1. 4B. Sleep Why do we sleep? Videos:
Narcolepsy:
Dog acting out a dream and runs into a wall:
It is likely that sleep evolved to fulfill some primeval function and took on multiple functions over time (analogous to the larynx, which controls the passage of food and air, but descended over time to develop speech capabilities).

2. Why do we sleep?
Sleep is a basic requirement for normal brain function:
Lack of sleep 
Mental fatigue: During Navy SEAL sleep deprivation training Stew Smith reports: after about 3 days hallucinations started to set in. Smith recalls mistaking an airplane for a flying horse, perceiving a bridge as a giant Pez dispenser, and seeing a muscular body builder where there was in fact a fire hydrant.
poor decision-making: in tests, those who have stayed awake for 24 hours perform similarly to those with a blood alcohol content of 0.1% (=3 drinks) on many mental and physical tasks.
shortened attention span
higher anxiety
impaired memory
impaired learning
a grouchy mood
a heightened risk of migraine and epileptic attacks
can more than double the risk of death from cardiovascular disease.
increased cancer growth and dampened the immune system's ability to control cancers (demonstrated in mice).
hinders the healing of wounds and burns (demonstrated in rats).

3. Total sleep loss
Chronic and complete insomnia ultimately leads to death in humans, rats, and flies alike.
Rats totally sleep-deprived died within 4 weeks (faster than food-deprived rats).
all sleep deprived rats showed a debilitated appearance,
lesions on their tails and paws
weight loss in spite of increased food intake
gradual reduction in core body temperature
buildup of cortisol, a natural immunosuppressant  failing immune system colonization of the body by normally symbiotic bacteria that usually reside only in the large intestine.
In humans,
Fatal familial insomnia: the average survival span is 18 months
The disease has four stages:
The person has increasing insomnia, resulting in panic attacks, paranoia, and phobias.
Hallucinations and panic attacks
Complete inability to sleep is followed by rapid loss of weight
Dementia, after which death follows.
Sleep deprivation in China in the 19th century; Nazi death camp experiments  3-4 weeks of sleep deprivation kill humans
4 weeks without food will not kill you, but 4 weeks without sleep will!
Everson, C. A., Bergmann, B. M., & Rechtschaffen, A. (1989). Sleep deprivation in the rat: III. Total sleep deprivation.  Sleep, 12(1),

4. During sleep, waste products of brain metabolism are removed from the interstitial space among brain cells where they accumulate.
Sleep, therefore, might be required for potentially toxic metabolites— the very results of a working brain—to be cleared from the tissue. The interstitial space between cells in a tissue is an underappreciated component of the nervous system, considering that it amounts to ~20% of the total volume of the living brain. In the absence of a lymphatic system in the brain, the interstitial space performs its duties, removing waste products that brain cells secrete. These metabolites are flushed away through the interstitial space by the flow of cerebrospinal fluid (CSF), which is filtered from blood and pumped into the brain by the choroid plexus at the ventricles, seeps through the interstitial space among brain cells, and is eventually pumped back into the blood stream at the meninges that surround the brain.
Same happens during anesthesia.
In waking, CSF flow is restricted to the brain surface— but expands deep into the tissue during slow-wave sleep.
The consequence is remarkable: The flow of CSF through the interstitial space is increased 20-fold in slow-wave sleep compared to flow of CSF during waking.

