8 - Continued

Question 1

What is the core tetrad of narcolepsy?

Answer 1

• Cataplexy (sudden muscle weakness)
• Sleep Paralysis
• Hypnagogic hallucinations
• Fragmented sleep

Question 2

How do people with narcolepsy demonstrate sleep continuity?

Answer 2

• Daytime nap REM (sometimes sudden)
• Can’t sustain REM during night sleep (fragmented sleep)
• REM sleep can occur without preceding nREM sleep (unique)

Question 3

Is narcolepsy an excess pressure for REM?

Answer 3

No, it is just an upset in the scheduling/regulation of REM

Question 4

The different components of REM sleep are organized in the pons, one may be suppressed and one may be expressed, leading to variation in REM expression. Is this the case for narcolepsy? What is narcolepsy linked to?

Answer 4

No.

William Dement and Emmanuel bred dogs so that they have a probability of narcolepsy. Found that a hypocretin receptor is missing in these dogs.

Question 5

Which allele is repeatedly shown to be present in people with narcolepsy?

Answer 5

DQB1*06.02 in HLA gene

There may be a form of narcolepsy without cataplexy. Classical narcolepsy has cataplexy, and is associated with this gene in the histoimmune complex (HLA)

Question 6

How are hypocretin/orexin systems critical to narcolepsy seen in dogs and mice?

Answer 6

When gene transfer or hypocretin infusions are administered, cataplexy like features disappear. Leading to conclusions that these mice were deficient in making their own hypocretin.

KO Mice: didn’t have functional hypocretin gene

Dogs: lacked hypocretin receptor

Humans: Hypocretin neurons likely attacked by own immune system, causing gradual degeneration in lateral hypothalamus

Question 7

What is revealed by hypocretin levels assayed from spinal taps in narcoleptic humans?

Answer 7

Hypersomnias: Normal levels in circulation
Narcoleptics: No/very little hypocretin in circulation
Control: Normal levels in circulation

Question 8

What type of disease is narcolepsy in humans?

Answer 8

Autoimmune disease

Over the course of development, they begin to lose thier hypocretin neurons.

Question 9

How is H1N1 virus associated with narcolepsy?

Answer 9

Influenza may produce a variety of sleep disorders from brain damage caused by a form of the vaccination that contained a substance that was strengthening the immune system to the virus. Resulted in 1000s of kids getting narcolepsy from the inoculation.

Almost all the kids were positive for DQBI*06.02 allele. It seems like these kids generated a very strong immune response against hypocretin neurons.

The more potent form of the vaccine shouldn’t be given to kids with the DQBi*06.02 allele

Question 10

What happens if you block hypocretin receptors when someone is coming out of anaesthesia?

Answer 10

They don’t come out of it.

Question 11

What is hypocretin’s principle role in sleep?

Answer 11

Regulating the transition into REM

Question 12

Where is the ventrolateral preoptic area (VLPO)?

Answer 12

Sits around the area where the optic chiasm forms

Rostral is the preoptic area

Surrounded by basal forebrain (critical for cortical arousal)

Question 13

What happens if you damage/stimulate the ventrolateral preoptic area (VLPO)?

Answer 13

• Damage results in big reduction in sleep

- Stimulation causes sustained onset of sleep

Question 14

What type of neurotransmitter do ventrolateral preoptic area neurons contain? What other important thing do they contain?

Answer 14

• GABA

- Galanin containing cells that show high c-fos immunoreactivity after sleep (indication of high activity)

Question 15

The core/peripheral part of ventrolateral preoptic area is dominant during?

Answer 15

Core VLPO: nREM
Peripheral VLPO: REM

VLPO has sustained firing and c-fos production during nREM sleep

Question 16

Where do preoptic area neurons send inhibitory projections to?

Answer 16

• Histaminergic TMN
• Serotonergic dorsal raphe nuclei
• Noradrenergic locus coeruleus
• Hypocretin neurons of perifornical lateral hypothalamus

Question 17

How do VLPO and mnPO neurons boost their own activity?

