Hypothalamic regulation of

sleep and circadian rhythms

Saper, Scammel, Lu
Nature, Volume 437
October 2005

AWAKE group meeting

Alex Dimitriu, MD
 Baron Constantin von Economo -
1916
Viennese neurologist
Discovered new type of
encephalitis that attacked
regions of brain involved in
sleep and wakefullness
Called it Encephalitis
Lethargica
Von Economos sleeping
sickness
Disease swept through Europe
/ North America during 1920s
Disease disappears next
decade, virus never identified
 Agenda
Recent advances in understanding brain
circuitry involved in sleep / wake
Properties of the switch that controls sleep
and wakefulness; narcolepsy
How basic drives (need for sleep) affect this
switch
Effects of drugs on sleep and wakefulness
 Von Economos Encephalitis
Majority of patients slept 20+ hrs/day
Arising only to eat and drink
Cognitive function intact, but would soon
return to sleep
This cycle lasted several weeks before
recovery
 Von Economo
Found lesion to
occur at the junction
of the midbrain and
the diencephalon
Proposed there was
an ascending
arousal system
originating in the
brainstem, keeping
the forebrain awake
Hypothalamus
Hypothalamus
 RAS
Von Economo proposes ascending arousal
system
During WWII Moruzzi and Magoun describe
ascending arousal pathway originating in
rostral pons and runs through midbrain
reticular formation
Coin the term ascending reticular activating
system (RAS)
 Reticular Activating System 2
branches
Ascending pathway to
thalamus (Yellow)
Activates thalamic relay
neurons, crucial for
transmission of information
to cerebral cortex

2 acetylcholine cell groups

Major source of input to
thalamic relay nucleii,
and reticular nucleus of
the thalamus is pair of

Pedunculo-pontine and
laterodorsal tegmental
nucleii (PPT, LDT)
 PPT LDT Neurons
Major input to thalamic relay nucleus
Produce Acetyl-choline (ACH)
Fire rapidly during wakefulness and REM
Most active periods of brain activity
In REM; cortical activation, loss of tone in muscles and active
dreaming
Much less active during non-REM (NREM) sleep when cortical
activity is low
Input of these neurons is crucial as they act as a gating
mechanism that can block transmission between thalamus and
cortex; ACH important to wakefulness
Other inputs to thalamus include, reticular formation, PPT/LDT,
monoaminergic systems, parabrachial nucleus. Also midline and
intralaminar nucleii in the thalamus.
 The 2nd activating Pathway
Bypasses the thalamus
Activate neurons in basal forebrain
and lateral hypothalamic area
Originates from monoaminergic
neurons in upper brainstem
including;
Noradrenergic locus ceruleus
(LC)
Serotonergic dorsal and
median raphe
Dopaminergic periaqueductal
grey matter
Histaminergic tuberomamillary
neurons
 Second Pathway (RED)
Monoaminergic Neurons
Norepinephrine,
Serotonin, Dopamine,
Histamine
Input to cortex also
augmented by
Lateral hypothalamic
(LHA) neurons
Melanin concentrating
hormone
hypocretin / hypocretin
most active during
wakefulness
Also basal forebrain
neurons, including
cholinergic and GABA
neurons
 Second Pathway (RED)
Lesions along this pathway, esp the LHA
result in coma or long-lasting sleepiness.
Neurons in this pathway fire fastest during
wakefulness, slower during NREM, and stop
during REM sleep.
ACH Cholinergic neurons most active
during wake and REM
Von Economos block ascending
pathways; produce impairment of arousal
Ascending Arousal System
 Encephalitis Lethargica

