Andrey Nailor, M.D.·Published 23 August 2007·8 min read
Key points
The activity of the cerebral cortex is critical in determining whether sleep or wakefulness occurs, but it does not generate the drive to enter sleep or wakefulness.
It was originally thought to be a homogeneous system, but the complexity of its structure and function is now realized.
This is located in the medulla and is noradrenergic.
This is situated in the upper dorsal pons and is noradrenergic.
The activity of the cerebral cortex is critical in determining whether sleep or wakefulness occurs, but it does not generate the drive to enter sleep or wakefulness.
This is due to the interaction of many influences, some of which are localized to specific areas of the central nervous system and others which are more diffuse (Fig. 2.10). The most important anatomical structures concerned with sleep–wake regulation are as follows.
Ascending reticular activating system (ARAS)
The ascending reticular activating system is a physiological entity which promotes wakefulness when it is active and allows sleep when it is inhibited or inactive (Fig. 2.6). It was originally thought to be a homogeneous system, but the complexity of its structure and function is now realized. It governs the homeostatic drive and many of the reflex components of the adaptive sleep drive, and is closely connected to the circadian sleep rhythms.
The ascending reticular activating system is largely contained in the brainstem reticular formation which is a loosely connected structure with small groups of cells and nuclei, large numbers of short interneurones and complex ascending and descending interconnecting tracts.
Most of the reticular formation lies in the central core or tegmentum of the pons and midbrain, but it also extends into the medulla, hypothalamus and thalamus. It has a complex microstructure and GABA is secreted at most of its synapses. It has an extensive influence over the sensory input to the brainstem, motor function of the cranial nerve nuclei and spinal cord, and the state of sleep or wakefulness.
It also has close links, through the hypothalamus, with endocrine control.
Nucleus of the solitary tract
This is located in the medulla and is noradrenergic. It has connections throughout the pons, hypothalamus and thalamus. It is more active in NREM sleep than in wakefulness and electrical stimulation in animals promotes sleep.
Locus coeruleus
This is situated in the upper dorsal pons and is noradrenergic. It has widespread connections in the brainstem, thalamus and basal forebrain. It is most active in wakefulness, partially suppressed in NREM sleep and inactive in REM sleep. It inhibits the activity of the LDT/PPT and is itself inhibited by GABA-ergic neurones.
Raphe nuclei
These are situated in the midline in the midbrain and are serotonergic. The most important is the dorsal raphe nucleus. The raphe nuclei are most active in wakefulness, partially suppressed in NREM sleep and inactive in REM sleep. They are inhibited by GABA-ergic neurones. They inhibit the activity of the LDT/PPT and project to the hypothalamus. They may
Written and revised by
Andrey Nailor, M.D.
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contribute to the autonomic and motor responses to arousal from sleep and to the emotional state.
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Laterodorsal tegmental and pedunculopontine tegmental (LDT/PPT) nuclei
These are situated in the dorsal pontine tegmental reticular formation and their neurones are cholinergic. They are inhibited by the locus coeruleus, raphe nuclei and tubero-mammillary nuclei. They connect to widespread areas in the brainstem and to the thalamus. They are the primary REM sleep generator [21] and when active inhibit both the locus coeruleus and the raphe nuclei. They are also involved in generation of REM sleep atonia and contribute to visual components of dreams and hallucinations.
Mesolimbic system
This arises in the midbrain ventral tegmental area and projects to the prefrontal cerebral cortex, and to the limbic system including the amygdala and hippocampus, and particularly to the thalamic reticular nucleus.
It is dopaminergic and appears to cause arousal in response to specific stimuli rather than sustained wakefulness.
Tubero-mammillary nuclei (TMN)
These nuclei are situated in the posterior hypothalamus and are histaminergic. They only receive afferent input from the ventrolateral preoptic nucleus (VLPO) and the orexin system in the lateral hypothalamus.
They inhibit particularly the VLPO and the LDT/PPT.
The TMN are most active in wakefulness, partially suppressed in NREM sleep and inactive in REM sleep. The TMN promote wakefulness and suppress both NREM and REM sleep.
Perifornical nuclei
These are located in the lateral hypothalamus and their neurones secrete orexins (hypocretins). They project to the brainstem aminergic centres, particularly the locus coeruleus, but also the raphe nuclei. They are excitatory at these sites, but lead to inhibition of the LDT/PPT. They are most active in wakefulness, which they promote, and they limit the duration of REM sleep, but have direct effect on the VLPO.
Suprachiasmatic nuclei (SCN)
The SCN are responsible for circadian rhythms and promote wakefulness. Lesions of the SCN are associated with excessive sleepiness.
{pagebreak} Preoptic area of hypothalamus (POA) This important anterior thalamic area is the main site of integration of homeostatic and circadian drives. It includes the VLPO and VMPO, which are close to the SCN, as well as osmoreceptors which secrete arginine vasopressin (AVP).