Answer 17

These preoptic nuclei also receive reciprocal inhibitory inputs from monoaminergic nuclei. Thus, as they become more active and release GABA/galanin in the raphe nuclei and LC, the resulting inhibition does two important things.

• It reduces the arousal- promoting activity of neurons in these nuclei that project to the thalamus or cortex;
• secondly, the loss of their inhibitory input to the preoptic region permits VLPO neurons to further increase their dominance of the reciprocal relationship. This arrangement permits the transition to sleep and the maintenance of lengthy sleep phases

Question 18

What are VLPO and hypocretin (fornical lateral hypothalamus) neurons important for?

Answer 18

Reducing instability between different arousing centers of the brain to regulate sleep and wakefulness.

SCN continually promotes arousal during the day (promotes hypocretin) and continuously promoting sleep during the night (VLPO)

SCN has projections to preoptic area

Question 19

What tells the VLPO when to put you to sleep?

Answer 19

Accumulation of adenosine

Question 20

How can adenosine accumulate in and out of a neuron?

Answer 20

Hydrolyzing ATP releases free adenosine, which is shuttled into the extracellular space.

Question 21

How do adenosine levels change in the cortex and the basal forebrain during sleep deprivation

Answer 21

They build and build

Adenosine level only falls during recovery sleep

In this way, adenosine is like a homeostatic substance!

Question 22

What are adenosine receptors critical for?

Answer 22

Waking and arousal.

Methylxanthine drugs (eg. caffeine and others) bind adenosine receptors, and prevent adenosine from getting through. They prevent sleepiness.

Question 23

Why is energy a misnomer for caffeine?

Answer 23

All caffeine does is block adenosine receptors. Energy comes from sugar, caffeine just prevents sleep.

Question 24

What does adenosine do?

Answer 24

Inhibits inhibitory projections to preoptic area (disinhibition of preoptic area promotes sleep)

Question 25

What produces adenosine?

Answer 25

Astrocytes

Question 26

What happens if you have mice that can’t secrete adenosine from astrocytes?

Answer 26

Caffeine is ineffective

Suggests that astrocyte release of adenosine is an important step in sleep promotion

Question 27

Describe glycogen storage in the brain and how it relates to sleep.

Answer 27

If a cell wants to store glucose, it stores glycogen molecules. Neurons don’t contain glycogen. Astrocytes do.

Theory of why we sleep: Maintaining brain energy metabolism. Brains that are awake are so active that they rely on stored glycogen. Astrocytes have the function of storing during sleep and release it during waking.

Question 28

Chronic or extreme cases of sleep deprivation has homeostatic mechanisms that aren’t good enough. Allostatic response may make up for homeostatic response. What does recent evidence suggest about the allostatic response? (3)

Answer 28

Mice were sleep deprived for three days, and then weeks later.

• Mice that had undergone sleep deprivation show blunted increase in SWA and REM sleep in general, compared to animals that have never been sleep deprived.
• Not full homeostatic response that would normally be shown
• Astrocytes probably are changing the way there are responding to sleep deprivation. Produce less adenosine once sleep deprived (hint of what allosteric response might be).

Question 29

Areas in the cortex that are used for a particular task (eg. exercising a limb for hours). Neurons in the motor cortex of that area are more active. What is shown during sleep?

Answer 29

Increased SWA at that region, than at other parts of the cortex.

Almost like that part of the cortex is more ‘sleepy.’

Increased adenosine release from astrocytes in that area produces more SWA (a hallmark for greater need for sleep)

The whole brain doesn’t become equally sleepy at once. When a region of the brain is repeatedly used, they build up more sleep need than the rest of the brain.

Question 30

What are prostaglandins in regards to sleep? (8)

Answer 30

• Produced by all cells
• Paracrine (distributed source and local action)
• Prostaglandin D2 (PGD2) in arachnoid, choroid plexus and near basal forebrain gets secreted into CSF
• PGD2 levels increased during sleep deprivation
• Can induce sleep onset with very small amounts of PGD2
• Can generate sleepiness, trigger sleep and compensate for lack of sleep
• PGD2 loses effectiveness if you block adenosine receptors
• A sleep regulatory mechanism that feeds into adenosine sleep regulatory mechanism

Question 31

When blood from sleep deprived dogs was injected into non-sleep deprived dogs and people concluded there was a circulating substance that made you sleepy. What is this sleep substance?

