along with
hypothalamic histaminergic and orexinergic neurons.
Default Network
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Anatomically interconnected regions of the anterior and posterior
midline, lateral parietal cortex, prefrontal cortex, and temporal lobe.
Active when meditating and not responding to external environment.
External stimulation leads to decreases in activity in these areas.
Why does two branches of the ARAS exist? Dorsal branch may be
more attuned to sensory input of non-visual nature while the ventral
branch passes close to the hub for visual and light input.
Orexin/Hypocretin
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Originates in lateral hypothalamus with strongest projection to LC.
Orexin consolidates wakefulness, suppresses REM sleep, and
enhances wakefulness during periods of starvation.
Feeding increases glucose, leptin and neuro-peptide Y inhibiting
orexin while fasting leads to activation of Orexin neurons.
Orexin levels peak in latter third of the day and remain increased
during four hours of extended wakefulness.
Orexin neurons decrease firing during quiet wake state, and cease
firing during sleep except during micro-arousals.
Orexin agonists increase wake while Orexin receptor antagonists
increase both NREM and REM sleep.
Orexin may stimulate histamine system. Low CSF histamine in
narcolepsy.
Orexin Circuits
Orexin
Norepinephrine
Histamine
Serotinin
Acetylcholine
Dopamine
Acetylcholine
Projections to spinal
motoneurons
Nature Reviews Neuroscience 2007;8:171181
Glutamate
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90% of glutamatergic projections are found in thalamic relay neurons
innervating cortex (layers III and IV). Other glutamatergic neurons are
in BF, claustrum, VTA, laterodorsal tegmentum, and hypothalamus
also project to cortex.
Glutamate transporters are expressed in cortically projecting orexin
and serotonin neurons.
Glutamate is major neurotransmitter released from rostral midbrain
and brainstem reticular formation neurons projecting to the thalamus.
At onset of conscious states (wake and REM sleep) thalamic relay
neurons are excited by acetylcholine, norepinephrine, and histamine
leading to a switch from synchronized bursts of NREM to tonic firing
able to transmit sensory information to cortex.
Roles for Wake Promoting Neurotransmitters
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Facilitation of LVFA: Acetylcholine, Glutamate
Inhibition of sleep-active neurons: Norepinephrine, Serotonin,
Acetylcholine
Maintenance of motor tone while awake: Norepinephrine
Consolidation of wake periods: Orexin
Maintenance of wake in novel environments: Histamine
Enhanced arousal to rewarding stimuli: Dopamine, Acetylcholine
Enhanced arousal to adversive stimuli: Norepinephrine, Serotonin,
Histamine
Consolidation of memories through synaptic plasticity: Acetylcholine,
Nor- epinephrine, Serotonin, Histamine, Dopamine, Orexins
Wake Promoting Modulatory System
LH (strongest projection to LC)
DRN*
BF
*Wake-on
NREM ↓
REM-off
TMN*
LC*
Non-REM Sleep
• Electrographic signs of NREM sleep
• Generation and maintenance of NREM
sleep
• NREM sleep homeostasis
• Functional aspects of NREM sleep
• Synthesis
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Generated in thalamic GABA-ergic
reticular and perigeniculate nuclei.
NREM EEG
Spindles
(7-15of cerebral
Hz) cortex being
Spindles are present
even in absence
recorded in thalamus and disappear with large thalamic reticular
lesions.
Spindles occur when aminergic input is slowly withdrawn during early
NREM sleep leading to bursts of action potentials in reticular neurons.
This leads to excitatory potential in cortical neurons signaled as
spindles.
Spindles are inhibited during wakefulness and REM sleep by tonic
firing of thalamic reticular neurons This switches to burst firing in
NREM. Tonic firing is induced by NE and Serotonin released from
ascending projections of LC and DRN.
Brainstem cholinergic and BF cholinergic and GABA-ergic input
inhibits spindles. REM-on cholinergic neurons inhibit spindles.
NREM EEG
Delta
(1-4
Hz)
and
Slow
(<1
Hz)
Oscillations
• Cortical and thalamic delta and slow oscillations result from
increased withdrawal of excitatory cholinergic and aminergic inputs
leading to hyperpolarization of the membrane potential of
pyramidal/thalamic relay neurons.
