Download Neurobilogy of Sleep

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Neurobiology Of Sleep
By
Ahmad Younis
Professor of Thoracic Medicine
Mansoura Faculty of Medicine
Neurobiology Of Sleep
• Patients with damage to the posterior
hypothalamus and rostral midbrain often had
excessive sleepiness, whereas those with injury
to the anterior hypothalamus had unrelenting
insomnia.
• Based on these observations, the anterior
hypothalamus contained neurons that promoted
sleep, whereas neurons near the hypothalamusmidbrain junction helped promote wakefulness.
Neurobiology Of Sleep
• The term neurotransmitter is currently applied to
situations in which one presynaptic neuron directly
influences another postsynaptic neuron.
• In neuromodulation, a given neurotransmitter regulates the
activity of diverse populations of neurons in the central
nervous system. Examples of neurotransmitters that are
also neuromodulators include acetylcholine (ACh),
serotonin (5HT), dopamine (DA), and histamine (HA).
• Neurons are often characterized with respect to sleep by
when they are most active. Some neurons are active during
wake, during rapid eye movement (REM) only (REM-on),
during REM and wake (wake/REM-on), during non–rapid
eye movement (NREM) only (NREM-on),or during NREM
and REM sleep .
MAJOR BRAIN AREAS IMPORTANT FOR
SLEEP AND WAKE
Hypothalamic Areas
1- Lateral Hypothalamus
•Neurons in the lateral and posterior hypothalamus are the
sole source of the awake-promoting neuropeptides
hypocretin 1 (Hcrt1) and hypocretin 2 (Hcrt2), also known as
Orexin A and Orexin B, respectively.
•Hcrt1 can attach to both Hcrt1 and 2 receptors, whereas
Hcrt2 attaches only to Hcrt2 receptors.
•Patients with narcolepsy with cataplexy have loss of 90% or
more of Hcrt-producing neurons and have low to
undetectable CSF levels of Hcrt1.
•Patients with narcolepsy without cataplexy has partial loss
of Hcrt neurons.
• Orexin (hypocretin)
neurons in the lateral
hypothalamic area
innervate all of the
ascending arousal
systems, as well as the
cerebral cortex.
• BF = basal forebrain ; LC =
locus coeruleus; LDT =
lateral dorsal tegmental;
PPT = pedunculo-pontine
tegmental; SN = substantia
nigra; TMN = tuberomammillary nucleus; VTA =
ventral tegmental area.
MAJOR BRAIN AREAS IMPORTANT
FOR SLEEP AND WAKE
• Hcrt neurons send abundant excitatory projections
to the dorsal raphe (Hrct1 and Hcrt2 receptors)
nucleus, the locus coeruleus (Hcrt1 receptors), and
the tuberomammillary nucleus (Hcrt2 receptors) .
• These areas in turn send inhibitory projections to
Hcrt neurons.
• Hcrt neurons have a strong excitatory effect on the
cholinergic neurons of the basal forebrain that
contribute to cortical arousal but have no effect on
GABAergic sleep-promoting neurons within the
ventrolateral preoptic (VLPO) area.
MAJOR BRAIN AREAS IMPORTANT FOR
SLEEP AND WAKE
• Hcrt appears to stabilize transitions between wake and
sleep.
• Hcrt neurons are relatively inactive in quiet waking but are
transiently activated during sensory stimulation.
• Hcrt cells are silent in slow wave sleep and tonic periods of
REM sleep, with occasional burst discharge in phasic REM).
• Hcrt cells discharge in active waking and have moderate
and approximately equal levels of activity during grooming
and eating and maximal activity during exploratory behavior.
• Hcrt cells are activated during emotional and sensorimotor
conditions similar to those that trigger cataplexy in
narcoleptic animals.
Orexin (hypocretin) neurons are active during wake and quiet
NREM sleep with some activity only during phasic REM sleep.
•
MAJOR BRAIN AREAS IMPORTANT FOR
SLEEP AND WAKE
2- Ventrolateral Preoptic Nucleus
• The VLPO is an area in the hypothalamus containing
neurons active during sleep. Most sleep-active neurons
in the VLPO are believed to be active during both NREM
and REM sleep
• Many of the VLPO neurons are activated by sleepinducing factors including adenosine and
prostaglandinD2. These neurons are sensitive to
warmth, and heating this area of the brain increases
their activity and decreases wake.