Answer 31

Factor S was fractionated out of blood. Capable of producing sleep.

In 1970s, it was identified as a small peptide molecule which contains neuraminic acid (not produced in mammals).

Peptides with neuraminic acid are found in bacteria, especially bacterial cell walls. Every Time a bacterium dies and gets metabolized, these peptides get released. The immune systems response to this peptide makes organisms sleepy (increased sleepiness common during infection or tumour burden)? Pro-inflammatory cytokines (interleukin 1β and tumour necrosis factor 1α) secreted in nervous system.

Question 32

What effect does interleukin 1β have on sleep? Theorize how.

Answer 32

• More nREM sleep
• More discontinuous nREM sleep
• Reduce REM sleep

This may be acting through serotonergic systems. IL1β may be increasing inhibitory serotonin activity on BF neurons OR inhibiting serotonin by collateral (5-HT1A autoreceptors)

Question 33

How can cytokines (IL1β and TNF) act on hypocretin neurons? What is evidence of this in cancer patients?

Answer 33

Activate GABA neurons that shut down hypocretin neurons (inhibiting arousal)

• IL1β blocking can decrease tumour burden lethargy

Question 34

How does a fever relate to sleep?

Answer 34

• Extremely useful in fighting infection
• Body temperature falls in SWS, reducing nREM sleep may explain why nREM sleep becomes discontinuous during immune activation (to prevent sustained loss in temperature)
• However, nREM sleep also saves energy, so there is more in total. In REM sleep, thermoregulatory systems are turned off, fever is very controlled, reduction in REM sleep will prevent irregular thermal regulation and dangerous fever.

(This is all speculative)

Question 35

Body temperature during sleep is only regulated by what two types of animals? How does this relate to sleep stages?

Answer 35

Mammals and birds

Only two animals that have both REM and nREM

Question 36

When you put people in continuous conditions and spontaneous (or forced) internal desynchronization occurs, what is the result in sleep patterns and temperature? (4)

Answer 36

• Falling asleep when body temperature reaches bottom of trough (having very short sleep period)
• May sleep for a very long time if they fall asleep at the peak of temperature rise (and therefore beginning of temperature fall)
• Physiologically, some preoptic nuclei are involved in brain temperature (and sleep regulation!)
• Link between melatonin and body temperature and melatonin and sleep regulation k

Question 37

Does distal temperature rise towards sleep onset or decrease? Proximal temperature?

Answer 37

Distal: rises
Proximal: drops

Changing skin temperature in elderly can change amount of sleep, including more SWS (good thing!)

Question 38

What was the first evidence that neurons found in the ventrolateral preoptic nucleus (VLPO) and median preoptic nucleus (MnPO) might be related to sleep regulation?

Answer 38

Damaging preoptic area led to drastic sleep loss and electrically stimulating the ventrplateral preoptic area triggered EEG synchronization and sleep onset.

Question 39

Which neurotransmitter and peptide characterize VLPO neurons, and what effects do they have on target nuclei related to arousal?

Answer 39

GABA and galanin. Inhibit wake-promoting regions such as the TMN, the dorsal Raphe nucleus, the LC, and the pfLH. This promotes sleep.
They receive inhibitory inputs from monoaminergic nuclei.

Question 40

Which subregions of the preoptic area have been linked to different aspects of sleep regulation?

Answer 40

• VLPO cluster region (uniformly active throughout sleep)
• VLPO extended region (active mostly during REM)
• MnPN (median preoptic nucleus) neurons show peak firing early in sleep.

All these neurons fire in anticipation of sleep onset as well.

Question 41

Which three systems have been suggested to contribute to state stability in regulation of sleep and waking?

Answer 41

The VLPO → initiates and maintains sleep

The pfLH (perifornical lateral hypothalamus) → reinforces bistability of states, so there’s no rapid flip flop back and forth

Circadian system → biased towards certain states at certain times.

