The sleep pathway

Question 1

Sleep pathway

Answer 1

The hypothalamus contains sleep-promoting neuronal populations: the ventrolateral preoptic area (VLPO) and median preoptic area (MNPO)
VLPO and MNPO primarily express the inhibitory neurotransmitters GABA and galanin, and project to the wake-promoting system
Adenosine has been shown to accumulate in VLPO
VLPO receives signalling inputs from suprachiasmatic nucleus
There are four adenosine receptors: A1R, A2AR, A2BR, and A3R
Adenosine activates adenosine receptors (A2AR) of VLPO and hence activating inhibitory neurons that inhibit ascending pathway
Moreover, adenosine activate the inhibitory receptor A1 expressed on ascending arousal areas such as BF
Caffeine is adenosine receptor antagonist

Question 2

Melatonin

Answer 2

Melatonin synthesis and secretion is enhanced by darkness and inhibited by light in response to photic information transmitted from the retina to SCN
Nearly 80% of the melatonin is synthesised at night, reaches a peak in the middle of the night (between 2 and 4 in the morning) and decreases gradually during the second half of the night
Melatonin activates high affinity ML1 sites and low affinity ML2 sites
ML1 receptors: GPCR that inhibits adenylate cyclase in target cells (of SCN), suppressing SCN stimulatory signaling
ML2 receptors (MT3), leads to phospho-inositides hydrolysis, inducing circadian rhythm phase shift
Melatoninreceptor stimulator:Ramelteon(Rozerem)

Question 3

The transitions between wakefulness and sleep are controlled by the “flipflop” switch

Answer 3

Activity of the monoaminergic ascending arousal systems inhibits the VLPO and activates the cortex, which leads to wakefulness. During sleep the VLPO inhibits the monoaminergic ascending arousal systems by direct GABAergic and galaninergic projections. Thus, via reciprocal inhibition each group inhibits the activity of the other, removing the inhibition onto itself, and thereby indirectly reinforcing its own activity

Question 4

Biogenic amines
NTs

Answer 4

-Dopamine
-Norepinephrine
-Histamine
-Serotonin
(5-HT)

Question 5

Amino acids

Answer 5

-Glutamate
-GABA

Question 6

SUMMARY

Answer 6

Sleep is subdivided into
Rapid eye movement sleep (REM)
Non-rapid eye movement sleep (NREM)
A wide range of neurotransmitters are involved in regulating sleep/awake cycle
Lack of sleep due to abnormality in sleep-awake homeostasis is called insomnia
Insomnia treated by benzodiazepines or Z-drugs
Excessive sleep due to abnormality in ascending reticular arousal system is called narcolepsy
Narcolepsy can be treated with amphetamines or H3 antagonist/inverse agonist