5. Glymphatic System
Until recently, the prevailing view was that the brain recycles wastes on its own - WRONG.
Beta-amyloid and other wastes are not recycled, but cleared by the glymphatic system.
The flow of glymphatic fluid increases during sleep because the space between the cells expands, which helps to push fluid through the brain tissue.
The brain removes unwanted proteins, sweeping them out for later degradation by the liver.
Brain drain. SciAm 2016 March.
The brain's blood vessels are surrounded by what are called perivascular spaces. They are doughnut-shaped tunnels that surround every vessel. The inner wall of each space is made of the surface of vascular cells, mostly endothelial cells and smooth muscle cells. But the outer wall is unique to the brain and spinal cord and consists of extensions branching out from a specialized cell type called the astrocyte.
This perivascular space constitute a neural lymphatic system.
Along with our laboratory members Jeff Iliff and Rashid Deane, we went on to confirm this hypothesis. Using chemical dyes that stained the fluid, combined with microscopic techniques that allowed us to image deep inside live brain tissue, we could directly observe that the pumping of blood propelled large quantities of CSF into the perivascular space surrounding arteries. Using astrocytes as conduits, the CSF then moved through the brain tissue, where it left the astrocytes and picked up discarded proteins.
The fluids exited the brain through the perivascular space that surrounded small veins draining the brain, and these veins in turn merged into larger ones that continued into the neck. The waste liquids went on to enter the lymph system, from which they flowed back into the general blood circulation. They combined there with protein waste products from other organs that were ultimately destined for filtering by the kidneys or processing by the liver.
Even healthy individuals who are forced to stay awake exhibit symptoms more typical of neurological disease and mental illness—poor concentration, memory lapses, fatigue, irritability, and emotional ups and downs. Profound sleep deprivation may produce confusion and hallucinations, potentially leading to epileptic seizures and even death. Indeed, lab animals may die when deprived of sleep for as little as several days, and humans are no more resilient. In humans, fatal familial insomnia is an inherited disease that causes patients to sleep progressively less until they die, usually within 18 months of diagnosis.
Norepinephrine appeared to regulate the volume of the interstitial area and consequently the pace of glymphatic flow. Levels of norepinephrine rose when mice were awake and were scarce during sleep, implying that transient, sleep-related dips in norepinephrine availability led to enhanced glymphatic flow.
_____________________________
Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration | Nature Neuroscience:

6. Faster metabolism  longer sleep duration
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
Sleep is universal among vertebrates, has been found in invertebrates, and even in jellyfish and warms.
Hypothesis: any animal with a nervous system requires sleep.
Because CSF perfusion of the interstitial space is limited to the surface of the brain during waking, and brain volume increases faster than brain surface area, larger brains should have a relatively larger volume of interstitial space to “buffer” the accumulation of sleep-driving molecules, and thus might be able to withstand much longer periods of waking before the inevitable switch to the waste-clearing state of sleep occurs.
African elephant: Wild African elephants sleep for the shortest time of any mammal, according to a study.
Scientists tracked two elephants in Botswana to find out more about the animals' natural sleep patterns.
Elephants in zoos sleep for four to six hours a day, but in their natural surroundings the elephants rested for only two hours, mainly at night.
The elephants, both matriarchs of the herd, sometimes stayed awake for several days.
During this time, they travelled long distances, perhaps to escape lions or poachers.
They only went into rapid eye movement (REM, or dreaming sleep, at least in humans) every three or four days, when they slept lying down rather than on their feet.Prof Paul Manger of the University of the Witwatersrand, South Africa, said this makes elephant sleep unique.
"Elephants are the shortest sleeping mammal - that seems to be related to their large body size," he told BBC News.
"It seems like elephants only dream every three to four days. Given the well-known memory of the elephant this calls into question theories associating REM sleep with memory consolidation.“ --

7. Sleep and memory
Researchers trained mice in a new skill - walking on top of a rotating rod
newly formed dendritic spines (filled arrowheads)
After a post-learning snooze, mouse nerve cells (shown) had more newly formed docking sites for other nerve cells (filled arrowheads).   
Researchers trained mice in a new skill - walking on top of a rotating rod.
They then looked inside the living brain with a microscope to see what happened when the animals were either sleeping or sleep deprived.
Their study showed that sleeping mice formed significantly more new connections between neurons - they were learning more.
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.

8. 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:
memory consolidation and
preparing the brain for new learning.
Information is shifted from hippocampus to neocortex

9. Sleep stages Sleep is highly structured
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 a short dream-filled state and then into slow-wave deep sleep