• A compact group of VLPO neurons (VLPO cluster)
projects to the tuberomammillary nucleus (TMN) and
inhibits the neuronal activity of that area.
MAJOR BRAIN AREAS IMPORTANT FOR
SLEEP AND WAKE
• A second group of VLPO neurons is located dorsal and
medial to the VLPO cluster neurons and the group is called
the extended VLPO (eVLPO) by some authors.
• The eVLPO neurons make up the majority of the
projections to the dorsal raphe nucleus (DRN) and locus
coeruleus (LC) as well as to the interneurons of the lateral
dorsal tegmental/pedunculopontine tegmental (LDT/PPT)
region.
• Most VLPO neurons appear to be active during both NREM
and REM. The neurons in the VLPO contain the
neurotransmitters gammaaminobutyric acid and galanin.
• The VLPO neuronal projections to the DRN, LC, and TMN
are inhibitory ,
• The neurons in the VLPO receive inhibitory projections
from the DRN, LC and TMN.
Inhibitory projections from the
ventrolateral preoptic area
(VLPO;gamma-aminobutyric
acid, galanine) during non–
rapid eye movement (NREM)
sleep to the tuberomamillary
(TMN), the raphe area, locus
coeruleus (LC), and
pendunculopontine
lateral/dorsal tegmentum
(PPT/LDT) area, substantia
nigra (SN), and ventral
tegmental area (VTA).
MAJOR BRAIN AREAS IMPORTANT FOR SLEEP
AND WAKE
3-Tuberomammillary Nucleus
• Histaminergic neurons are confined to the posterior
hypothalamus in the area called the tuberomammillary
nucleus..
• TMN neurons project to the cerebral cortex, amygdala,
substantia nigra (SN), DRN, LC, and nucleus of the
solitary tract.
• HA acting at H1 receptors is associated with
wakefulness, and antihistamines (H1 receptor blockers)
cause drowsiness or sleep.
• Conversely, H3 receptor agonists cause sleepiness
possibly by stimulating autoregulatory receptors that
decrease HA release.
MAJOR BRAIN AREAS IMPORTANT FOR
SLEEP AND WAKE
• The TMN receives stimulatory input from the lateral
hypothalamus (Hcrt).
• The TMN firing rate is high during wake, lower during NREM,
and absent during REM .
• In contrast to REM sleep, during attacks of cataplexy, TMN
neurons have a high firing rate associated with preservation
of consciousness.
• Low CSF HA has been found in patients with narcolepsy
with and without low Hcrt.
• The low HA may be a marker rather than a cause of
sleepiness because lesions of the TMN have minimal
effecton wakefulness.
• This mean that HA is not essential for wakefulness in
general. HA may be important at the onset of wakefulness.
•
Brainstem Regions
1-Dopamine Regions
• Neurons producing dopamine (DA) are abundant in the SN
and ventral tegmental area (VTA). Previously, studies
suggested that DA neurons do not change their firing rates
substantially across sleep stages. However, extracellular
DA levels are high in several brain regions during
wakefulness.
• DA agonists acting at D1, D2, and D3 receptors increase
waking and decrease NREM and REM sleep.
• DA blockers of D1 and D2 receptors can promote sleep. In
patients with low DA activity such as in Parkinson’s
disease, low doses of DA agonists (pramipexole,
ropinirole) that bind D2/D3 autoreceptors on DA neurons
can actually cause sleepiness by reducing DA signaling.
• Amphetamines promote wakefulness by increasing DA
Brainstem Regions
2- Reticular Formation
• The reticular formation is a loose collection of
neurons extending from the caudal medulla to
the core of the midbrain.
• Wakefulness depends on the activity of the
ascending reticular activating system (ARAS).
• This system projects to higher brain centers.
One pathway ascends dorsally to the thalamus,
and the second ascends ventrally through the
lateral hypothalamus and forebrain .
