Yip Yip Snore: Sleep and Narcolepsy

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Yip Yip SnoreSleep and Narcolepsy

• SHP Neurobiology of Development and Disease

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Control System for Sleep

• The retina takes information from the environment
  and sends it to the circadian clock
• The clock integrates information and passes it to
  hypothalamic regions for processing sleep-wake
  switch
• Further ascending signals of the pathway regulate
  wakefulness control systems in the cortex.

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Early Work into Arousal and Sleep

• In 1916, Boron Constantin von Economo
  characterized a strange viral infections in
  patients that were sweeping through Europe
• Called encephalitis lethargica, this virus caused
  lesions in the brain that caused patients to
  sleep for more than 20hrs a day, emerging only to
  eat and drink.
• After studying lesions in these patients brains,
  Economo was able to piece together a preliminary
  circuit controlling arousal and wakefulness.
• There is an ascending arousal system originating
  in the brainstem that keeps the forebrain awake.

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Narcolepsy

• Second leading cause of daytime sleepiness next
  to sleep apnea.
• Incidence estimated at 0.2-1.6 cases per 1000 in
  European countries. In US and Japan thought to be
  greater than or equal to multiple sclerosis
• Often not diagnosed until years after onset of
  the illness due to people not seeking treatment.

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Narcolepsy Symptoms

• Overwhelming daytime sleepiness despite adequate
  rest that can come in the form of sleep
  attacks.
• Hypnogogic hallucinations vivid hallucinations
  that occur while falling asleep and waking up.
• Sleep paralysis muscle paralysis and inability
  to speak while falling asleep and waking up
  (lasting seconds to minutes)
• Cataplexy sudden, episodic loss of muscle tone
  (from weakness to paralysis) often in response to
  an emotional state.

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Deletion of Orexin Elicits Narcoleptic Symptoms

• The neurohormone orexin (aka hypocretin) has been
  shown to be important in wakefulness and arousal.
  
• Loss of orexin signaling is implicated in the
  cause of narcolepsy.

Labelling of orexin in knockout mice
Movie of orexin -/- mice
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Orexin Knockout Mice are Narcoleptic

• Orexin mice demonstrate narcoleptic behavior by
  EEG
• Rapid transition between wake and sleep can be
  seen in the mutant animals.

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But is Orexin Important in the Human Disease?

• Studies done in narcoleptic patients demonstrate
  that they have loss of orexin neurons (80-95)

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Gliosis In Narcoleptic Patients Signifies
Neurodeneration

• Gliosis is apparent in narcoleptic patients in
  areas where orexin neurons should be.

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Narcolepsy an Autoimmune Disorder?
Control antibody

• Narcoleptic patients have been found to have
  antibodies present in their blood against
  prohypocretin and its cleavage products.
• These may bind to orexin neurons in the brain and
  target them for destruction (as occurs in Type I
  diabetes).

Human serum
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Mechanism of Autoimmunity

• Body can generate autoantibodies by infectious
  agents or tissue damage.
• Some pathogens avoid detection by mimicking
  selfness which is imperfect and as body raises
  immune response towards pathogen, it raises
  antibodies against endogenous targets
• Tissue damage can release protein into the body
  which can stimulate immune system against the
  mislocalized proteins

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Dogs are a Leading Model for Narcolepsy

• There is a mutation prevalent in some breeds of
  dogs that produces a congenital narcolepsy
  condition closely phenocopying the human disorder
• This is due to a point mutation in the orexin
  receptor

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Schematic Flow of the Ascending Arousal Network
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VPLO and Its Projections into the Ascending
Pathway
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Wakefulness Controlled By a Flip-Flop Switch?

• Vigilance is controlled by a flip-flop switch in
  which there are two mutually exclusive states and
  a rapid transition in between.
• The theoretical orexin switch controls the
  balance between sleep and wake and activation of
  the VLPO and LC/TMN/Raphe areas of the brain.

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Arousal Also Has a Genetic Component

• Known as Circadian Rhythms, there are a
  genetically encoded biological clock conserved
  from cyanobacteria to humans.
• This is a negative transcriptional feedback loop
  that can be reset by light.
• This circuit lies in the superchiasmatic nucleus
  of the brain (SCN) and neurons fire rhythmically
  thoughout the day. This is controlled by the
  genetic circuit and persists even in dissociated
  in vitro culture.

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Circadian Transcriptional Circuitry
Drosophila
H sapiens
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Intregration for Circadian Rhythms

• Superchiasmatic nucleus (SCN) sends information
  to the dorsomedial hypothalamus (DMH) which sends
  information to other output areas.
• Medial preoptic area (MPO) controls
  thermoregulation of the body.
• ventrolateral preoptic nucleus (VLPO) controls
  sleep cycles.
• Lateral hypothalamus (LHA) to stimulate orexin
  neurons and control wakefulness.
• Paraventricular nucleus (PVH) to control
  corticosteroid cycles.

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