10. Slow-wave (deep, non-REM) sleep
During deep sleep Loud noise, smells are unlikely to wake you up
Neuronal ensembles are activated into synchronous firing by hippocampus (fire together – wire together  stronger synapses) Many neurons fire in synchrony 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 (stage 3 and 4), they usually do NOT report vivid, bizarre, emotional and story-like dreams. They may still report a thought, that can often be interpreted as a description of a single mental frame, an experience resulting from a discharge of an existing neuronal ensemble.
At the high point of slow oscillations, memory from different parts of brain are replayed synchronously which leads to memory consolidation: Deep-sleep: 2007 “Coordinated memory replay in the visual cortex and hippocampus during sleep”
“Here we studied multicell spiking patterns in both the visual cortex and hippocampus during slow-wave sleep in rats. We found that spiking patterns not only in the cortex but also in the hippocampus were organized into frames, defined as periods of stepwise increase in neuronal population activity. The multicell firing sequences evoked by awake experience were replayed during these frames in both regions. Furthermore, replay events in the sensory cortex and hippocampus were coordinated to reflect the same experience. These results imply simultaneous reactivation of coherent memory traces in the cortex and hippocampus during sleep that may contribute to or reflect the result of the memory consolidation process.”
unlike terrestrial mammals, dolphins, whales, and seals cannot go into a deep sleep. The consequences of falling into a deep sleep for marine mammalian species can be suffocation and drowning. Thus, dolphins, whales, and seals engage in unihemispheric sleep, which allows one brain hemisphere to remain fully functional, while the other goes to sleep. The hemisphere that is asleep, alternates so that both hemispheres can be fully rested. Just like terrestrial mammals, seals that sleep on land fall into a deep sleep and both hemispheres of their brain shut down and are in full sleep mode.

11. Sleep, therefore, might be required for potentially toxic metabolites— the very results of a working brain—to be cleared from the tissue. The interstitial space between cells in a tissue is an underappreciated component of the nervous system, considering that it amounts to ~20% of the total volume of the living. In the absence of a lymphatic system in the brain, the interstitial space performs its duties, removing waste products that brain cells secrete. These metabolites are flushed away through the interstitial space by the flow of cerebrospinal fluid (CSF), which is filtered from blood and pumped into the brain by the choroid plexus at the ventricles, seeps through the interstitial space among brain cells, and is eventually pumped back into the blood stream at the meninges that surround the brain.
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.

12. 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, bizarre, emotional and story-like dreams (80%).
Eyes move rapidly under closed lids, scanning actions in our dreams; 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
-lesions to specific regions (like V4 or V5) selectively affect dream representation of color [Solms M. Dreaming and REM sleep are controlled by different brain mechanisms. Behav Brain Sci 2000;23:843e50.] or movement [Kerr NH, Foulkes D. Right hemispheric mediation of dream visualization: a case study. Cortex 1981;17:603e9.].
-most prefrontal lobotomy patients complain of global cessation of dreaming.[Solms M. Dreaming and REM sleep are controlled by different brain mechanisms. Behav Brain Sci 2000;23:843e50.]
-lesions in the lateral prefrontal cortex (lPFC), which cause waking deficits of self-monitoring and decision-making, have no effect on dreaming .[Solms M. Dreaming and REM sleep are controlled by different brain mechanisms. Behav Brain Sci 2000;23:843e50.]
“Single-neuron activity and eye movements during human REM sleep and awake vision”
After an 8mg dose of galantamine, 42 percent of participants reported having lucid dreams.

13. What causes one to fall into sleep?
Circulating hormonal signal?
A signal form a certain brain nucleus?
Accumulation of metabolites?

14. Melatonin - a hormone that anticipates the daily onset of darkness
Photosensitive cells in the retina detect light and indirectly send signal into the pineal gland that produces melatonin.
Photosensitive cells in the retina detect light and directly signal the suprachiasmatic nucleus (SCN), entraining its rhythm to the 24-hour cycle in nature. Fibers project from the SCN to the paraventricular nuclei (PVN), which relay the circadian signals to the spinal cord and out via the sympathetic system to superior cervical ganglia (SCG), and from there into the pineal gland.
Light absorbed through the skin at the back of the knees also regulates the body's biological clock.  - Refured in 2002

15. If one girl falls asleep, can the other girl stay awake?
Circulating hormones?
If sleep is caused by circulating hormones, both girls have to fall asleep at the same time (since they share the same blood circulation system).
They do not. One girl can sleep while the other is not.

