The brainstem contains many small neural networks that regulate essential functions, including the arousal system, cardiovascular and respiratory control, and the control of somatic muscle tone.

This section is concerned with the arousal system that causes the brain to wake up. In particular, the regions of the brainstem concerned with arousal include the cholinergic neurones of the basal forebrain (the Nucleus Basalis and the nucleus of Meynert), the rostral projections of the noradrenergic nucleus known as the locus coeruleus, and the raphe nuclei that contain serotonin. These systems receive non-specific inputs from all the major sensory systems - somatosensory, proprioceptive, auditory, visual, etc, any of which can give rise to arousal from sleep. These non-specific pathways are essential role for the transition from sleep to waking and consciousness, and project rostrally to the thalamus and on to the cortex: they are known by the term ascending reticular activating system.

The cholinergic, noradrenergic and serotoninergic pathways that are involved in arousal have been described previously. They all project throughout the cortex, to the thalamic relay and reticular nuclei, and the hypothalamus; and they are all involved in the process of arousal.

The Sleep-Waking Cycle is controlled by the hypothalamus, with two centres alternating in activity; the anterior hypothalamus promotes sleeping, whereas the lateral hypothalamus promotes arousal. The'Flip-Flop' hypothesis is outlined below.

Models of systems that alternate between two states, such as sleep and awake, are often drawn as consisting of two groups of neurones, each promoting one state, and connected by inhibitory pathways. So the arousal centre inhibits the sleep centre, and vice versa, and when one is dominant the other is silent.

The flip-flop switch model suggests that the neurones that cause sleep are in the ventrolateral pre-optic area of the hypothalamus (VLPO) and that they inhibit the arousal system. When the arousal system is active, the VLPO neurones become silent, and the subject is awake (and vice versa for sleep).

The arousal system is activated from the many sensory systems that cause people to wake up - loud noises, bright lights, somatosensory inputs etc. But in the absence of such inputs there is a basic system controlling the sleep-waking cycle that depends on groups of neurones that alternate in their functions.

The ventrolateral preoptic nucleus (VLPO) (analagous to the intermediate nucleus of the human hypothalamus) is active during non-REM sleep, and releases the inhibitory transmitters GABA and galanin on neurons that, when active, promote arousal. The VLPO is in turn inhibited by neurons from brain regions involved in the arousal system.

Synchronisation of the EEG is promoted by the VLPO, whereas desynchronisation is promoted by the arousal system (see below). So sleep is an active process - not simply a withdrawal of activity - and the stages of sleep occur in a relatively predictable sequence, and appear to be controlled by different cell groups with different neurotransmitters, driven by the basic flip-flop circuit.

The activity of some neurones in the VLPO is promoted by serotonin, and is inhibited by the cholinergic and noradrenergic pathways of the arousal system. Another group of VLPO neurones is inhibited by serotonin. So the roles of these groups of cells and of serotonin has still to be resolved.

The arousal system consists of

• Cholinergic neurones at the pontine/midbrain border (including the dorsolateral tegmental nucleus and the pedunculopontine nucleus). Cholinergic activity is highest when awake and remains high during REM sleep, and is reduced or absent in non-REM sleep.
• Noradrenergic neurones of the locus coeruleus in the upper pons. Brainstem monoaminergic activity is highest while awake, reduced during non-NREM sleep, and absent in REM sleep.
• Serotoninergic neurones of the raphe nuclei in the midline of the medulla and pons.
• Histaminergic neurons of the tuberomamillary nucleus. These become active as soon as a person is awake but are completely silent during REM sleep.

Hypothalamic Nuclei involved in the Sleep/Waking Cycle   Top

Although not really part of the brainstem reticular formation, several hypothalamic nuclei are involved, along with the brainstem, in the sleep waking cycle. The suprachiasmatic nucleus determines the rhythm of sleeping and waking, and the lateral hypothalamic nuclei that contain orexins have recently been found to be of importance in arousal. Similarly the neurones of the anterior hypothalamus (VLPO) actively promote sleep. Both operate in part by their connections with the brainstem systems.

The Orexins (Orexins A and B) are two excitatory neuropeptide transmitters produced from the same gene by groups of neurones in the lateral and posterior hypothalamus. The axons of orexin neurones project to the cerebral cortex and brainstem nuclei, including the locus coeruleus, the raphe nucei and the ventral tegmental area.

Orexin neurons excite dopaminergic, noadrenergic, and cholinergic neurones and stimulate food intake, wakefulness and energy metabolism.

They are also involved in arousal, and deficiency of orexins can lead to the sleep disorder narcolepsy.

*

The diagram opposite shows the main interactions of orexin (hypocretin) neurones with cholinergic (BF, PPT), noradrenergic (LC), histaminergic (TMN) and serotoninergic (DR, CR) neurones that promote waking, as well as with the VLPO that promotes sleeping. Orexins seem to act as modulators of the sleep-waking cycle.

• A10: ventral tegmental area
• BF: basal forebrain cholinergic nuclei
• CR: serotoninergic caudal raphe
• DR: serotoninergic dorsal raphe
• LC: noradrenergic locus coeruleus
• LDT/PPT: laterodorsal tegmental nuclei/pedunculopontine cholinergic nuclei
• PRF: pontine reticular formation
• TMN: histaminergic tuberomammillary nucleus
• VLPO: ventrolateral preoptic area (GABA, Galanin).