Chap 19' Rhythms of the brain

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Chap 19. Rhythms of the brain EEG
electroencephalogram 1875 Dr. Richard Caton on
dog and rabbit brains 1929 Dr. Hans Berger.
First description of human EEG Waking and
sleeping EEGs are different Main application
epilepsy and sleep research Figure 19.2
Standard position Figure 19.3 Generation of
electrical fields Figure 19.3 Synchronous
firing Figure 19.4 A normal EEG
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EEG rhythms Beta gt14 Hz. Active cortex Alpha
8-13 Hz. Quiet waking state Theta 4-7 Hz. Some
sleep Delta lt4 Hz. Deep sleep In general, High
freq rhythms alertness, waking and dreaming Low
freq rhythms Nondreaming sleep, pathological
state of coma
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The generation of synchronous rhythms Hypothesis 1
) Pacemaker 2) Collective behavior Or both
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A Two-neuron oscillator can generate rhythms
One neuron oscillator can generate rhythems
(Figure 19.8)
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Rhythms in the thalamus drive rhythms in the
cerebral cortex (pacemaker) But some cortical
neurons generate rhythms by collective
interactions
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Functions of brain rhythms 1. A way to
disconnecting the cortex from sensory inputs. 2.
A way to construct a perception. 30-80 Hz
cortical rhythms Imagine you are trying to catch
a baseball (baseballness) Criticisms -
Intriguing but unimportant by-products -
Unfortunate but unavoidable consequences -
Unwanted but tolerated by necessity Conclusion -
Convenient window on the functional states of
the brain - Cant tell what a person is thinking,
but can tell whether a person is thinking
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The seizures of epilepsy Seizure the most
extreme form of synchronous brain
activity Generalized seizure excitation of the
entire cerebral cortex of both
hemispheres Partial seizure a circumscribed area
of the cortex Epilepsy a repeated seizures (a
symptom rather than a disease) Causes upset of
the delicate balance Seizure-causing
conditions Withdrawal of alcohol or
barbiturates GABA receptor antagonists Anticonvul
sants GABA agonists or Na channel blockers
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Generalized seizure All cortical neurons are
involved Consciousness lost Tonic, clonic
(rhythmic), or tonic/clonic Absence
seizure Occur during childhood Generalized 3 Hz
EEG (ltless than 30 sec) Consciousness
lost Subtle fluttering of the eyelids or a
twitching of the mouth Partial seizure Small
area of cortex involved Motor clonic movement
of part of a limb Hughlings Jackson (1800s)
progression of seizure- related movement
across the body?somatotopic map Sensory
abnormal sensations, or aura Odd smell or
sparkling lights Deja vu the feeling that
something happened before Hallucination
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Crunelli and Leresche Childhood absence
epilepsy genes, channels, neurons and
networks.Nat Rev Neurosci. 2002
May3(5)371-82. Only two mutations have been
discovered in people with childhood asbsence
epilepsy (CAE) and additional neurological
disorders these affect the gene GABRG2, which
encodes a GABA (g-aminobutyric acid) receptor
subunit, and CACNA1A, which codes for a subtype
of Ca2 channel.
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The functional states of the brain Non-REM
sleep an idling brain in a movable body REM
sleep an active, hallucinating brain in a
paralyzed body (exception REM) See Table
19.1
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Sleep cycle Figure 19.10 -90 min cycle -Stage
1, 2, 3, 4, 3, 2, 1 and REM -REM sleep only after
the non-REM sleep - Non-REM sleep (75 of time)
and REM (25) -General reduction in the duration
of non-REM sleep -General increase in the
duration of REM sleep -Average length of 7.5 hr
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Somnambulism (sleepwalking) -18 of the
population, 16.7 at age 11 to 12 years of age,
boys are more prone to.. - Occurs during the
first stage 4 non-REM sleep - Often moves around
the room/house/outside with open eyes -
Incomprehensible mutterings are usually the case
- In some sleepwalking cases, the child may
urinate in an inappropriate place - The child
may use obscene words that would not be used when
awake - Can avoid objects and climb stairs -
Cognitive function and judgment severely
impaired - The child may fall and injure
themselves - Difficult to awaken?Guide hand back
to bed - No memory of the incident
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• Somniloquy Sleep talking
• Sleep terror
• - Occurs during the first stage 3 or 4 non-REM
  sleep
• - Most common in children (5-7 yrs)
• - Scream in the middle of the night, shrieking
  and flailing
• - Bright and cheerful in the morning
• - No recollection
• Nightmare
• Vivid and complex dream
• Uncontrollable panic
• Occurs during REM sleep (cf. sleep terror)

