7 - Physiological regulation of sleep and arousal

Question 1

What is the inverted U shape of arousal?

Answer 1

A model that shows that best type of arousal (peak of the arch, medium arousal) and the worst (either end, no arousal or too much arousal)

Question 2

Circadian rhythms are at what level of arousal?

Answer 2

There is a global change in the arousal of system that overlies all the short term (immediate) arousal related changes.

Question 3

Which type of amino acids gives rise to neurotransmitters?

List the three amino acids that are involved in sleep NTs and their five NT products.

Answer 3

Aromatic amino acids

Tyrosine (DA and NE)
Tryptophan (melatonin and serotonin)
Histidine (histamine)

All, except melatonin, concentrated in small clusters in the brainstem or hypothalamus.

Question 4

How are sleep neurotransmitter neurons and their projections organized in the brain?

Answer 4

All, except melatonin, concentrated in small clusters of neurons (nuclei) in the brainstem or hypothalamus and project extremely widely in the brain

Melatonin contained in pineal gland, which secretes directly into CSF, which bathes the whole brain and spinal cord.

Question 5

Norepinephrine is expressed in neurons in what two regions?

Answer 5

• Tegmental pons
• Medulla

A1-A7 are noradrenergic regions

Question 6

What is the stria terminalis?

Answer 6

A tract of noradrenergic projections

Question 7

What is locus coeruleus latin for?

Answer 7

Blue spot

Question 8

What noradrenergic nuclei is most important for sleep?

Answer 8

Locus coeruleus

Question 9

How is noradrenergic neuron firing during sleep and wakefulness? (3)

Answer 9

When the animal is awake, NE neurons fire at high rates. When the animal is asleep (nREM), NE neurons fire at low rates.

Firing rates either stay low, or get lower during REM sleep.

Question 10

What does noradrenergic firing do to regions of the brain and how is this shown with EEG?

Answer 10

• Generally activates them

- Wind up with desynchronized EEG in the cortex

Question 11

Most of the patterns that you get out of NE release (naturally or artificially) is consistent with what kind of response? What is the ONE exception to this?

Answer 11

Activation

• Activates sympathetic nervous system
• Deactivates parasympathetic nervous system

Nervi conarii coming out of paraventricular nucleus centre projects to pineal gland and promotes the transition to sleep.

Question 12

Where do dopamine projections originate from?

Answer 12

• Substantia nigra (A9) projects to striatum (nigrostriatal pathway)
• VTA (A10, in pons) projects to cortex, limbic structures and (mesocorticolimbic pathway)

Mesocorticolimbic pathway most involved in sleep, also in motivation, reward etc.

Question 13

Why does it not look like dopamine is involved in sleep?

Answer 13

Because dopaminergic neurons don’t show changes with circadian state

• Levels of dopamine higher in wakefulness, but this isn’t dramatic/reflected in the firing rates

Question 14

What is evidence that dopamine is involved in sleep? (3)

Answer 14

Knock out of D2 receptors in mice.

They show increase in nREM and REm sleep, and decrease in wakefulness.

AND

Modafinil is a drug that has potent alerting/arousing effects, that seems to act through adrenergic and D2 receptors.

AND

Dopamine transporters (DAT) differ in their ability to transport dopamine and terminate transmission when subject given caffeine (more sensitive to caffeine with less DAT) and homeostatic regulation of sleep, and especially REM sleep. Dopamine somehow facilitates REM sleep

Question 15

How do levels of dopamine transporter effect EEG activity?

Answer 15

Low DAT levels: amplification of dopaminergic effect making transient REM like states

High DAT levels: reduction of REM sleep

Question 16

What happens when you knockout dopamine transporters in mice?

Answer 16

• Stress response in novel environments

- Burst of REM during waking

Question 17

What is meant by ‘dreaming is a psychotic state?’

Answer 17

Psychosis: an individual experience events that other people don’t experience (eg. hallucinations)

Dreams are like psychosis (reality that others don’t experience), especially because as a dreamer you suspend disbelief.

Question 18

Cocaine, amphetamines, methamphetamines and L-DOPA etc. can generate psychotic episodes. What are the implications of this in sleep?