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Burst firing at delta frequency is an intrinsic membrane property of
thalamo- cortical cells and potentiates intrinsic rhythms in these cell
groups.
Neocortical slow oscillation (0.5-1 Hz) cycles represent a moving
wave beginning in prefrontal-orbital cortex and spreading posteriorally
through all NREM stages and bind together spindles and delta waves.
Slow oscillations is generated within cortex and strongly influences
thalamus through CT projections. They consist of prolonged
depolarizations associated with extracellular gamma activity (up)
separated by prolonged hyperpolarizations (down states) when most
cortical neurons are silent.
Up State is caused by excitatory glutamatergic synaptic input.
Generation and Maintenance of NREM Sleep
Ventrolateral Pre-optic Nucleus (VLPO)
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Historical observation: Patients with influenza during 1918 pandemic
exhibited insomnia and at autopsy had damages to pre-optic (PO)
nucleus. Lesions of PO/BF in cats cause long-lasting insomnia.
PO/BF contains a large number of neurons that utilize GABA and
have a sleep-on and wake-off firing pattern. Many of these neurons
are also temperature sensitive.
Ventrolateral pre-optic nucleus (VLPO): Sleep active neurons contain
GABA and galanin and project heavily to nuclei of ARAS especially
the histaminergic TMN. Lesions of the VLPO decrease delta power
and increase sleep disruption. Neurons are all inhibited by NE and
ACH and most inhibited by serotonin. Neurons are excited indirectly
by adenosine.
VLPO neurons receive direct input from retina and indirect input from
suprachiasmatic nucleus (SCN) via dorsomedial hypothalamus. Light.
Generation and Maintenance of NREM Sleep
Median Pre-optic Nucleus (MnPO)
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Located just dorsal to the Third Ventricle and contains a large
population of GABA-ergic sleep-active neurons which project to and
inhibit wake promoting neurons of ARAS in peri-fornical lateral
hypothalamus, DRN, and LC.
MnPO neurons are active during sleep deprivation but mainly active
during sleep. MnPO neurons increase activity in response to
homeostatic sleep pressure.
VLPO neurons may function to consolidate sleep and maintain sleep
depth.
Wake to NREM Sleep Transitions
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Anterior hypothalamic sleep promoting area first proposed by Von
Economo
Core neurons of VLPO project heavily to wake-promoting
histaminergic neurons of tuberomammillary nucleus (TMN) of
posterior hypothalamus and to wake-promoting serotonin DRN
neurons and norepinephrine LC neurons in brain stem.
GABA and galanin inhibit TMN, DR, and LC neurons. Serotonin and
nor- epinephrine inhibit most VLPO neurons. Mutually inhibitory
interactions between VLPO and TMN/DRN/LC act as sleep/wake
switch via feedback loop.
Orexins stabilize wake state through strong stimulation of wakepromoting neurons.
Sleep-promoting VLPO neurons have fast transitions around statechanges. Firing rate of BF wake-active neurons change more slowly.
Physiol Rev. Vol 92. July 2012, p. 1113.
Brown, R.E. “Control of Sleep and Wakefulness” Physiol Rev. 2012;92:1113.
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Adenosine
Rise in adenosine level in certain brain areas correlate with time
awake. The caudal BF containing cortically projecting wake-active
neurons is prime example. Adenosine is a by-product of metabolism
of all cells.
Glutamatergic stimulation of BF neurons leads to increase in
extracellular adenosine. Adenosine may also originate from
astrocytes in cortex.
Adenosine dampens neuronal activity and promotes sleep via presynaptic inhibitory effects on excitatory glutamatergic neurons, wakeactive cholinergic neurons, and orexin neurons as well as on
inhibititory GABA-ergic inputs to the sleep-active VLPO neurons.
Prolonged sleep deprivation upregulates A₁ receptor messenger RNA
and protein in BF and cortex. BF is critical site for adenosine effects
through A₁ and A₂ receptors.
Caffeine promotes wakefulness by blocking Adenosine A₂A receptors
in shell region of nucleus accumbens.
Nitric Oxide (NO)
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Nitric oxide promotes NREM sleep.