Question 42

Which brain regions have been proposed to be principal targets of adenosine’s sleep promoting action? (3)

Answer 42

• Cholinergic basal forebrain
• tuberomammillary nucleus
• VLPO

Question 43

Which two roles played by astrocytes links them closely to regulation of sleep?

Answer 43

They contain the brain’s store of glycogen, which is replenished during sleep. They also release adenosine.

Question 44

What evidence links adenosine to the physiological consequences of chronic sleep restriction?

Answer 44

Brains of mice that underwent chronic sleep restriction had lower adenosine levels that acute sleep restricted or naïve mice. This ties in with the theory that altered adenosine responses are a part of the shift to allostatic mechanisms after chronic sleep restriction.

Question 45

What evidence links prostaglandin D2 (PGD2) to sleep and how are its actions tied to those of adenosine?

Answer 45

• PGD2 levels increase as sleep deprivation increases.
• Injection into CSF induces sleep onset very shortly.
• Preventing its action prevents recovery characteristics of sleep after sleep deprivation.

It seems that it is adenosine-depended because blocking a certain adenosine receptor eliminates PGD2 effects. It’s likely that PGD2 acts by causing adenosine release.

Question 46

What effects do muramyl peptides have on mammalian sleep? Where do these peptides come from and what is their functional relation to the immune system?

Answer 46

They increase sleep. They come from bacterial cell walls. They evoke strong immune responses, and are responsible for sleep-inducing effects of infection.

Question 47

What physiological role for hypocretin in sleep regulation is suggested by the symptoms of narcolepsy in humans and the effects of hypocretin treatments in animal models?

Answer 47

• It is suggested that hcrt neurons from in the pfLH project to various pontine nuclei where they orchestrate the correct timing and duration of REM sleep components.
• This makes sense because loss of hcrt neurons is key in narcolepsy, REM components are generated in different pontine nuclei and REM components appear when they’re not supposed to in narcolepsy.
• Evidence from animal models: transferring hcrt gene into dorsolateral pons neurons lessened narcoleptic symptoms in mice.
• Alternatively, hcrt may modulate the balance of activation of other neurochemical systems, allowing consolidation of wake and sleep, and confinement of behaviours to their appropriate states. An imbalance of the mechanisms that bring about NREM, REM and waking could lead to unstable shifts between them.
• Hcrt may act as a switch that allows state transition into a stable state.
• Hcrt may also contribute to the synchronous appearance and maintenance of REM components, which is why in narcolepsy components may be expressed independently, fragmentally, and in the wrong states.
• In cats, injecting hcrt into nucleus pontis oralis (important in REM initiation) during quiet sleep resulted in rapid switch to REM. When injected during waking, it prolonged waking at the expense of sleep.
• Suggests that hcrt plays a role in regulating state transitions, rather than inducing certain states.

Question 48

What are the effects of interleukin-1β on sleep? What is the mechanism of this? How can these several changes in sleep be interpreted as beneficial for an individual while combating a bacterial infection?

Answer 48

• Interleukin (IL)-1β and tumour necrosis factor (TNF)α are produced by the immune systems in response to infection
• IL-1β increases nREM but disrupts continuity
• Reduces REM
• One of the proposed targets on which IL-1β may act is a neurochemical system already known to be involved in sleep regulation, namely, serotonergic raphe neurons
• One speculative interpretation of how IL-1β can promote sleep is that it causes 5- HT to be released from serotonergic neurons. When 5-HT is released from axon terminals in the basal forebrain, it results in inhibition of wake-promoting cholinergic neurons, and thereby promotes sleep onset. When IL-1β is injected into the raphe nuclei, however, (where the 5-HT somata are found), the resulting release of 5-HT would affect autoreceptors that suppress firing of serotonergic neurons, thereby reducing the release of 5-HT in the cortex where it normally has an arousing influence. Thus, the actions of IL- 1β at each site could contribute to decreased arousal and increased sleepiness
• Another mechanism by which immune system activation inhibits activity and food intake is via an indirect action on pfLH Hcrt neurons. Hcrt neurons play an important role in generating arousal and locomotor activity (see §8.2.1). Inflammatory cytokines, particularly IL1-β, activate GABAergic lateral hypothalamic neurons, which inhibit the activity of Hcrt neurons, thereby reducing arousal and activity. Suppression by IL1-β of the normal nocturnal release of Hcrt via this indirect mechanism appears to play a critical role in generating the lethargy characteristic of rats suffering from infection or bearing a tumour burden

Question 49

How can the effects of interleukin-1β on sleep be interpreted as beneficial for an individual while combating a bacterial infection?