Answer 18

These substances shut down dopamine transporter. Cocaine actually reverses DAT, pushing DA back into synaptic cleft. Facilitating DA transmission can cause psychosis.

When L-DOPA is given to Parkinson’s patients a side effect can be hallucinations.

This can link high dopamine transmission to dreams.

Question 19

How does schizophrenia provide further evidence for DA’s involvement in dreams.

Answer 19

When you have people with schizophrenia, the positive symptoms (hallucinations, disordered thought etc.) are associated with excess dopamine.

All antipsychotics act by blocking dopamine receptors.

Question 20

What is the clock gene CLOCK and what does KO show?

Answer 20

• Transcriptional factor

KO causes manic phase of bipolar disorder (close to schizophrenia) from ventral tegmental area (dopamine implication)

Question 21

What did Solms argue about dreams?

Answer 21

They are a result of dopamine projections to the cortex.

Evidence is brain damage in tegmental (mesocorticolimbic) pathway can inhibit dreams.

Question 22

What is ritalin?

Answer 22

methylphenidate

ADHD meds for increasing dopamine transmission.

Question 23

What is narcolepsy? What was used to treat it? (3)

Answer 23

Falling asleep at random times

• Amphetamines initially used to treat (but stopped because of addiction and that sort of thing)
• Modafinil used now, but it’s not as effective (or addictive/pleasurable)
• MAO inhibitors could increase catecholamine neurotransmission (used for antidepressants for a while, but nasty side effects) .

Question 24

Selective reuptake inhibitors of serotonin and NE have mostly replaced MAO inhibitors for antidepressants. How is this linked to sleep?

Answer 24

Activation/arousal/wakefulness

These drugs can have effects on sleep

Question 25

Where do serotonin projections originate from?

Answer 25

• Raphe nuclei in pons, medulla that pretty much project anywhere
• Caudal raphe nuclei project down spinal column
• Rostral (dorsal) raphe nuclei project ascending projections

Question 26

What happens to sleep if you block serotonergic transmission?

Answer 26

NO SLEEP

Though this is a temporary effect. Animals eventually regain sleep.

Question 27

How are serotonin levels during wakefulness, nREM and REM.

Answer 27

Serotonin levels highest during wakefulness

• Levels go down during nREM sleep
• Basically no serotonin during REM (disinhibition of REM-important brainstem)

Question 28

What happens if you release serotonin on cholinergic neurons on the brainstem? Why is this important for sleep?

Answer 28

Inhibits their activity and withdrawal of serotonin is critical in the activation of REM sleep

Question 29

What is hypocretin? How does it interact with serotonergic neurons

Answer 29

Raphe neurons (arousing) and hypocretin neurons project to each other.

Hypocretin is arousing and activates serotonin neurons

Serotonin inhibits hypocretin neurons (counter intuitive)

Question 30

What happens to serotonin if you knockout the hypocretin gene? How is this explained?

Answer 30

You get mice that are less arousable

• Show increases in nREM sleep
• Increases in serotonin firing (you would assume the opposite because hypocretin inhibits raphe nuclei)
• You end up with fragmented sleep

Explanation: Hypocretin neurons usually active in dark phase, they activate serotonin neurons in order to prevent runaway activation of hypocretin neurons themselves in order to get inhibition from serotonin (self limiting their arousal)

Question 31

What is the effect of SSRI drugs on sleep?

Answer 31

Used as antidepressants because they result in arousal, good mood etc. (people that suffer from depression don’t have deficit in serotonin, it’s multicausal)

Daytime drowsiness from cholinergic inhibition or nighttime arousal

Question 32

What can 5-HT1A receptors do in the raphe nuclei?

Answer 32

Decrease firing of most neurons on which it is found

Some neurons have autoinhibition from 5-HT1A (recurrent collateral) to inhibit itself from having a very high firing rate. Putting a serotonin agonist in the brain through a drug will activate cortical neurons through disinhibition.

Question 33

True or false? Serotonin functions as a cortical arouser

Answer 33

true

Question 34

How do 5-HT (serotonin) levels change in the cortex in different states? Is there separation between left and right cortices in seals, where one cortex awake the other is not?