Formation: Neuronal NO synthase (nNOS) is highly expressed in BS
cholinergic neurons, Endothelial NO synthase (eNOS) in blood
vessels, and Inducible NO synthase (iNOS) increases with sleep
deprivation.
nNOS is highest in awake brain and causes rise in brain NO levels.
Sleep active cortical interneurons also contain nNOS. Majority of
cortical GABA-ergic interneurons that express nNOS also express
Fos during recovery sleep following sleep deprivation. Fos expression
parallels SWS.
NO rises in early stages of sleep deprivation.
NO produced by iNOS affects BF and causes sleep through release
of adenosine, inhibition of neuronal activity, inhibition of adenosine
kinase, and stimulation of co-release of ATP which is degraded to
adenosine.
Prostaglandin D₂ (PGD₂)
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PGD₂ meets all criteria for sleep promotion. Infusion of PGD₂ into
Third Ventricle or pre-optic area (PO) of brain increases sleep in
dose-dependent manner. Levels of PGD₂ in CSF increase with
increased wake time.
Effects of PGD₂ is mediated through the prostaglandin receptor 1
(DP₁R). Blocking receptor decreases sleep time.
PGD₂ sleep effects occur at the level of leptomeninges and
subarachnoid space. Expression of lipocalin-type prostaglandin
synthase (L-PGDS) and DP₁R is mainly observed in rostroventral
SAS near BF. L-PGDS and PD₁R expression is co-localized with
cells producing adenosine.
Synthesis of PGD₂ is upregulated in CSF of African sleeping sickness
and is also increased in CSF of patients with OSA.
Cytokines
Interleukin-1 (IL-1) and Tumor Necrosis Factor
Alpha
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IL-1 and TNF-∝: Administration of either leads to NREM sleep.
IL-1 causes fatigue and sleepiness in humans.
Endogenous brain and plasma levels of IL-1 and TNF alpha increase
with increased sleep propensity. Plasma levels of IL-1 peak at sleep
onset in humans. Messenger RNA (mRNA) levels increase with sleep
deprivation.
Sleep effects are mediated through IL-1 type receptor and TNF-55kDa receptor. TNF-alpha inhibits expression of clock genes.
Extracellular ATP release associated with neurotransmitter release
during waking prompts astrocytic production of IL-1 and TNF-alpha.
Adminstration of IL-1 into DRN or LC induces sleep probably via 5HT-₂ receptor.
TNF-alpha regulates sleep intensity and synaptic homeostasis.
Slow Wave Sleep
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In deep sleep, the activity of brain regions comprising the default
network become de-coupled especially in frontal cortex. Local cortical
differences in delta power during NREM sleep reflect the extent to
which the cortical area was active during prior wake period as well as
the wake period’s duration. This may reflect increased synaptic
potentiation during waking.
The increased energy consumption during waking is reflected in
increased release of homeostatic sleep factors such as adenosine
and the early NREM surge in ATP production. Synaptic plasticity is a
major component of brain energy use.
Cerebral metabolic rate (CMR) decreases 44% during sleep with 25%
decrease in CMR of oxygen.
NREM Sleep Summary
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Sleep induction is mediated by homeostatic factors adenosine and
nitric oxide in BF and neocortex and by increased activity of median
pro-optic nucleus GABA neurons that inhibit the wake-promoting
neurons of ARAS.
Circadian influences are mediated by direct retinal and indirect SCN
projections to GABA-ergic sleep-promoting neurons in VLPO and
other regions of pre-optic area and BF.
Once sleep is induced, the silence of cortically-projecting wake-active
neurons is maintained by increased firing of VLPO neurons and other
preoptic/BF GABA neurons along with post-synaptic inhibition of
ARAS neurons through activation of GABA and galanin.
As ARAS excitatory influences are withdrawn, thalamic and cortical
neurons become progressively hyperpolarized entering the range of
membrane potentials conducive to rhythmic bursting giving the EEG
signs of NREMS.
REM Sleep
• Electrographic signs of REM sleep
• Muscle atonia and twitches
• PGO waves and rapid eye movements
• REM sleep control mechanisms
• Relation of REM to dreams
Pontine Generation of REM Sleep Phenomena
Brown, R.E. “Control of Sleep and Wakefulness” Physiol Rev. 2012;92:1129.
simultaneous with rapid eye movements.