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• Sleep in the bottlenose dolphin
• Total of 12 hr per night
• A new meaning to half asleep
• - Left sleep (2h), right (2h) and awake (1h)

2 hr
2 hr
1 hr
Microsleep in Indus dolphin 4-6 sec each, adds
up to 7 hrs a day
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Why do we sleep? Theories 1) Restoration To
rest? Quiet rest is not a substitute for
sleep To recover? No identified physiological
process restored by sleep 2) Adaptation A
stroll in the moonlight is far too risky for a
squirrel living in owl and fox territory
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The longest all-nighter - In 1963 - Randy
Gardner (17-years-old high school student) - No
sleep for 11 days (264 hours, world record for
continuous wakefulness) - Day 2 irritable,
nauseated, trouble remembering, could not even
watch television - Day 4 mild delusion,
overwhelming fatigue - Day 7 Tremor, slurred
speech, no alpha rhythms - Day 10 beat one of
the observers, but gave a coherent account of
himself at a national press conference After the
ordeal, 15hr straight sleep, awake for 23 hrs,
sleep for 10.5 hr and normal No lasting harmful
effects in contrast to rats
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• Sleep-deprived rats die!
• -Continuous sleep deprivation for about two weeks
  or more ?death (Allan Rechtschaffen sleep
  laboratory, Univ of Chicago).
• - Two animals lived on a rotating disc over a
  pool of water, separated by a fixed wall.
• Brainwaves were recorded continuously into a
  computer program that almost instantaneously
  recognized the onset of sleep.
• When the experimental rat fell asleep, the disc
  was rotated to keep it awake by bumping it
  against the wall and threatening to push the
  animal into the water.
• The cause of death was not proven but was
  associated with whole body hypermetabolism.

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• Drummond et al.
• Altered brain response to verbal learning
  following sleep deprivation.
• Nature. 2000 Feb 10403(6770)655-7.
• - 35 hours of sleep deprivation and fMRI
• Prefrontal cortex and parietal lobe were more
  active.
• The PFC was more responsive during verbal
  learning.
• Although sleep deprivation significantly impaired
  free recall compared with the rested state,
• Better free recall in sleep-deprived subjects was
  associated with greater parietal lobe activation.
  
• - Dynamic and compensatory changes

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Functions of dreaming and REM sleep REM rebound
in REM-sleep deprived people No psychological
harm in REM-sleep deprived people Sigmund
Freud - Disguised wish-fulfillment - Unconscious
way to express our sexual and aggressive
fantasies Hobson and McCarley -
Activation-Synthesis hypothesis - Random
discharges of pontine neurons?thalamus?Cortex -
The cortex try to synthesize a sensible story
out of disparate images?bizarre and nonsensical
dream
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• REM sleep and Memory
• - Dr. Avi Karni
• - Training Identification of the orientation of
  a small line in a very short period of time
• - Enhanced performance after overnight sleep
• - No enhancement when REM-sleep, but not non-REM
  sleep, was deprived
• - Sleep-learning (listening to a tape..)
• No scientific background
• Sleep is a profoundly amnesic state

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Sleep-dependent learning a nap is as good as a
night.Mednick S, Nakayama K, Stickgold R. Nat
Neurosci. 2003 Jul6(7)697-8.
Figure 1 Same-day improvement in no-nap, 60-min
nap and 90-min nap groups, with and without REM
and SWS.
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• Neural mechanisms of sleep
• Wakefulness
• Increased activity of diffuse modulatory system
  (NE, 5-HT and Ach).
• Some cholinergic neurons enhance critical REM
  events.
• Falling asleep
• - Decreased modulatory activity
• - Ach, sometimes, have an opposite effect.

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Gallopin et al. Identification of sleep-promoting
neurons in vitro Nature. 2000 Apr
27404(6781)992-5. - Located in the preoptic
area and more specifically, in the ventrolateral
preoptic nucleus (VLPO). - Two-thirds of the
VLPO neurons are multipolar triangular cells that
show a low-threshold spike matches that of
cells active during sleep in the same region. -
NT GABA by RT-PCR - Inhibited by NE, Ach and
5-HT, but not by histamine.
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• REM-Wake (PET scan)
• Primary visual cortex equally active
  (internally generated images)
• Extrastriate cortex and limbic system more
  active (emotions)
• Frontal lobes less active (less high-level
  integration)
• REM-SWS (non-REM sleep) less active primary
  visual cortex,
• and extrastriate cortex is more active.

