IMPORTANCE OF SLEEP

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IMPORTANCE OF SLEEP

• Spend 27 years asleep
• Most die during sleep
• Common complaint in medicine
• Somnogenic agents are big business
• Several primary sleep disorders
• Longevity linked to sleep duration
• Sleepiness causes accidents, nuclear reactors etc
• Sleepiness bad for mental and physical performance

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WHILE ASLEEP ONE

• Does not eat, drink, socialize or reproduce
• One is subject to predation
• IMPLICATION
• Sleep has a very important adaptive value

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TYPES OF SLEEP

• NON-RAPID EYE MOVEMENT SLEEP
• high amplitude EEG slow waves
• relaxed EMG
• regulated decrease in Tbr
• RAPID EYE MOVEMENT SLEEP
• low amplitude fast frequency EEG
• flat EMG
• increasing Tbr
• vivid dreams

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THE MEASUREMENT OF SLEEP

• No direct measure of sleep
• Inferred from EEG, EMG, EOG, EKG, Tbr,
  respiration, motor activity
• No single parameter of any measurement always
  indicative of sleep

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States of vigilance in the rat
NREMS
EEG
Movements
8 sec
REMS
EEG
Movements
Wakefulness
EEG
Movements
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Sleep cycles in the rat
Blood pressure
Tcrt
SWA
State
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All functions of the body are altered during
sleep.

• Behavior
• Motor and sensory functions
• Mental activity
• Autonomic functions
• Hormone secretions

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PHYSIOLOGICAL CHANGES DURING SLEEP- EXAMPLES

• Metabolic rate decreases
• Hypercapnic response reduced
• Airway resistance increased
• Heart rate decreased (NREM) variable (REM)
• Gastric acid secretion decreased
• Growth hormone increased
• Prolactin increased latter half of night
• Urinary output decreased
• Gut motility decreased

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Sleep-associated GH secretion in humans
(Spiegel et al., 2000)
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ACTIVATIONAL CIRCUITS

• Raphe serotonin
• LC noradrenalin
• PH histamine
• RF glutamate
• BF acetylcholine
• DLTn - acetylcholine

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REM SLEEP REGULATORY CIRCUITS

• LDT laterodorsal tegmental nucleus Ach
• PPT pedunculopontine tegmental n. Ach
• Meso-, medio-pontine tegmentum
• Midbrain reticular activating system Glu
• Locus coeruleus NE
• Raphe nuclei 5-HT
• Lateral hypothalamus orexin

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NREM SLEEP REGULATORY CIRCUITS

• Median preoptic nucleus (mPOA)
• Ventrolateral preoptic nucleus (VLPO)
• Both mPOA and VLPO have gabaergic neurons
  projecting to activational networks and have
  sleep-active and wake-active neurons. Their
  proposed role is one of inhibition of the
  activating networks.

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BIOCHEMICAL REGULATION OF SLEEP

• The transfer of CSF from a sleep-deprived animal
  to a normal recipient animal induces sleep in the
  recipient.
• Expression of many genes is sleep-wake dependent
• A brain molecular network regulates sleep
• The molecules affect each other and interact with
  neurons to change firing patterns of neuronal
  networks

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IDENTIFICATION OF A SLEEP REGULATORY SUBSTANCE

• Induces sleep
• Inhibition of it reduces sleep
• Levels vary in brain with sleep propensity
• Acts on known sleep regulatory circuits
• Varies with pathology

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PROCESS SSLEEP REGULATORY SUBSTANCES
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NREMS after ip injected GHRH in mice
Normal (heterozygous) mice

Mice with GHRH-R deficiency (lit/lit mice)
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NREMS response to influenza virus is deficient in
the lit/lit mouse
Heterozygous
Lit/lit
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HUMORAL MECHANISMS OF SLEEP IMPLICATIONS FOR
SLEEP FUNCTION
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• Sleep is a fundamental property of groups of
  highly interconnected neurons (neuronal groups)
• Homeostatic sleep mechanisms can not be separated
  from sleep function
• Sleep function deals with neural connectivity
• The need for sleep is derived from the advantages
  of a flexible microcircuitry

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SLEEP MECHANISMS

• There is activity-dependent (A-D) production of
  sleep regulatory substances (SRS)
• These A-D SRSs act in autocrine, juxtacrine and
  paracrine fashions to change electrical
  properties of nearby neurons thereby altering
  input-output relationships (i-o)
• Altered i-o relationships for a collection of
  highly interconnected neurons (neuronal group) is
  an altered state

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SLEEP FUNCTION

• The A-D SRSs are also growth factors that provide
  for the structural basis of synaptic efficacy and
  neural connectivity
• The altered i-o relationships provide stimulation
  for, and thereby preservation of, synapses not
  stimulated by the prior environmental input

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Sleep is a property of neuronal groups
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Sleep is not a whole brain phenomenon

• Dolphin sleep is unilateral.
• Sleep intensity (EEG slow wave power) is greater
  in areas differentially activated during prior
  waking.
• Application of SRSs onto the cortex induces EEG
  asymmetries.
• Unilateral inhibition of a SRS by application of
  SRS inhibitors to the cortex attenuates
  sleepdeprivation induced EEG slow wave power
  unilaterally.
• Clinical observations suggest that patients can
  be asleep and awake simultaneously.

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Evoked Response Potential (P1-N1) varies with
state, time and side
David Rector, 2003
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Isolated cortical islands lacking thalamic inputs
exhibit oscillating field potentials.

• Implication
• Intrinsic activity of the cortex induces EEG slow
  waves

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Regardless of what part of the brain is lesioned,
if the animal/human survives, it sleeps.

• Implications
• Sleep is very robust
• No specific area is necessary for sleep
• Sleep is an intrinsic property of surviving
  viable groups of neurons
• Sleep is self organizing

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SLEEP FUNCTION DEALS WITH NEURAL CONNECTIVITY
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SRSs with activity-dependent production

• NGF BDNF IL1 TNF NO adenosine

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SRSs implicated in synaptic plasticity

• NGF BDNF IL1 TNF NO PRL VIP PACAP
  adenosine prostaglandins somatotropic axis
  EGF FGF GDNF NT3 NT4 IL2 IL6 IL8 IL18
  IFN gamma TGF beta PAF estrogen

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The need for sleep is derived from the advantages
of a flexible microcircuitry
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While asleep one

• Does not eat, drink, reproduce or socialize.
• Is subject to predation
• Implication
• Sleep has an important adaptive value.

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Experience modifies the microcircuitry of the
brain
Yet

• Many aspects of behavior and physiological
• regulation are genetically determined
• Learning-induced changes in the microcircuitry
• need to be preserved

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ACTIVITY-DEPENDENT SYNAPTIC EFFICACY

• Hebbian positive and negative (waking)
• Synaptic Scaling a regulatory mechanism to keep
  Hebbian connectivity in check (sleep)

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• Sleep is not only for neural
• connectivity but it is because of it
• Sleep need is derived from the flexible
• microcircuitry, its use-dependent rules,
• and the necessity of preserving those
• synaptic networks responsible for
• innate and learned memories

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Sleep-associated unconsciousness

• Is needed because output activity of
  SRS-modulated neuronal groups is incongruent with
  environmental input.
• Has its origins in the mechanisms of neuronal
  group state shifts.
• Is the consequence of the collective properties
  of neuronal group state.

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