Neuroscience - Sleep and Narcolepsy

Question 1

What are the 4 different sleep stages?

Answer 1

1) Awake
2) Drowsy
3) NREM
4) REM

Question 2

How many stages of NREM slep are there?

Answer 2

4

Question 3

Describe the EEGs of all sleep stages (wave patterns)

Answer 3

1) Awake - low voltage, fast beta waves
2) Drowsy - alpha waves
3) Stage 1 NREM - theta waves
4) Stage 2 NREM - theta waves with intermittent spindles and k-complexes
5) Stage 3&4 NREM - Deep (slow-wave) sleep - delta waves
6) REM (dream) sleep - low voltage, random, fast, mixed frequency with saw-tooth waves

Question 4

Increased heart rate, respiratory rate and head movements all coincide with what stage of sleep?

Answer 4

REM

Question 5

For wake, NREM ad REM sleep, describe the sensation and perception, thought and movement

Answer 5

Wake:

• vivid, externally generated
• logical, progressive
• continuous, voluntary

NREM:

• Dull or absent
• Logical, repetitive
• Episodic, involuntary

REM:

• Vivid, internally generated
• Illogical, bizzare
• commanded but inhibited

Question 6

What are the 3 distinct groups of neurons that promote wakefullness and sleep?

Answer 6

Wake active:
monoaminergic neurons (noradrenaline, serotonin, histamine) in the brain stem and hypothalamus

Sleep-active: GABA-ergic neurons in the hypothalamus

REM-active: Cholinergic neurons in the brain stem

Question 7

How do, wake, sleep and REM active neurons work?

Answer 7

Wake-active: promote wakefulness by directing excitatory effects on thalamocortical neurons and inhibition of sleep-active neurons

Sleep-active: promote sleep by inhibiting wake-active neurons

REM-active: activity rises and declines periodically during sleeping

Question 8

What are Orexin and hypocretin and what are their receptors?

Answer 8

• Peptides
• Hypocretin found in hypothalamus
• Bind to G-protein couples receptors
• Hypocretin 1 to HcrtR1
• Orexin A to OX1R

Question 9

What circuit controls wake-active and sleep-active?

Answer 9

FLIP-FLOP circuit

Question 10

How does the flip-flop circuit work?

Answer 10

• Acts like a seesaw to prevent intermediate states
• Reciprocal inhibition between the groups
• Neuronal input on either site controls sleep and wakefulness

Question 11

What 2 processes drive sleep?

Answer 11

1) Sleep homeostasis

2) Circadian rhythm

Question 12

How does sleep homeostasis control sleep?

Answer 12

• Sleep deficit accumulates

- Sleep-promoting substances such as adenosine build up and act to inhibit wake neural pathways

Question 13

How does caffeine keep you awake?

Answer 13

Caffeine acts as a adenosine receptor antagonist to promote wakefullness

Question 14

How does circadian rhythm control sleep?

Answer 14

Endogenous rhythm due external factors such as daylight

Question 15

What are the characteristics of circadian rhythm?

Answer 15

• Endogenous rhythm of 24 hours
• Generated by a master clock in neurons of the superchiasmatic nucleus (SCN) of the hypothalamus
• Rhythm is synchronised by time setters, notably the light-dark cycle
• Secondary or slave clocks present in several peripheral organs e.g heart, intestines, and coordinated by the master clock

Question 16

What happens to molecular signals in the clock neurons?

Answer 16

Transduced into electrical signals that are transmitted to other regions of hhypothalamus and brain to regulate feeding, locomotion, temp, hormone secretion, sleep-waking etc

Question 17

What are “morning larks” and “night owls”

Answer 17

People we have slightly shifted circadian rhythm (up to ~2 hours)

Question 18

Give an example of a sleep disorder involving a bigger shift in circadian rhythm

Answer 18

Familial Advanced Sleep Phase Syndrome (FASPS)

early wake and inability to stay up at night

Question 19

What are the symptoms of insomnia and what are the causes?

Answer 19

• Inability to sleep for adequate periods

- Stress, jet-lag, caffeine, shift work, depression

Question 20

What are the treatments for insomnia?

Answer 20

Lifestyle changes

Sleep-promoting medication

Question 21

What are the characteristics of narcolepsy?

Answer 21

• Inability to stay awake (sleep attacks - 30 secs to 30 min duration)
• Cataplexy - loss of muscle tone without loss of consciousness - in about 70% of narcolepsy patients
• Normal sleep disturbances
• Dream-like hallucinations at wake-sleep or sleep-wake
• Sleep paralysis

Question 22

What molecule is reduced/absent in narcolepsy patients?

Answer 22

Orexins

Question 23

What experimental evidence is there for this?

Answer 23

• Dramatic reduction in the cerebrospinal fluid in narcoleptics

Question 24

How does orexin maintain wakefulness?

Answer 24

Provides excitatory effects on the wake-active neurons (flip-flop switch in wake position)

Question 25

How does loss of orexin function cause the symptoms of narcolepsy?

Answer 25

• Sudden transitions between wake and sleep due to unstable switch
• Cataplexy (REM-like state) due to loss of wake-active inhibition of REM-active neurons

Question 26

How many cases of narcolepsy are due to orexin deficiency?

Answer 26

Very few in humans

Question 27

What are the 2 main risk factors for narcolepsy?

Answer 27

1) Susceptibility genes: most associated with immune system
- Class II HLA - mutant allele found in 98% of narcoleptics
- T cell receptor and others

2) Infectious agents
- Upper airway infection by streptococcus pyogenes and influenza A

Question 28

What is the most likely explanation for the majority of narcolepsy cases?

Answer 28

Autoimmune attack on orexin neurons

Question 29

What are the current treatments for narcolepsy?

Answer 29

• Amphetamines - promote wakefulness by raising monoamine transmitter levels
• Ticyclic anti-depressants, MAO inhibitors, SSRIs - to treat cataplexy
• Benzodiazepines - seditive to aid night time sleep

Question 30

What are the potential future treatments for narcolepsy?

Answer 30

• Orexin-replacement therapy

- Stem cell replacement