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Control of onset and offset of REM by brain stem
neurons
Ach
NE, 5-HT
REM-on cells Cholinergic neurons in the
pons REM-off cells Adrenergic and serotonergic
neurons in the LC and raphe nuclei
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REM sleep brain disorder - Normal REM sleep
spinal motor neurons inhibited (a hallucinating
brain in a paralyzed body!) - Adaptive mechanisms
to protect ourselves - Patients act out their
dreams - A man, who was in a football game in his
dream, tackled his bedroom bureau - A man, who
was defending his wife from attack, was actually
beating her in her bed - Disruption of the brain
stem mediates the REM disorder.
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Narcolepsy -a bizarre disabling disturbance of
sleep and waking A form of epilepsy -Around 1 in
2,000 adults -Appears between the ages of 15 and
30 years, and involves four characteristic
symptoms 1. Excessive Daytime Sleepiness 2.
Cataplexy Muscular paralysis Consciousness is
remained Collapse into a state similar to REM
sleep Brought on by strong emotional expression
(laughter, tears, surprise and sexual arousal)
Last less than a minute
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• 3. Sleep paralysis
• Loss of muscle control during the transition
  between sleep and waking
• 4. Hypnogagic hallucination
• Graphic dream, often frightening
• Accompany sleep onset
• Dreams flow smoothly with real events
• Narcolepsy and Orexin
• - Narcolepsy in orexin receptor mutation
• - Emmanuel Mignot (Stanford Univ) isolated the
  gene for canine narcolepsy using positional
  cloning
• - Masashi Yanagisawa (Univ. Texas SWM) orexin
  (ligand) KO mice are also narcoleptic.
• HypocretinNat Rev Neurosci. 2003
  Aug4(8)649-61.

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• Neural circuits for Narcolepsy
• - Ach
• Ach agonist can induce REM sleep
• A significantly low dose of Ach ago can induce
  muscle atonia in narcolepsy patient
• - DA
• An increased activity of VTA induce cataplexy
  in narcoleptic animals, but not in normal animals
• Treatments
• Frequent naps
• Amphetamine
• Modafinil (Mechanisms not well known)
• Tricyclic antidepressant (REM-suppressant effects)

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• Sleep-promoting effects of adenosine
• - Caffeine and theophylline antagonists of
  adenosine receptors
• - Administration of adenosine or AdR agonists
  increases sleep
• - Ad level progressively increases during
  sustained waking state
• - Molecular mechanisms inhibition of diffuse
  modulatory systems for Ach, NE and 5-HT
• A hypothesis (for Why do we need sleep)
• Brain activity ? glycogen depletion in astrocyte
  ? increased release of adenosine ? sleep ?
  replenishment of glycogen ?
• Ad decrease ? wake up!

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• Circadian rhythm
• Circa around
• Dies day
• Dr. Jen Jacques dOrtous de Mairan
• - Mimosa continued to raise and lower leaves in a
  dark closet
• Conclusion The plant was still somehow sensing
  the suns movement
• Dr. Augustine de Candolle
• Found 22 hr rhythm in a similar plant
• Likely to have an internal biological clock

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• - Zeitgebers (time givers)
• - Free run
• (25 hr cycle in human)
• - Entraining
• - Desynchronization of behavioral clock and
  physiological clock (implication?)
• Bright light is the best cure for jet lag
• Triangle the point of the days lowest body temp

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• SCN (suprachiasmatic nucleus)
• - A brain clock
• - Tiny vol. 0.3 mm2
• Neurons are among the smallest
• Elec. Stimulation? shifts in the circadian
  rhythm
• Removal ? elimination of circadian rhythm in
  physical activity, sleep and waking, and feeding
  and drinking.

