Sleep

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Sleep
Why do we sleep?
• Sleep is a basic requirement for normal brain function.
• Lack of sleep 
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Mental fatigue,
poor decision-making,
shortened attention span,
higher anxiety,
impaired memory,
impaired learning,
a grouchy mood
a heightened risk of migraine and epileptic attacks
lack of sleep can more than double the risk of death from
cardiovascular disease
• depriving mice of sleep increased cancer growth and
dampened the immune system's ability to control
cancers
• Sleep deprivation hinders the healing of burns on rats
Total sleep loss
• Chronic and complete insomnia ultimately leads to death in
humans, rats, and flies alike.
• Rats totally sleep-deprived died within 11-32 days (faster than
food-deprived rats).
• All sleep deprived rats showed a debilitated appearance,
lesions on their tails and paws, and weight loss in spite of
increased food intake.
• In humans, Fatal familial insomnia: the average survival span
is 18 months
The disease has four stages:
1. The person has increasing insomnia, resulting in panic attacks,
paranoia, and phobias.
2. Hallucinations and panic attacks
3. Complete inability to sleep is followed by rapid loss of weight
4. Dementia, after which death follows.
• Sleep is universal among vertebrates and has been found
in invertebrates
• The total number of hours of daily sleep varies from as
much as 20 hours in small animals like bats to as little as
3 to 4 hours in big animals such as giraffes and elephants
• Faster metabolism  longer sleep duration
• Smaller animals have faster metabolism  longer sleep
• During sleep,
waste
products of
brain
metabolism
are removed
from the
interstitial
space among
brain cells
where they
accumulate.
• In waking, CSF flow is restricted to the brain surface—
but expands deep into the tissue during both slow-wave
sleep. The consequence is remarkable: The flow of CSF
through the interstitial space is increased 20-fold in slow
sleep compared to flow of CSF during waking.
Conclusions:
• Main function of sleep is maintenance.
• Metabolism is a dirty process.
• During sleep, waste products of brain metabolism
are removed from the interstitial space.
• During sleep there is also increased production of
oligodendrocytes that repair axons.
Sleep and memory
Researchers trained mice in a new skill - walking on top of a rotating rod
sleeping mice formed significantly more new connections between neurons
• Sleep is good for memory consolidation (conversion of memory into
permanent memory).
• Memory improvement is most dramatic for procedural memory (riding
a bike, skating, playing the piano).
• Even a short nap can really improve memory.
Sleep and memory
• Important memories are consolidated.
• Unimportant memory traces are deleted:
• That includes most memories.
• Synapses encoding that memory are
disintegrated,
• synaptic spines are retracted.
• It is very important to forget!
• Sleep is important for both for
• memory consolidation and
• preparing the brain for new learning.
Sleep stages
Non-REM sleep = slow wave sleep = deep sleep
• Sleep is highly structured
• 1 complete cycle (Non-REM stage and REM stage) = 1.5hours
• The night sleep starts with you quickly falling down into deep sleep
Slow-wave (deep, non-REM) sleep
• During deep sleep Loud noise,
smells are unlikely to wake you up
• Many neurons are synchronized
(firing together in that training of
neuronal ensembles by
hippocampus) so we see high
amplitude EEG with low
frequency ~1Hz (Delta waves).
• Muscles are not paralyzed, so
sleep-walking, sleep-talking, and
bedwetting occur in this stage.
• If you wake up from slow wave
sleep you feel dreadful.
• When people are woken from
slow-wave sleep, they usually do
NOT report dreams.
• During slow-wave sleep CSF flow expands deep into the
brain tissue. The consequence is remarkable: The flow
of CSF through the interstitial space is increased 20-fold
in slow sleep compared to flow of CSF during waking.
REM (Rapid Eye Movement / Paradoxical sleep)
• EEG readings are irregular in frequency
and low in amplitude—similar to those
observed in awake individuals.
• When people are woken from REM
sleep, they usually report vivid dreams.
• Eyes move rapidly under closed lids,
breathing becomes irregular and heart
rate increases.
• Motor neurons are completely inhibited
(so that you don’t enact your dreams;
common experience: nightmare want
to run  but cannot move muscles).
• Horses and many other animals can be
in deep sleep while standing, but must
necessarily lie down for REM sleep
because of inhibition of tonic muscles).
• People even lose some of the ability to
regulate their body temperature during
REM
What causes one to fall into sleep?
• Circulating hormones?
• Brain nuclei?
• Accumulation of Adenosine?
• Melatonin - a hormone
that anticipates the
daily onset of darkness
• Produced in the pineal
gland.
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In these sisters: One brain can be
asleep while the other brain may be
awake  brain nuclei
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The Hensel girls are the rarest form of
conjoined twins, the result of a single
fertilised egg which failed to separate
properly in the womb.
They have two spines (which join at the
pelvis), two hearts, two oesophagi, two
stomachs, three kidneys, two gall
bladders, four lungs (two of which are
joined), one liver, one ribcage, a shared
circulatory system and partially shared
nervous systems.
From the waist down, all organs,
including the intestine, bladder and
reproductive organs, are shared.
While they were born with three arms,
one was removed surgically.
Although Brittany - the left twin - can't
feel anything on the right side of the
body and Abigail - the right twin - can't
feel anything on her left, instinctively
their limbs move as if co-ordinated by
one person, even when typing e-mails on
the computer.
It is rare for twins conjoined the way that
Abby and Brittany are to survive into
adulthood, but despite this they are in
good health, without heart defects or
organ failure.