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PGO waves are prominent in visual circuits of thalamocortical circuits
suggesting a role in dream imagery.
Ponto-geniculo-occipital Waves (PGO)
LDT/PPT
(acetylcholine)→LGN→Occipital
Generalized
activation
of limbic, parahippocampal,Cortex
and other thalamic
pathways also noted phase-linked to REMs is seen on fMRI.
PGO waves originate in LDT/PPT cholinergic neurons projecting to
LGN.
Subcoeruleus and parabrachial area (SubC/PB) fire synchronously
with PGO waves by triggering bursts in cholinergic thalamic projecting
neurons.
Theta Oscillations
PFR (Glutamatergic)→Basal forebrain
(MS/vDB)→Hippocampus
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Low-frequency theta (4-7 Hz) has been recorded in human
hippocampus during sleep as short (1 sec) bursts not correlated with
rapid eye movements. It was not seen in basal temporal lobe or
frontal cortex in REM.
The generation of theta rhythm begins in brain stem in region just
dorsal to LC called the pre-coeruleus (PC).
PC provides major glutamatergic input to the MS/vDB ( medial septum
and vertical limb of diagonal band) and contains cells that are active
during REM sleep.
Cortical Activation
Thalamus (HDB, SI, MCPO)→Cerebral Cortex
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Activation-synthesis hypothesis of dream generation: During REM
sleep, the brain is activated internally through the brain stem.
Visual sensory system and vestibular system is activated through
PGO activity. Motor activity during dreans is inhibited by atonia of
REM sleep.
Brain areas associated with emotional behavior and memory
formation are activated during REM sleep including hippocampus and
amygdala providing emotional content to the dream.
PET and fMRI scans during REM sleep dreams show increased blood
flow and oxygen consumption in pontine tegmentum, thalamus,
amygdala, basal ganglia, anterior cingulate, and occipital cortex.
Amygdala activation adds negative content such as fear and anxiety.
Deactivation of frontal cortex may explain lack of insight, distortion of
time, and inability to recall dreams on waking.
Rapid Eye Movements
PRF/MRF Saccade Generators→Colliculus
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Tonic and Phasic Components to REM Eye Movements: Downward
and convergent movement of both eyes due to relaxation of lateral
rectus muscles and tonic contraction of medial rectus muscles in tonic
phase. Phasic eye movements occurs in isolation or in bursts in
phase with PGO waves.
Paramedian reticular formation closely rostral and caudal to abducens
motor nucleus is responsible for rapid eye movements.
Pattern is due to inputs from both inhibitory and excitatory burst
neurons.
Muscle Atonia
Subcoeruleus (SubC)→Bulbar ventral gigantocellular nucleus (GIV)→Spinal
Cord
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Inhibition on Motoneurons During REM Sleep: Somatic and spinal
moto- neurons are hyperpolarized by inhibitory postsynaptic potentials
(IPSP’s) and become resistant to excitatory inputs. Inhibitory
neurotransmitters glycine and GABA are involved in this process.
Disfacilitation of Excitatory Inputs During REM Sleep: Motoneurons
receive excitatory input from brain stem norepinephrine and serotonin
during waking depolarizing them and increasing excitatory sensitivity.
LC nor- epinephrine shuts off during REM sleep and DRN neurons
decrease firing during cataplexy.
Muscle twitches are caused by phasic glutamatergic input.
Descending Circuits Producing Muscle
Atonia
Pathway A
During REM sleep descending
subcoeruleus glutamatergic projections excite glycinergic
neurons
of bulbar reticular formation.
medullary ventral gigantocellular
nucleus
GiV GABA-ergic/glycinergic
output
inhibits spinal motoneurons
A
B
Pathway B
Direct SubC glutamatergic
projection to inhibitory interneurons of the ventral horn.
Physiol Rev 92;2012:1126
Brain Stem Control of Atonia and Muscle Twitches
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Small lesions of subcoeruleus abolish REM muscle atonia.
More widespread lesions of reticular formation are rquired for
expression of dreamlike activity.