Answer 49

(lengthened, but interrupted, NREM sleep, and reduced REM sleep) - may play a role in fighting infections. The benefits of changes in NREM sleep may also relate to the energy costs of generating a fever, which involves intense muscle activation in the form of shivering in order to raise body temperature.

• Increased amounts of NREM sleep (along with reduced motor activity) may compensate for these energy costs because metabolism is reduced during NREM sleep.
• On the other hand, the discontinuity of NREM sleep during infection may prevent the characteristic fall in body temperature seen during sustained NREM sleep episodes, which would be counter-productive while trying to maintain an elevated core temperature.
• Finally reduced REM sleep amounts may be beneficial in maintaining a fever because thermoregulation is disrupted and shivering is absent during REM sleep

Question 50

Body temperature regulation and sleep are closely related. List five different kinds of relations that have been described between body temperature and sleep regulation.

Answer 50

1. homeothermy, the physiological regulation of body temperature around a high value that is modulated on a circadian basis, evolved in birds and mammals, which are the two groups showing both NREM and REM sleep in most of its members.
2. sleep onset and termination are both closely linked to the daily rhythm of body temperature in people.
3. The preoptic area, which plays a critical role in the regulation of sleep, also houses the core regulatory systems involved in body temperature control.
4. Melatonin
5. Peripheral vasodilation, occurs when an individual lies down and relaxes at night, and the resulting increase in peripheral skin temperature (lower core temp) predicts the timing of sleep onset

Manipulating skin temperature, without affecting core body temperature, has also been reported to influence sleep continuity and quality.

Question 51

Describe preoptic area control of temperature

Answer 51

houses the core regulatory systems involved in body temperature control.

Neurons in the preoptic area respond to changes in the temperature of this region by altering firing rates, and their output engages the regulatory mechanisms that maintain temperature within the homeostatically defended range as well as the mechanisms that are involved in inducing fever

Artificially heating this region causes increased firing of warm-sensitive preoptic neurons and an increase in sleep propensity. In addition, these warm-sensitive neurons increase their firing rates during naturally occurring NREM sleep phases. Thus, the same brain region, and probably some of the same neurons, that are involved in increasing heat loss and reducing temperature set point on a daily basis also promote NREM sleep, which is characterized by a further fall in body temperature.

Question 52

How do the temporal relations between sleep and circadian rhythms in people change during long-term housing in constant, time-free environments?

Answer 52

Very long or very short sleep, depending on when they fell asleep (based on circadian rhythm temperatures)

Question 53

Describe how regional changes in temperature in different parts of the body have been linked to sleep onset and to the patterns of sleep shown during the night.

Answer 53

Manipulating skin temperature, without affecting core body temperature, has also been reported to influence sleep continuity and quality. While the effects depended on age and other factors, a principal finding was that heating to induce a very small increase in skin temperature of proximal body regions (i.e., the trunk region and upper limbs) resulted in increased amounts of SWS and better sleep continuity, especially in older participants (Raymann et al., 2008). This observation is particularly interesting because SWS amounts were increased to levels not generally reported among healthy older people being studied under normal laboratory conditions.

Question 54

When do VLPO and MnPN neurons show peak firing rates?

Answer 54

• VLPO neurons tend to maintain high discharge rates throughout lengthy sleep episodes
• MnPN neurons tend to show peak firing early in a sleep episode and somewhat lower sustained activity during continuing sleep
• The MnPN region has been shown to be responsive to increased REM sleep pressure, and neurons there are hypothesized to play a central role in REM sleep homeostasis