Answer 34

Active waking: lots of serotonin
Quiet waking: Less serotonin

Explanation: Lots of motor activity and arousal show highest levels of 5-HT

Sound asleep: very low levels
REM: lowest levels

No lateralization for any of these, despite one being awake and one not. Serotonin does not play a role in regulating sleep, just arousal.

Question 35

What is one explanation for increased suicide rates when given serotonin/NE reuptake inhibitors?

Answer 35

When depressed, might not have will to take action. But serotonin increases activation…

Question 36

What is the basal forebrain?

Answer 36

A collection of cholinergic nuclei

Cholinergic projections from BF to cortex are critical for cortical arousal

Question 37

When are cholinergic neurons active/non-active?

Answer 37

Waking: Very active
nREM: low levels
REM: Very active (different from NE and 5-HT!)

ACh helps selectively desynchronize the cortex by activating thalamic or BF neurons that project to the cortex

Question 38

What happens if you use muscarinic antagonists (atropine and muscarine from deadly nightshade plant)?

Answer 38

• Decreased arousal

Used as religious or recreational hallucinogens or poison from severe CNS depression.

Question 39

How does smoking affect sleep?

Answer 39

Through increasing alertness through increased cortical activation (nicotinic agonist).

Increased arousal/cortical activation.

Question 40

What affect do cholinesterase inhibitors have on sleeping people?

Answer 40

Will trigger REM sleep through cortical arousal.

Question 41

How is memory impairment correlated with cholinergic neurons? How can this be treated?

Answer 41

Cholinergic projections from BS to cortex are decreased in AD and normal aging.

Indirect or direct depression of cholinergic system causes dementia like symptoms.

This can be treated with acetylcholinesterase blockers, but this won’t prevent the problem from progressing.

Question 42

True or false? There is a cholinergic projection to the SCN from the basal forebrain

Answer 42

True!

Dr. Semba helped with that one :)

Question 43

What are REM-ON neurons?

Answer 43

Neurons that are active during REM sleep

These start the desynchronization of the cortex through the thalamus/BF

Active the REM sleep production zone neurons on the pons (nucleus pontus, locus coeruleus alpha and others!), which go on to make characteristics of REM sleep.

Question 44

How do we know cats dream?

Answer 44

Destroyed area near locus coeruleus responsible for atonia during REM sleep.

Sound asleep cats stalking and pouncing, snarling, fearful expression, attacking, biting etc.

These are probably cats acting out their dreams.

Question 45

What is the REM sleep behaviour disorder?

Answer 45

Occurs in middle age and older men.

Symptoms include strong kicking or rhythmic leg movement, striking out with fists. Getting out of bed and engaging in violent and complex behaviours.

People with REM behaviour disorder very likely to develop neurodegenerative disorders like Parkinsons. Evidence for degeneration of dopaminergic motor centres associated with atonia. REM behaviour disorder is beginning of progressive neurodegeneration.

Very rare in women, perhaps because women are less violent and therefore it’s detected less often. Or the male brain might be susceptible to this kind of neurodegeneration.

Question 46

What does Hobson’s reciprocal interaction (structural) model for REM sleep regulation state?

Answer 46

There are REM-ON and REM-OFF cells

REM-ON: Cholinergic
REM-OFF: Aminergic (NE locus coeruleus and 5-HT raphe nuclei)

The dynamic model shows a cycle between these cells where these two systems oppose each other, one shuts down the other and then vice-versa.

• LC inhibits NE cells
• Raphe nuclei inhibit 5-HT cells
• Cells in tegmentum activate each other (positive feedback) causing very quick transition into REM
• During waking cholinergic and non-cholinergic neurons from tegmentum activate raphe and LC
• GABAergic neurons inhibit 5-HT raphe and NE Locus coeruleus during sleep

Question 47

How is REM sleep terminated?

Answer 47

Throughout REM, is there is continuous buildup of activity in noradrenergic and serotonergic nuclei, which eventually gets big enough to trigger exit from REM sleep.

Question 48

How is REM sleep rapidly ‘turned on?’

Answer 48

Mesopontine tegmentum neurons signal to each other in a positive feedback loop that quickly builds cholinergic activation of REM and inhibition of 5-HT and NE

Question 49

What is modafinil used to treat?