Selective inactivation of glutamatergic transmission of SubC and
nearby LDT region reduced atonia and led to motor behavior during
REM sleep.
Neurons in SubC fire tonically just prior to and during muscle atonia of
REM sleep.
Application of cholinergic agents to SubC cause quickly a REM like
state including atonia.
REM Sleep Flip-flop Switch Proposal
Orexin neurons are wake-active and act to switch into wake state.
Orexin neurons reinforce the activity of arousal neurons.
Orexin inputs to vlPAG-LPT prevent the onset of REM phenomena except in sleep.
Absence of orexin activates sleep-on switch and REM phenomena during wake.
Nature, 441:1 June 2006, 592.
REM Sleep Flip-flop Switch Proposal
Extended part of ventrolateral preoptic nucleus (eVPLO) contain REM-active
neurons containing inhibitory neurotransmitters galanin and GABA.
eVLPO projections inhibit the REM-off site in mesopontine septum at opening
of fourth ventricle known as ventrolateral periaqueductal gray matter (vlPAG).
vlPAG contains neurons that express the orexin 2 receptor.
Complete lesions of either vlPAG or LPT doubles amount of REM sleep.
LPT lesions increase REM during light period, SOREMP and cataplexy.
Nature 441:1 June 2006, 592.
REM Sleep Flip-flop Switch Proposal
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Serotoninergic dorsal raphe nucleus (DRN) activates REM-off
neurons.
Noradrenergic locus coeruleus (LC) neurons activates REM-off
neurons.
DRN-LC is not part of the mutually inhibitory flip-flop switch.
Nature 441: 1 June 2006, 592.
REM Sleep Flip-flop Switch Proposal
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Pedunculopontine and laterodorsal tegmental (PPT-LDT) cholinergic
neurons are REM-on and inhibit lateral pontine tegmentum (LPT).
These neurons are not inhibited by LPT so are not part of switch.
nNOS is located within PPT, LDT, and DRN. NOS knockout mice
have less REM sleep. NO produced by nNOS in brainstem cholinergic
neurons promotes REM sleep.
Nature 441: 1 June 2006, 592
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Sublateral dorsal nucleus (SLD) in other species is subcoeruleus area
or peri-locus coeruleus. The periventricular gray matter includes
includes a dorsal extention of the SLD and precoeruleus (PC) area.
SLD GABA-ergic REM-on neurons inhibit GABA-ergic REM-off
neurons of the vl-PAG-LPT and vice versa.
Lesions leading to 90% loss of SLD neurons fragment and diminish
REM sleep. Motor tone preservation occurs even during EEG REM
sleep.
Lesions to both SLD and PC areas abolish REM sleep.
GABA-ergic neurons in REM-on and REM-off regions are mutually
inhibitory.
Nature 441: 1 June 2006, 592
Brainstem Mechanisms of REM Sleep Generation
Ventrolateral Periaqueductal Gray
Dorsal deep Mesencephalic Reticular
Nucleus
Dorsal Para-Gigantocellular Reticular Nucleus
Sublaterodorsal Nucleus (Precoeruleus)
Ventral Gigantocellular Reticular Nucleus
TMN and LH not included
as being Wake-on rather
than REM-off
Pflugers Arch/Eur J Physiol (2012)463:43-52.
Forebrain Control of REM Sleep Timing
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Additional factors influencing timing of REM sleep: time of day, light
exposure, temperature, nuitritional status, sleep homeostasis, stress,
and emotional state.
Orexin controls REM sleep: Orexin neurons receive direct input from
SCN and indirect input via dorsomedial hypothalamus. Orexin
neurons have a wake-on, REM-off pattern of firing. Orexin excites
wake-active, REM-inhibiting serotoninergic DRN and noradrenergic
LC neurons. Loss of orexin causes narcolepsy.
Preoptic hypothalamus control of REM sleep: Preoptic area receives
indirect projections from SCN via medial preoptic area and
dorsomedial hypo- thalamus. Lesions of VLPO area of hypothalamus
lead to loss of REM sleep.
Diurnal variation of REM sleep: Orexin suppression during active
period and eVLPO promotion during inactive period.