Sleep and Arousal

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Sleep and Arousal

• Lecture 9
• NRS201S
• John Yeomans

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EEG Changes in Sleep

• Waking Alpha (10 Hz) and beta/gamma waves (40
  Hz).
• Slow-Wave sleep From alpha to spindles (14 Hz)
  and delta (1-4 Hz).
• REM sleep Cortical arousal and muscular atonia.
  Also called paradoxical or dream sleep.
• Triggered in pontine reticular formation.

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Gamma Alpha
Hours
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REM Sleep

• Brain is active, and eyes are active.
• Muscles of body are profoundly inhibited
  (atonia).
• Subjects report dreams, when awoken.
• NE and 5HT neurons silent. Ch neurons active.
• In slow-wave sleep, brain and eyes are quiet, but
  muscles are more active.

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Transection studies
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Brain Areas--Early Studies

• Coma (prolonged unconsciousness) due to injury in
  dorsal reticular formation.
• Stimulation of RF leads to arousal.
• Ascending path for cortical arousal.
• Descending path for atonia.
• Critical area in dorsal pontine reticular
  formation.

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Diffuse Arousal Systems

• Locus coeruleus Norepinephrine neurons (A6).
• Mesopontine Cholinergic neurons (Ch5,6).
• Raphe Serotonin neurons (B5,6).
• Tuberomammilary Histamine neurons.
• Lateral hypothalamus Orexin/Hypocretin neurons.
• Basal forebrain Cholinergic neurons (Ch1-4).

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Norepinephrine and Serotonin
Active in Waking and in Slow-Wave Sleep
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Mesopontine Ch5,6
Basal Forebrain Ch1-4)
Cholinergic Arousal Systems Active in Waking
and REM Sleep
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Model of REM Sleep Systems
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Sleep Disorders

• Insomnia (too little sleep).
• Sleep apnea (loss of breathing in REM, too much
  atonia?).
• Narcolepsy/cataplexy (daytime sleepiness and
  REM/atonia attacks).
• Triggered by arousal (e.g. laughing, running).
• Due to loss of orexin/hypocretin neurons in
  humans, or receptors in dogs and mice.

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Narcolepsy

• Orexin 2 receptors lost in dogs (Mignon).
• O/H neurons lost in humans.
• O/H gene or receptors in mice.
• O/H neurons active in waking arousal, and needed
  to inhibit atonia.
• In narcolepsy, arousal can activate REM/atonia
  neurons, if O/H signal is lost.
• Which neurons and how? Ch5,6?

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Loss of O/H neurons Daytime sleepiness, Cataplex
y (atonia) induced by arousal.
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Circadian Rhythms

• March 17, 2006
• PSY391S
• John Yeomans

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Timing of Motivated Behaviors

• When is best season to feed and mate? Seasonal
  periods of activity and breeding based on
  availability of food. Based on axis of earth
  around sun.
• When is best time of day to feed?
  Diurnal/nocturnal to find food and avoid
  predators. Based on earths rotation relative to
  sun.
• Circadian clock built into all plants and animals
  to help survival.

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Measuring Rhythms in Hamsters
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Rhythms

• Endogenous clock Measured in constant
  conditions, still 23-25 hr. free running
• Rhythm is lost when SCN lesioned in mammals, or
  pineal gland in birds.
• Rhythm is restored by transplanting new SCN.
  Period of donor SCN.
• Tau mutant hamster has 20 hr rhythm.
• Therefore, SCN is endogenous clock for activity.

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Free running 24.1 hr
No rhythm
Tau mutant SCN
19.8 hr rhythm of donor SCN
Ralph et al. 1990
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Retinal Paths to SCN and IGL
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Entrainment

• Entrainment by light, temperature, or
• arousing stimuli.
• Photic entrainment in mammals due to
• retinohypothalamic path to SCN.
• Rods and cones not needed for entrainment!
• Search for new receptors in ganglion cell
• layer led to melanopsin.
• Melanopsin ganglion cells directly activated
• by light, indirectly by rods and cones.
• Huge dendrites and receptive fields,
• insensitive to light, but stable (no
  adaptation)

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Projections of Melanopsin Neurons

• Melanopsin neurons provide most of input
• to SCN.
• Provide input to pretectal nucleus for
• pupillary reflex.
• Provide input to intergeniculate leaflet of
• thalamus. IGL?SCN.
• IGL needed for arousing inputs to clock.

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Entrainment by Arousal

• Clock can be shifted by food, exercise, footshock
  and sex.
• Allow animals to adjust rhythms to biologically
  significant opportunities.
• Like light, shift can be up to 3 hours.
• Shifts depend on phaseLight shifts best in dark
  phase, arousal shifts best in light phase.

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Intergeniculate Leaflet Arousal Shifts Circadian
Rhythms
Cain et al. 2001
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Arousal Shifts Circadian Rhythms in Hamsters
Arousal (footshock, exercise, reward)
Cain et al. 2001
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Evolution of Retina?

• How could eye evolve? Greatest problem for Cajal.
• Circadian clock with direct access to light.
• Light detectors, no spatial informationdirect
  input to clock.
• Eye cupSpatial information, focussing, with
  pupil and lens later.
• Dark and light vision (cones and rods) with
  adaptation.
• Two eyeballs with muscles, for distance
  perception and fast movements in space.

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Non-photic entrainment IGL to SCN
SCN Clock
?
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Circadian Genes

• How does endogenous clock work?
• Clock mechanism found in plants, simple animals
  and many body cells.
• Clock genes found in mutant fruit flies. How?
• Take the flies who fly at odd hours. Map genes.
• per No rhythm, long rhythms, short rhythms.
• Tim, cry, dbt.
• Map genes onto 4 fly chromosomes.
• Study functions of proteins PER, TIM, DBT.

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Mutations Alter Rhythms in Flys and Mice

• per, tim are needed for 24 hr rhythms.
• Mutations lead to short, long or no rhythm.
• dbt mutations alter enzyme, casein kinase,
  leading to short rhythm in Drosophila.
• Homologous genes (per1-3, cry, tau) found in mice
  and humans.
• Transcription factors Clock and Cycle start each
  cycle. These are also regulated.

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Clock Genes and Negative Feedback

• per, cry genes transcribed in nucleus.
• Per, Cry proteins are translated in cytoplasm.
• Per/Cry dimers inhibit Clock/Cycle transcription
  factors in nucleus.
• Less Per, Cry? less inhibition.
• New per, cry transcribed 24 hrs later.
• Tau gene makes a casein kinase that degrades Per.

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Molecular Model of Clock
Nonphotic input from thalamus IGL?
Gene transcription proteins
Negative feedback loop
Photic input from retina