Adenosine / Caffeine
• Local control of alertness level
• As neurons fire, they use ATP and produce adenosine.
• With a continued wakeful state, over time adenosine
from ATP accumulates in synapses.
• Adenosine activates adenosine receptors that increase
drowsiness.
• The caffeine molecule is a competitive inhibitor of
adenosine.
• As a result, caffeine temporarily prevents or relieves
drowsiness, and thus maintains or restores alertness.
Central control of
alertness level:
Reticular formation
• Reticular formation
in brainstem is
important for setting
alertness level
• The reticular formation has projections to the thalamus and the
cerebral cortex that allow it to exert control over which sensory
signals reach the cerebrum and come to our conscious attention.
• It plays a central role in states of consciousness like alertness and
sleep (pacemaker for slow sleep Delta waves).
• Injury to the reticular formation can result in irreversible coma.
Neuropeptide Orexin – the ultimate flip
flop switch between sleep and wakefulness
• Orexin is neurotransmitter released in hypothalamus by
a small nucleus that consist of 10,000 to 20,000
neurons.
• Orexin strongly excites various brain nuclei important in
wakefulness.
• Orexin-producing cells integrate metabolic, circadian
and sleep debt influences to determine whether an
individual should be asleep or awake.
• Central administration of orexin strongly promotes
wakefulness, increases body temperature and
locomotion, and elicits a strong increase in energy
expenditure.
• Insomniacs taking an orexin blocker, suvorexant, fell
asleep faster and slept an hour longer.
“Orexin flip flop
switch”
System that
promotes sleep
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System that
promotes wake
The most common form of narcolepsy, in which
the sufferer briefly loses muscle tone
(cataplexy), is caused by a lack of orexin in the
brain due to destruction of the cells that
produce it.
• Narcolepsy results in excessive daytime
sleepiness, inability to consolidate wakefulness
in the day (and sleep at night), and cataplexy,
which is the loss of muscle tone in response to
strong, usually positive, emotions.
• One woman in England has been declared dead
three times and once woke up in morgue.
• Example: http://youtu.be/qVu-IcLoZtU
What causes one to fall into sleep?
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Circulating hormones? – Yes. E.g. melatonin
Brain nuclei? – Yes. E.g. Reticular formation
Accumulation of Adenosine? – Yes.
Conclusion: all of the above with the Orexin
switch
Circadian rhythm
• Circadian rhythm = 25.3h
• This might explain why it is
easier to travel west,
compared to jetlag problems
associated with traveling east.
• Optimal travel: go west and
cross one time zone a day 
you will never feel a jetlag
• Photosensitive cells in the
retina control the 24-hour
cycle of several subcortical
nuclei, that, in turn, control
the pineal gland.
• Interestingly: most organs
have their own 24-hours
clocks
• Melatonin anticipates the
daily onset of darkness –
central control of local
circadian rhythms
• Melatonin is safe aid for
falling into sleep. Jetlag –
take melatonin to help you
fall asleep
Disorders of sleep
• Slow-wave deep sleep
– Sleep talking
– Bedwetting
– Sleepwalking
• Can be triggered by stress, alcohol, sleep deprivation
• Individuals engage in complex behavior while sleepwalking
• REM Sleep Behavior Disorder
– Muscles are NOT inhibited  physical activity during REM sleep:
• Dream about diving and dive from bed
• Dream about playing football and tackle a bed partner
– Often associated with a neurological disorder or a tumor
• REM Sleep paralysis:
– Muscles are inhibited but the brain is almost awake
• Some people think they are abducted by aliens and strapped down for probing.
• Narcolepsy
– Narcolepsy results in excessive daytime sleepiness, inability to
consolidate wakefulness in the day (and sleep at night), and cataplexy
when individual suddenly falls asleep (into REM sleep, with all their
skeletal muscles paralyzed)
Sleep apnea
• is a sleep disorder characterized
by pauses in breathing during sleep.
• Each pause in breathing for several seconds can wake
you up.
• Result: lack of normal continuous sleep  sleepiness
during the day, lack of attention, spontaneous nap.
• Common in middle aged overweight people
(prevalence in men over 25%), very high prevalence in
truck drivers.
Micro-sleep
• Sleep-deprived humans will fall in micro-sleep.
One part of the brain falls asleep, while the rest
of the brain is active.
• While driving you might miss sensory
information from the red light or a car in front of
you, even when the rest of the brain (motor
cortex) is not sleeping and is able to drive the
car.
Short daytime naps
• Consist of deep slow wave
sleep,
• In the early phases of deep
sleep people report vivid
hallucinations that are shorter,
more static and more
thoughtlike than the dreams
that occur during REM sleep.
• These visions are typically more
like snapshots than narratives
and do not include a self.
• Even a short nap can really
improve memory
• Stop
REM is essential
Barbituric
acid, the
basic
structure of
all
barbiturates
The core structure of
benzodiazepines.
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During 1970s the main hypnotic (from Greek Hypnos =sleep: drugs that induce sleep) drugs
were barbiturates
Prescribed to treat insomnia, barbiturates are agonists of ionotropic GABA receptor
Ethanol, barbiturates, benzodiazepines all increase conductance of ionotropic GABA receptor
Barbiturates significantly reduce the amount of REM sleep 
Abrupt withdrawal of barbiturates results in REM rebound in terrible nightmares
Barbiturates have now largely been replaced by safer benzodiazepines (triazolam, flurazepam)
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