By Daniela Pace MDS2033 Nervous System 2

MD2

Describe the mechanism of the sleep-wake cycle

The sleep wake cycle involves complex connections between the cerebral cortex, the thalamus
and the brainstem. The inhibitory neurotransmitter serotonin is said to be the main
neurotransmitter associated with sleep.
Areas in the brain associated with sleep are: the raphe nucleus containing serotonergic neuronal
fibres signalling to the brainstem reticular formation, thalamus, hypothalamus, most areas of the
limbic system neocortex of the cerebrum and to the spinal cord terminating in the posterior horns
where they can inhibit sensory signals, including pain. The nucleus tractus solitarius is also
concerned with sleep, as well as the rostral part of the hypothalamus and the diffuse nuclei of the
hypothalamus. Stimulation of the mentioned nuclei causes sleep.
The reticular activating centre is thought to be involved in wakefulness. When sleep centres are
not activated, the reticular activating nuclei are released from inhibition and can thus release
excitatory neurotransmitter acetylcholine (ACh) to the cerebral cortex and the peripheral nervous
system. The cerebral cortex and peripheral nervous system in turn send positive feedback signals
back to the reticular activating nuclei to further sustain wakefulness. Furthermore, wakefulness is
also sustained by the activation of the locus coeruleus via noradrenergic neurons, the raphe
nuclei via serotonergic nuclei and the tuberomammillary nucleus (TMN) via histamine-
containing neurons. TMN also produces orexin which provides excitatory stimulation to the
locus coeruleus and raphe nuclei where there are orexin receptors, thus sustaining wakefulness.
After the brain remains activated for many hours, the neurons in the activating system become
fatigued, causing weakening of the positive feedback loop of the reticular nuclei and cerebral
cortex and sleep-promoting effects of the sleep centres to take over, leading to sleep. The circuits
responsible for the awake state are inhibited by the neurons in the ventrolateral preoptic nucleus
(VLPO) of the hypothalamus.
During slow wave sleep monoaminergic and cholinergic systems are inactive. However, during
rapid eye movement (REM) sleep cholinergic neurons are active as ACh is released via the
reticular activating system.
The sleep wake cycle is a complex system and pathologies in any component of this system can
lead to sleep disorders. Lesions in the VLPO produce insomnia. While loss of orexin signalling
as a result of defective receptors or destruction of orexin-producing neurons causes narcolepsy.
Lesions in the raphe nuclei of the tractus solitarus can cause high states of wakefulness.