Download Sleep-wake cycles: EEG

Sleep-wake cycles: EEG
• Wakefulness: fast, low voltage and
desynchronized electrical activity (bwaves)
• Sleep: progressively slower, higher
voltage and more synchronized
electrical activity of the cortex (awaves)
• REM-sleep: partial arousal without
wakefulness characterized by
desynchronized electrical cortical
activity, rapid eye movement loss of
muscle tone, erection and dreaming
Sleep –wake cycle: clinical observation
1st World war
Encephalitis lethargica (« spanische Grippe »)
• Von Economo’s observations
– Lesions in the basal forebrain and lateral preoptic area
» Prolonged wakefulness, insomnia
– Lesion in the posterior, lateral hypothalamus and midbrain
» Patients sleep for weeks
http://www.youtube.com/watch?v=puJCjUsgq7o&feature=related
Sleep-wake cycle: experimental work
– Diencephalon basal forebrain and mid-rostral brain stem
express two, stable firing states to produce rest or arousal
(flip-flop)
Lesions and electrical stimulation
• Sleeping centers
Ventrolateral preoptic nucleus
– Sleep active neurons in the lateral
preoptic area
• VLPO neurons c-FOS positive during
sleep
– Use the neurotransmitter GABA and galanin
– Lesions provoke loss of 70% of non-REM and
REM-sleep
Initiation of sleep is driven by
the VLPO
Sleep active neurons
(c-FOS)
Galanin-positive
neurons
Sleep-wake cycles: experimental work
Most belong to the « ascending reticular activating system » of Moruzzi and Magoun
• Wake centers
– Wake active neurons in monoaminergic
nuclei
• Monoaminergic nuclei: locus coeruleus, dorsal
raphe
• Cholinergic: laterodorsal tegmental nucleus
(LDTG) and basal nucleus of Meynert
• Histaminergic: tuberomammillary nucleus
– Wake promoting peptidergic neurons in LHA
• Hypocretin cells in the lateral hypothalamus
stimulate the center of the ascending reticular
system, thus contributing to wakening
– Hypocretin defect – narcolepsy (sudden sleep
attacks), fall in REM-sleep
Sleep-wake cycle: summary
Wakefulness
NREM-sleep
Sleep-wake cycle: summary
REM-sleep
Sleep-wake cycles: the hypocretin system
a success story of genomic based biology
• Gautwick et al. (1996): subtractive
hybridization aimed at identifying mRNA’s
species that are expressed only in discrete
nuclei within the hypothalamus
– New hypothalamic mRNA (hypocretin 1
and 2) found by in-situ hybridization to
occur in the lateral hypothalamus
• Sakurai et al. (1998) transfected cell lines that
stably express each of the 50 orphan GPCRs
and then measured Ca2 + fluxes
– Identified the hypocretin 1 and 2 receptors
• Genetic linkage studies in Doberman
Pinschers with narcolepsy (1999)
– The defective canine gene encodes the
hypocretin 2 receptor
http://www.youtube.com/watch?v=Jhw6ahl_XaI
Sleep-wake cycles: the hypocretin system
• Narcolepsy: autoimmune disease,
1:2’000 people
• excessive daytime sleepiness
• cataplexy (muscle weakness
precipitated by strong emotions
(laughter or surprise)
• sleep paralysis
• hypnagogic hallucinations
• Hypocretin receptor KO mice
– Cataplexic attacks
– More time spent in REM-sleep
http://www.youtube.com/watch?v=Jhw6ahl_XaI
Sleep-wake cycles: the hypocretin system
Anatomo-physiological studies
• Hypocretin contained in dense
core vesicles
• Projections from the lateral
hypothalamus to various nuclei
involved in arousal
• Hypocretins are excitatory
peptides
Sleep-wake cycles: the hypocretin system
• Human narcolepsy (2000)
– Hypocretin undetectable in 37 of
42 narcoleptic
– Few or none hypocretin neurons
in the hypothalamus at autopsy
– One patient with a mutation in
the hypocretin gene
Hypocretin opposes REM sleep