http://www.youtube.com/watch?v=5lNVtUlroZc
 Hypersomnia vs. Insomnia
Von Economo also observed an opposite
response in some victims of Encephalitis
lethargica
Rather than sleepy, some became
insomniac and only slept for few hours each
day
Became tired, difficulty falling asleep, slept
short time, then awoke unable to return to
sleep.
 VLPO promotes sleep
Later experiments revealed a hypothalamic site
involving lateral preoptic area where lesions
caused similar insomnia
VLPO neurons then found to send major outputs
to cells that participate in arousal
Damage to these neurons caused insomnia in Von
Economos pts.
In animals, lesions to VLPO reduced both REM
and NREM sleep by 50%
VentroLateral Preoptic Nucleus
(Hypothalamus)
 VLPO
VLPO neurons particularly active during sleep, and
project inhibitory neurotransmitter GABA, and
Galanin.
VLPO Cluster
More heavily innervates histaminergic neurons, closely
linked to transitions b/w arousal and wakefulness.
VLPO Extended
Damage to extended VLPO inhibits REM sleep more
specifically
Also the extended VLPO is main output to the LC and
DR; key in gating REM sleep
 VLPO
Norepinephrine (NE) and Serotonin (5HT)
inhibit the VLPO.
Tuberomammillary secrete Histamine,
GABA
No VLPO receptor for Histamine
GABA inhibits VLPO neurons
Therefore, the VLPO can be inhibited by
the same arousal systems that it inhibits
during sleep
 The Flip Flop Switch
A circuit containing mutually inhibitory elements
sets up a self-reinforcing loop, where activity in one
of the competing sides shuts down inhibitory inputs
from the other side, and therefore reinforces its own
action
Flip Flop circuits avoid transitional states because
when either side begins to overcome the other, the
switch flips into alternative state.
Explains why sleep wake transitions are abrupt
Dangerous for animals to have impaired alertness when
awake
Useless for animals to spend sleep periods half awake
 Instability of the Switch
Small pertubation can give one side advantage, turn off
alternative state abruptly
Falling asleep while driving
Mathematical models of these biologic switches show:
Weakening either side of a switch causes switch to ride closer to
the transition point between both states
Increase number of transitions regardless of which side is
weakened
Animals with VLPO lesions
Fall asleep twice as often
Wake more often during sleep cycle
Only sleep for of time per session
 Unstable Switch
Mid-Sleep, wake up unable to fall back
asleep, chronically tired, falling asleep
briefly and fitfully during wake cycle
Similar pattern seen in elderly pts
Have similar loss of neurons in VLPO
associated with aging.
 Monoamine nucleii inhibit VLPO = inhibit supression of
monoamine nucleii, hypocretin, cholinergic PPT, LDT neurons
hypocretin reinforces monoaminergic tone (no hypocretin
receptors on VLPO)
 In sleep, firing of VLPO inhibits monoaminergic cell groups,
relieving its own inhibition. (enhancing its own activity) VLPO then
inhibits hypocretin

hypocretin, in both cases, believed to stabilize this unstable switch

 Narcolepsy
1998 2 groups of scientists discover group
of neuropeptides produced by neurons in
posterior LHA (lateral hypothalamus).
One year later, discovery that lack of these
neuropeptides results in narcolepsy in
animals.
Next year deficiency in human in CSF found
in narcoleptics
 Hypocretin
Narcolepsy;Believed to be autoimmune /
neurodegenerative disease
Begins in 2nd / 3rd decade of life
hypocretin neurons very active in wakefulness
and while exploring environment
hypocretin neurons have ascending pathways
to cortex, and descending pathways to
midbrain cholinergic/monoaminergic nucleii of
arousal centers
 Hypocretin
hypocretin and VLPO have mutual projections,
but VLPO does not have hypocretin receptors
So, hypocretin neurons reinforce arousal
centers, but do not inhibit VLPO
Asymmetric relationship helps stabilize the flip
flop switch
Narcoleptics (lack hypocretin) have de-
stabilized switch; easily doze off during day,
wake often at night
 Why we sleep
Like body temperature, the body always
tries to return sleep to a set-point.
Sleep deprivation, followed by compensatory
recovery
Model proposed by Borberly and colleagues
describes 2 drives for sleep
Circadian
Homeostatic
 Why we sleep Homeostatic
Homeostatic influence results from accumulation
of some substance during prolonged
wakefulness
VLPO neurons do not accumulate need for sleep;
just start firing 2x as fast with sleep onset so
influenced by something else
During prolonged wakefulness, energy producing
brain systems run down and ATP levels deplete,
ADP levels accumulate
Extracellular adenosine levels rise with time
Adenosine injected into BF of cats induces sleep
blocks adenosine receptors.
 Circadian regulation
Confirmed 24 hour circadian rhythm in sleep drive
Cells in suprachiasmatic (SCN) nucleus fire in 24
hour cycle, even on their own in cell culture reset
daily by light
Bulk of SCN output projected to SPZ
(supraventricular zone)
Ventral lesions disrupt sleep wake rhythms
Dorsal lesions impair body temperature rhythms
Major output of SPZ is DMH (Dorsomedial nucleus
of hypothalamus)
 Circardian Regulation
Light SCN SPZ DMH VLPO and hypocretin neurons
Dorsomedial nucleus of hypothalamus projects
to inhibitory signals (GABA) to VLPO and
excitatory signals (glutamate) to LHA (activating)
Complex 3 stage system allows varying
sleep/wake cycle behavior despite fixed daylight
schedule
SCN always active in light cycle and VLPO active in
sleep
 Circadian Regulation - DMH
Allows animals to
vary sleep wake
behavior based on
food source, daylight
hours Finland bats
become diurnal for
of the year to eat
more insects

Lesions of DMH
prevent these shifts

DMH lets you adjust

to new time zones
 Conclusion
RAS Reticular Activating System (ON)
LDT, PPT (via ACH) Activate thalamic relay
Monoaminergic Pathways (ON)
Norepinephrine, Serotonin, Dopamine, histamine
Activate Basal forebrain, hypocretin, and cortex
Hypocretin (ON)
enhances Monoaminergic tone
VLPO (OFF)
Inhibited by monoamines, and inhibits monoamines
Adenosine (OFF)
 Conclusion
Circadian Cycles (ON)
Light SCN SPZ DMH
Inhibit VLPO
Activate hypocretin neurons

VLPO vs Hypocretin
Hypocretin cannot turn off VLPO but
VLPO can turn off hypocretin
so they function independently
FIN