Answer 49

Sleep-increasing disorders, like narcolepsy. It may also be used to increase arousal during things like military mission.

Activity with both D1 and D2 activity

Question 50

What two regions of the brain have neurons that synthesize ACh?

Answer 50

• Basal forebrain

- Mesopontine tegmentum

Question 51

What are the two nuclei of the mesopontine tegmentum?

Answer 51

• Laterodorsal tegmental (LDT)

- Pedunculopontine tegmental nuclei (PPT)

Question 52

Which mesopontine region has cholinergic neurons that are selectively active during REM sleep?

Answer 52

Laterodorsal tegmentum (LDT)

Question 53

What effects does the anticholinesterase agent physostigmine have on state when given systemically to people during NREM sleep and REM sleep?

Answer 53

Physostigmine is an AChE inhibitor (therefore, a promoter of cholinergic activity) and activity depends on the state of the individual:

• Given systemically to people during NREM sleep, it induces a transition to REM sleep
• Given during REM sleep, it induces waking

Question 54

What effect does stimulating laterodorsal tegmental and pedunculopontine tegmental (LDT/PPT) neurons have on cortical function, and by what routes does it have this effect?

Answer 54

Stimulation of the mesopontine tegmental region
containing the LDT and PPT also causes cortical activation.

These cholinergic cells, however, do not project directly to the cortex; rather, they exert their effects on arousal by activating thalamic or basal forebrain neurons, both of which project to and activate the cortex

The tegmental arousal system may include other neurotransmitters in addition to ACh, but the pharmacological evidence suggests cholinergic neurons play a critical role in generating cortical arousal in waking and REM sleep by activating thalamic and basal forebrain neurons.

Question 55

Which symptoms have been attributed to degeneration of cholinergic forebrain neurons in Alzheimer’s disease? What is the impact of treatment with cholinesterase inhibitors?

Answer 55

Severe loss of cognitive function and disruption of sleep-wake rhythms in dementing conditions, like Alzheimer’s disease, have been attributed to degeneration of basal forebrain cholinergic neurons

AChE inhibitors (e.g., donepezil [Aricept]), which promote cholinergic activity, can have beneficial effects on memory and other cognitive symptoms of Alzheimer’s disease, but they do not affect the underlying disease process, so the benefits tend to be transient.

Question 56

By which two routes does increasing activity of laterodorsal tegmental and pedunculopontine tegmental (LDT/PPT) neurons trigger cortical desynchronization during REM sleep?

Answer 56

• Basal forebrain
• Thalamus

Cholinergic LDT and PPT neurons in the midbrain tegmentum play a critical role in triggering the transition to REM sleep; damage to this region reduces REM sleep amounts.

Neurons in the LDT/PPT become more active seconds before onset of REM sleep and maintain high firing rates during REM sleep (‘REM-On’ neurons). Some LDT/PPT projections reach the basal forebrain where they activate (cholinergic) neurons that project to cortex; these pathways are selectively involved in promoting cortical activation during REM sleep.

Other LDT/PPT neurons are active during both REM sleep and waking; these are LDT/PPT neurons that project to the thalamus, and appear to regulate cortical activation via release of ACh onto thalamic neurons during both states.

Moderate activation of PPT neurons may help trigger REM sleep, while intense activation promotes waking

Question 57

Which regions receive projections from LDT/PPT neurons that are selectively involved in initiating REM sleep but not in cortical desynchronization during waking?

Answer 57

Pontine projections to the thalamus may also be involved in generating the PGO (ponto- geniculo-occipital) spikes that characterize REM sleep.

Other LDT/PPT neurons are selectively active only in anticipation of REM onset and during REM sleep, but not during wakefulness. These neurons project to the REM sleep induction zone located in and around the nucleus pontis oralis in the pontine tegmentum, consisting of the medial pontine reticular formation (mPRF) and locus coeruleus α (LCα). These neuronal groups are involved in the expression of many components of REM sleep, including muscle atonia, rapid eye movements and autonomic activation

Question 58

What two neuronal groups are involved in the expression of many components of REM sleep, including muscle atonia, rapid eye movements and autonomic activation

Answer 58

Nucleus pontis orallis:

• Medial pontine reticular formation (mPRF)
• Locus coeruleus alpha