Dorsal RAS
• Lateral Dorsal Tegmentum/Pedunculopontine Tegmentum.
Neurons in the LDT and PPT areas that are located in the
dorsal midbrain and pons make up the majority of the dorsal
RAS pathway through the pons and are cholinergic.
• Some of the neurons are active during wake and REM sleep
(wake/ REM-on), whereas others are active mainly during REM
sleep (REM-on).
• Acetylcholine (ACh) release in the thalamus is high during wake
and REM sleep. The cholinergic neurons from the LDT/PPT
densely innervate the thalamus (especially the medial and
intralaminar thalamic nuclei),lateral hypothalamus, and midbrain.
• During REM sleep but not wake or NREM sleep. Wake/REM-on
neurons are active during wake and REM sleep .
• Other cholinergic neurons in the basal forebrain (BF) project to
the cortex, hippocampus, and amygdala. The firing rate of these
neurons is high during wake and REM and low during NREM.
Reticular activating system (RAS). The ventral RAS includes neurons from
the locus coeruleus, dorsal raphe nuclei, tuberomammillary nucleus (TMN),
and lateral hypothalamus (LH). The dorsal RAS includes projections from the
lateral dorsal tegmental (LDT) and pedunculopontine tegmental (PPT) areas.
Ventral RAS
• The ventral RAS projects through the lateral
hypothalamus terminating on magnocellular
neurons in the substantia innominata, medial
septum, and diagonal band . These regions
contain neurons that project to the cortex.
• The ascending projections of this branch are
joined by input from the TMN and lateral
hypothalamus.
• The ventral RAS is composed of projections
from the DRN (5HT) and LC (norepinephrine
[NE]).
Dorsal Raphe Nucleus DRN serotonergic neurons
are active during wake, less active during NREM,
and minimally active during REM sleep.
• The influences of DRN neurons are mainly
stimulatory. They are part of the RAS network
Locus Coeruleus Neurons in the LC utilize NE as
the neurotransmitter and innervate wide areas of
the brain with chiefly stimulatory effects.
•LC firing rates are high during wake, lower during
NREM, and absent during REM sleep .
Basal Forebrain Cholinergic neurons in the BF
excite cortical pyramidal cells.
•GABA BF neurons disinhibit cortical neurons.
•Lesions that destroy BF ACh and GABA neurons
increase delta power.
CONTROL OF NREM SLEEP
•During NREM sleep, the VLPO neurons are active
and inhibit the firing of neurons in the TMN, DRN,
and LC .
•The Orexin neurons do not innervate the VLPO but
stimulate the TMN, DRN, or LC more or less
depending on the sleep state. Orexin neurons are
active during wake.
•This mutually inhibitory system functions as a flipflop switch transitioning between the two states .
NREM flip-flop switch. During NREM, the ventrolateral preoptic area (VLPO)
inhibits hypocretin neurons as well as the locus coeruleus (LC),
tuberomammilary nucleus (TMN), dorsal raphe nucleus (DRN) areas
promoting sleep. During wake, the hypocretin neurons stimulate the LC,
TMN, and DRN areas, which are active and inhibit the VLPO neurons.
eVLPO = extended ventrolateral preoptic area; ORX = Orexin (hypocretin).
FEATURES OF REM SLEEP
• The tonic features include EEG
desynchronization (reduction in cortical EEG
amplitude),theta rhythm generation by the
hippocampus (saw tooth wave in the EEG),
suppression of muscle tone (atonia) , absent
thermoregulation, penile erections in males, and
constriction of pupils.
• The phasic features of REM sleep include
ponto-geniculo-occipital (PGO) waves that
precede and occur during REM sleep, irregular
respiration and heart rate (sympathetic bursts),
and REMs.
FEATURES OF REM SLEEP
• The PGO waves start in the pons and transit to
the lateral geniculate nucleus (LGN) of the
thalamus and from there to the occipital area.
• PGO waves are believed to be an integral part of
REM sleep but are not seen in the cortical EEG.
Recording requires electrodes placed into the
appropriate brain areas.
• The density of the PGO waves correlates with
the amount of eye movement measured in REM
sleep.
Posbiopsy procedure