16. 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 coordinated by one person, even when typing s 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.
In these sisters: One brain can be asleep while the other brain may be awake  brain nuclei

17. Neurological control of sleep
The brain's nuclei control states of arousal, sleep, and transitions between these two states
the ascending reticular activating system
the ventrolateral preoptic nucleus,
the widely-projecting system of orexin neurons in the lateral hypothalamus
parafacial zone,
nucleus accumbens core,
lateral hypothalamic melanin-concentrating hormone neurons
supraoptic nucleus in the hypothalamus[1]
[1] 2019 A Common Neuroendocrine Substrate for Diverse General Anesthetics and Sleep
General-anesthesia-activated neurons (AANs) are identified in hypothalamus
•AANs consist mainly of neuroendocrine cells in and near the supraoptic nucleus
•Activation of AANs promotes slow-wave sleep and extends general anesthesia
•Inhibition of AANs shortens general anesthesia and disrupts natural sleep

18. Central control of alertness level: Reticular formation
Reticular formation in the brainstem is important for setting alertness level
2016 A human brain network derived from coma-causing brainstem lesions
The researchers analyzed 36 patients with brainstem lesions, of which 12 led to coma and 24 did not. Mapping the injuries revealed that a small "coma-specific" area of the brainstem - the rostral dorsolateral pontine tegmentum - was significantly associated with coma. Ten out of the 12 coma-inducing brainstem lesions involved this area, while just one of the 24 control lesions did.
which other parts of the brain were connected to these coma-causing lesion? Two areas in the cortex of the brain were significantly connected to the coma-specific region of the brainstem:
in the left, ventral, anterior insula (AI),
in the pregenual anterior cingulate cortex (pACC).
Both regions have been implicated previously in arousal and awareness.
The reticular formation has projections to the thalamus and 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 (it is a pacemaker for slow-wave sleep Delta waves).
Injury to the reticular formation can result in irreversible coma.

19. Ventrolateral preoptic nucleus
Ventrolateral preoptic nucleus neurons are active during sleep and damage to them causes insomnia*
When the ventrolateral preoptic nucleus cells are stimulated one to four times per second, they fire each time they are stimulated, resulting in sleep
If you stimulate them faster than that, they begin to fail to fire and eventually stop firing altogether, resulting in wakefulness
Activating the ventrolateral preoptic nucleus cells caused a fall in body temperature (body temperature dips slightly during sleep)
*2018, Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice

20. Neuropeptide Orexin is the ultimate flip flop switch between sleep and wakefulness
Figure 3. Mechanisms by which orexin system maintains consolidated sleep and wakefulness. The figures represent the functional interaction between orexin neurons, wake-active centers, and sleep-active centers during various states of sleep and wakefulness. Arrows show excitatory and lines show inhibitory input. The thickness of arrows and lines represent relative strength of input. Circle sizes represent relative activities of each group of neurons
Awake state. Orexin neurons send excitatory input to wake-active neurons, which send inhibitory feedback projections to orexin neurons. This system might maintain the activity of wake-active neurons. A small decrease in the activity of wake-active neurons results in decreased inhibitory influence to orexin neurons. Orexin neurons, therefore, are disinhibited and increase their excitatory influence on wake-active neurons to maintain their activity. These wake-active neurons send inhibitory projections to the POA sleep center and excitatory projections to the thalamus and cerebral cortex.
(B) Sleep state. GABAergic neurons in the sleep center are activated and send inhibitory projections to wake-active neurons and orexin neurons to maintain a sleep state.
(C) Model of narcolepsy. Sleep-active neurons in the POA inhibit wake-active neurons and in turn are inhibited by them, thus forming a mutually inhibitory system. This system can cause unnecessary transition between the states, because when either side begins to overcome the other, the switch abruptly turns into the alternative state.
Amygdala promotes move to REM sleep. Inhibited by orexin. Cataplexy  move into REM directly
System that promotes sleep
System that promotes wake

21. Neuropeptide Orexin is the ultimate flip flop switch between sleep and wakefulness
Orexin is the neurotransmitter released in hypothalamus by a small nucleus that consist of 10,000 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.
*perifornical area and lateral hypothalamus

22. Narcolepsy
Narcolepsy results in excessive daytime sleepiness and cataplexy, whereby a person falls into REM sleep, with all their skeletal muscles paralyzed in response to strong, usually positive, emotions.
One woman in England has been declared dead three times and once woke up in morgue.
Narcolepsy is caused by a lack of orexin in the brain due to destruction of the cells that produce it.
Narcolepsy:
Amygdala promotes move to REM sleep. Inhibited by orexin. Cataplexy  move into REM directly

23. 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 competitive inhibitor of adenosine.
As a result, caffeine temporarily prevents or relieves drowsiness, and thus maintains or restores alertness.