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SCN lesion in squirrel monkey
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Mutant hamster clocks Golden hamster
perfectionists of circadian timing Normal 24
hr One tau mutation (dominant) 22 hr Two tau
mutations 20 hr SCN ablation circadian rhythms
entirely lost SCN transplantation rhythms
back SCN (22 hr) transplantation 22 hr rhythms
! SCN (20 hr) 20 hr rhythms?hard to get
entrained to normal 24 hr light-dark
cycle?activity cycle shifts through. Elderly
people shorting of rhythms? overwhelming
sleepiness early evening and waking up at
300-400 am
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What makes teens like to sleep late? The
circadian rhythm in humans triggers the pineal
gland (located at the base of your brain) to
discharge a surge of hormone called melatonin.
Melatonin makes people drowsy as the evening
winds down. The pineal gland slows its production
of melatonin in early morning just in time for
you to wake up. Puberty causes a circadian phase
delay, or a shift of as much as two hours in the
daily schedule of sleep and wakefulness. For
three to five years after the onset of puberty,
teenagers experience a kind of ongoing case of
biological jet lag. Researchers still don't
understand why.
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Inputs and outputs of the SCN Input
Light Light detector Not rod or cone
cells! Pathway Retinohypothalamic
pathway Receptive field Large nonselective,
Respond to luminance, but not to
orientation/motion Mysterious photoreceptor
(cryptochrome-containing?) Output To other
hypothalamic regions, midbrain,
diencephalon Neurotransmitters GABA (primary)
and vasopressin
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Melanopsin-positive and intrinsically
photosensitive RGC (one of the 10 breakthroughs
that Science announced at the end of 2002
Science. 2003 Oct 17302(5644)408-11. ) A
photopigment-like molecule, melanopsin,
located in a specific population of the RGCs,
is responsible for resetting (entraining) the
biological clock.
Fig. 1. The third eye.
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Circadian rhythms of the isolated SCN neurons
Action potentials not required for the intrinsic
rhythms (not blocked by TTX)
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Clock genes Drosophila Period (per) Timeless
(tim) Clock Negative feedback loop
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Panda et al. Circadian rhythms from flies to
human Nature 417, 329 - 335 (16 May 2002)
Seymour Benzer
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Figure 2 Schematic diagrams showing anatomic
features of Drosophila and rodent central
oscillator.
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Fig. 3. Drosophila and mammalian circadian clock.

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A clockwork web circadian timing in brain and
periphery, in health and disease.Hastings MH,
Reddy AB, Maywood ES. Nat Rev Neurosci. 2003
Aug4(8)649-61.
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McDonal et al. Microarray Analysis and
Organization of Circadian Gene Expression in
Drosophila. Cell 2001 107
567-578. -Coupled with an analysis of clock
mutant (Clk) flies, a cell line designed to
identify direct targets of the CLOCK (CLK)
transcription factor and differential
display. -134 cycling genes?a wide range of
diverse processes. - Gene clusters, for
transcriptional coregulation. - All oscillating
gene expression is under clk control - An even
larger number of genes is affected in Clk flies,
suggesting that clk affects other genetic
networks. - As we identified a small number of
direct target genes, the data suggest that most
of the circadian gene network is indirectly
regulated by clk. ?
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The known major Drosophila cycling genes (per,
tim, vrille (vri), clk, cryptochrome (cry), and
takeout) were included in this list.
Fig 1.The mRNA Curves for Known Cycling Circadian
Genes
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• Panda et al.
• Coordinated transcription of key pathways in the
  mouse by the circadian clock.Cell. 2002 May
  3109(3)307-20.
• 1 The Genomics Institute of the Novartis Research
  Foundation, San Diego
• - Gene expression profiling to identify cycling
  transcripts in the SCN and in the liver.
• Approximately 650 cycling transcripts, specific
  to either the SCN or the liver.
• a relatively small number of output genes are
  directly regulated by core oscillator components
• Major processes regulated by the SCN and liver
  were found to be under circadian regulation.
• Rate-limiting steps in these various pathways
  were key sites of circadian control

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Fig 1.Circadianly Regulated Genes in the SCN and
Liver
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Fig 4. Circadian Expression of Vesicle
Trafficking Components and of Kcnma1 in the SCN
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Figure 3. Circadian Regulation of Components of
Protein Turnover in the SCN Genes involved in
protein folding and proteasome-mediated protein
degradation Figure 5. Circadian Regulation of
Components of Oxidative Phosphorylation in the
SCN Figure 6. Circadian Regulation of Components
of Energy Metabolism in Liver Figure 7.
Circadian Regulation of Cholesterol Metabolism in
Liver