Hypothalamic regulation of sleep and circadian rhythms

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Hypothalamic regulation of sleep and circadian
rhythms
Saper, Scammel, Lu Nature, Volume 437 October 2005

• AWAKE group meetingAlex Dimitriu, MD

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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

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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

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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

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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

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Hypothalamus
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Hypothalamus
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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)

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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)

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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.

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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

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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

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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

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Ascending Arousal System
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Encephalitis Lethargica

• http//www.youtube.com/watch?v5lNVtUlroZc

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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.

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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

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VentroLateral Preoptic Nucleus (Hypothalamus)
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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

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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

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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

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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 ¼ of time per session

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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.

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• Monoamine nucleii inhibit VLPO inhibit
  supression of monoamine nucleii, hypocretin,
  cholinergic PPT, LDT neurons
• hypocretin reinforces monoaminergic tone (no
  hypocretin receptors on VLPO)

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• 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

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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

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Hypocretin

• NarcolepsyBelieved 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

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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

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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

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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

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blocks adenosine receptors.
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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)

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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

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Circadian Regulation - DMH

• Allows animals to vary sleep wake behavior based
  on food source, daylight hours Finland bats
  become diurnal for ½ of the year to eat more
  insects
• Lesions of DMH prevent these shifts
• DMH lets you adjust to new time zones

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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)

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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

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FIN