24. What causes one to fall into sleep?
Brain nuclei? – Yes. E.g. Reticular formation
Circulating hormones? – Yes. E.g. melatonin
Accumulation of Adenosine? – Yes.
Conclusion: all of the above with Orexin acting as flip flop switch

25. What is the natural period of one circadian cycle (a natural day duration)?
The natural period of one circadian cycle in this experiments = 25.3h
circadian: from Latin circa "about" + diem "day“
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

26. Photosensitive cells in the retina control the 24-hour cycle of several subcortical nuclei, that, in turn, control the pineal gland.
Most organs even individual cells in the body have their own 24-hours clocks
Circadian clock system helps regulate 40% of our genes, orchestrating rhythms for eating, body temperature and blood pressure.
Melatonin anticipates the daily onset of darkness – central control of local circadian rhythms
Analogy: mechanical watch. Its accuracy is never perfect, needs time adjustment every day.
Melatonin is safe aid for falling into sleep. If you have Jetlag, you can take melatonin to help you fall asleep
Photosensitive cells in the retina detect light and directly signal the suprachiasmatic nucleus (SCN), entraining its rhythm to the 24-hour cycle in nature. Fibers project from the SCN to the paraventricular nuclei (PVN), which relay the circadian signals to the spinal cord and out via the sympathetic system to superior cervical ganglia (SCG), and from there into the pineal gland.
Light absorbed through the skin at the back of the knees also regulates the body's biological clock.  - Refured in 2002

27. Why circadian rhythms are important?
For many reasons, including: It matters when to take medicine!
Tylenol: when too much is taken, the liver can be damaged. Tylenol overdose is behind more than 78,000 emergency room visits a year in the U.S.
Experiment in mice:
when you give mice a large dose in the morning, liver is fine
in the evening  the liver dies.
For humans, it shall be reversed (as mice are nocturnal). A large dose in the morning is dangerous for the liver! Mechanism: see next slide
Stats: up to 82 percent of mammalian genes are expressed in a cyclical pattern of highs and lows. This means there is a time aspect to biology.
Fifty-six of the 100 most commonly used drugs target rhythmically expressed proteins, meaning the time of dosing matters.
The emerging field of chronomedicine is testing timed treatments of diseases such as cancer and rheumatoid arthritis to maximize safety and efficacy.
Personalized monitoring of circadian rhythms may determine different optimal treatment times for each person.
Chronomedicine has not yet reached clinical practice.
Scientific American (July 2018), 319, 50-57  Published online: 19 June 2018 | doi: /scientificamerican
The Clocks within Our Cells
Veronique Greenwood
Acetaminophen = Tylenol

28. Circadian clocks are ancient
Circadian clocks are ancient. They may not be as old as life itself, but various timekeeping systems that allow organisms to respond to the planet's daily cycles exist in groups as disparate as plants, bacteria and mammals. In mammals, a region in the brain called the suprachiasmatic nucleus acts as the circadian pacemaker, taking cues from sunlight. This helps to set the cellular clocks that tick in nearly every cell in the body, including liver cells (shown here). Within individual cells, two core clock proteins, BMAL1 and CLOCK, trigger the expression of many other proteins, sparking a daily feedback loop that inhibits BMAL1 and CLOCK levels before allowing them to rise once again.

29. Disorders of sleep Slow-wave deep sleep REM Sleep Behavior Disorder
Sleep talking
Bedwetting
Sleepwalking
Can be triggered by stress, alcohol, sleep deprivation
Individuals engage in complex behavior while sleepwalking
REM Sleep Behavior Disorder
If muscles are NOT inhibited  physical activity during REM sleep:
Dream about diving and dive from a bed down onto the floor
Dream about playing football and tackle a bed partner
Video: a dog acts out a dream, runs into a wall:
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)

30. Sleep apnea is 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.

31. Micro-sleep
Sleep-deprived humans will fall into 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.
Brain can sometimes sleep one part of cortex (one department) at a time.
For example, you can drive a car (motor cortex not sleeping) but fail to notice another car cutting in to your lane.
As a result it is very dangerous to drive in a sleepy state – often you cannot control all the neurons in your brain.
MICROSLEEP
My last column, “To Sleep with Half a Brain,” highlighted the growing realization of sleep researchers that being awake and asleep are not all-or-none phenomena. Just because you're asleep doesn't necessarily imply that your entire brain is asleep. Conversely, as I will describe now, we have also learned that even when you're awake, your entire brain may not be awake.
A case in point for sleep intruding into wakefulness involves brief episodes of sleep known as microsleep. These intervals can occur during any monotonous task, whether driving long distances across the country, listening to a speaker droning on or attending yet another never-ending departmental meeting. You're drowsy, your eyes get droopy, the eyelids close, your head repeatedly nods up and down and then snaps up: your consciousness lapses.
In one experiment attempting to explore this condition, participants had to track a randomly moving target on a computer monitor with a joystick for 50 minutes. While straightforward, this visuomotor task demands nonstop attention that becomes difficult to sustain after a while. Indeed, on average, participants had 79 microsleep episodes per hour, lasting between 1.1 and 6.3 seconds apiece, with an attendant drop in performance. Microsleep shows up in the EEG record by a downward shift from activity dominated by the alpha band (8 to 13 Hz range) to oscillations in the theta band (4 to 7 Hz).
Perniciously, subjects typically believe themselves to be alert all the time during microsleep without recalling any period of unconsciousness. This misapprehension can be perilous to someone in the driver's seat. Microsleep can be fatal when driving or operating machinery such as trains or airplanes, hour after tedious hour. During a microsleep episode, the entire brain briefly falls asleep, raising the question of whether bits and pieces of the brain can go to sleep by themselves, without the entire organ succumbing to slumber.
Indeed, Italian-born neuroscientists Chiara Cirelli and Giulio Tononi, who study sleep and consciousness at the University of Wisconsin–Madison, discovered “sleepy neurons” in experimental animals that showed no behavioral manifestation of sleep. In this research, 11 adult rats had microwires implanted into their frontal motor cortex, which controls movement. Inserted into the cortical tissue, the sensors picked up both the voltage called the local field potential (LFP), akin to the EEG, in addition to the spiking activity of nearby nerve cells. As expected, when awake, the LFP was dominated by low-amplitude, fast waves readily distinguishable from the larger and slower waves characteristic of non-REM deep sleep [see box below].
At the level of individual neurons, the awake animals' cortical cells chatted away in an irregular, staccato manner over an extended period. Conversely, during deep sleep, cortical neurons experienced pronounced “on” periods of neural activity and “off” times during which they are silent. This neuronal reticence occurs simultaneously all over the cortex. It alternates with regular on periods, leading to the rising and falling brain waves that are the hallmark of deep sleep.
Knowing all this, the researchers decided to probe further. Instead of letting the rats go to sleep at their usual bedtime, the experimentalists engaged the animals in a rodent version of late-night video gaming, continuously exposing them to toys and other objects to sniff, explore and play with. They tapped on the cage and otherwise prevented them from assuming a sleep posture or becoming drowsy. After four hours of such excitement, the rats could finally slumber.
As expected from previous animal and human studies, by the end of the sleep deprivation phase, the LFP began to shift to lower frequencies, compatible with the idea that the pressure for the animals to sleep steadily built up. Closer inspection of the electrical signatures, however, revealed something unexpected: occasional, sporadic, silent periods of all or most of the neurons in the recorded brain region [see box below] without the animals showing either behavioral or EEG manifestations of microsleep. These short, off-like episodes were often associated with slow waves in the LFP. The opposite happened during recovery sleep, toward the end of this six-hour period, when the pressure to sleep had presumably abated. At this point, large and slow waves in the LFP became more infrequent, and neuronal activity turned more irregular, as it did during wakefulness.
It appears that when awake but sleep-deprived, neurons show signs of sleepiness, whereas after hours of solid sleep, individual neurons start waking up. Careful statistical analysis confirmed these trends: the number of off periods increased during the four hours the rats were forced to stay awake, and the opposite dynamic occurred during recovery sleep.
One question was whether any one neuron fell asleep independent of any other neuron. Or was this occurrence more of a global phenomenon, whereby all neurons simultaneously transition to an off period? The answer, obtained by implanting a second array of microwires into a second cortical region—the parietal cortex, a quite distinct region from the motor cortex—was “yes” to both questions.

32. 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

33. Stop

34. 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.

35. REM is essential
Barbituric acid, the basic structure of all barbiturates
The core structure of benzodiazepines.
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)