Ventrolateral preoptic nuclei (VLPO)
These are situated inferiorly to the SCN and lateral to the third ventricle, adjacent to the ventromedial preoptic nuclei (VMPO). Their neurones secrete both GABA and galanine which are inhibitory neurotransmitters. They inhibit all the aminergic brainstem arousal nuclei, including the locus coeruleus, raphe nuclei, mesolimbic system and also the tuberomammillary nuclei.
The dorsal part of the VLPO promotes NREM sleep, and its medial extension, which projects particularly to the LDT/PPT, induces REM sleep. The VLPO activity is not related to circadian rhythms, but increases with sleep deprivation. The VLPO is active in sleep and inactive during wakefulness. Its widespread inhibitory connections give it the potential to cause a synchronized reactivation of the sleep promoting centres, but it is inhibited by the aminergic arousal systems, particularly the tuberomammillary nuclei, as well as the cholinergic basal forebrain.
Ventromedial preoptic nuclei (VMPO)
These are particularly involved with temperature control, but also modify sleep–wake function.
Median preoptic nucleus (MPN)
This is located in the hypothalamus, dorsal to the third ventricle, and is GABA-ergic. It receives input from the SCN and projects to the cholinergic neurones in the basal forebrain and to the perifornical nuclei. It is active during sleep, particularly stages 3 and 4 NREM sleep. {pagebreak} Subparaventricular zone This is close to the SCN and input from this is integrated with other influences which modify circadian rhythms of sleep, temperature (via the VMPO), behaviour and endocrine control.
Dorsomedial nucleus
This receives fibres from the subparaventricular zone and inhibits the VLPO. It is particularly involved with temperature control and feeding behaviour, as well as arousal. It also projects to the paraventricular nucleus and the perifornical nuclei.
Basal forebrain (substantia innominata)
This lies just anterior to the preoptic area of the hypothalamus. It contains groups of neurones which have important influences on sleep.
Basal nucleus of Meynert
Its neurones are activated by glutamatergic neurones from the pons as well as the locus coeruleus, raphe nuclei and perifornical nuclei. They are cholinergic and are inhibited by accumulation of adenosine.
Neurones related to the amygdala, nucleus accumbens and ventral putamen
These are heterogeneous. Some are GABA-ergic neurones which are active particularly in stages 3 and 4 NREM sleep and project to the LDT/PPT. Others secrete glutamate or galanine as transmitters.
{pagebreak} They project widely to the SCN and to the limbic system. This area of the basal forebrain acts as an ascending pathway of the reticular activating system and provides a ventral extra-thalamic relay to the cerebral cortex. It is active in wakefulness and in REM sleep, but inactive in NREM sleep. Adenosine accumulates in the extracellular spaces, attaches to A1 receptors and hyperpolarizes (inhibits) the cholinergic basal forebrain neurones, promoting NREM sleep.
Limbic system
The limbic system regulates both the autonomic nervous system and emotional reactions to external stimuli and memories, thereby making these systems more flexible and adaptive. It regulates mental state, motor activity – for instance related to fight or flight – and sexual activity, and responds to other stimuli such as those associated with thirst and hunger.
The most important areas within the cerebral cortex are the anterior cingulate gyrus, the para-hippocampal gyrus and the hippocampal formation in the temporal lobe, as well as the orbitofrontal region of the prefrontal cortex. The limbic cortex gives representation for autonomic function such as cardiovascular and gastro-intestinal control and is involved in behaviour related to emotion. It is inactive in NREM sleep, but active in REM sleep.
The non-cortical components of the limbic system include the amygdala, nucleus accumbens, part of the basal forebrain (basal nucleus of Meynert), and parts of the hypothalamus and some thalamic nuclei. In the midbrain the limbic system comprises the periaqueductal grey matter whose descending impulses influence motor nuclei, respiratory activity and cardiovascular aspects of autonomic function, particularly sympathetic responses.
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Thalamus
The thalamus is the final common path for most of the information reaching the cortex from receptors, apart from olfaction, and from the brainstem. The thalamus modifies these inputs, in effect acting as a gate determining which of the stimuli reach the cortex and in what form, although thalamic activity is itself regulated by the cerebral cortex. As the homeostatic drive to sleep wanes, the ability of the thalamus to block transmission to the cortex weakens and arousals occur.
The thalamic reticular nucleus is especially important in interacting with the cerebral cortex and determining the state of arousal. It has groups of excitatory neurones, which release glutamate, and inhibitory neurones, which release GABA at their synapses.
Intrathalamic relay neurones modify the thalamic activity whereas other neurones form the thalamocortical projection fibres. There is reciprocal activity between the thalamus and cerebral cortex through these fibres and thalamic excitation is followed by inhibition by corticothalamic impulses. Their timing determines the frequency of the bursts of thalamic stimulation of the cortex which varies from 0.6 to 1 Hz [22].
The thalamus filters and modifies activity from the ascending reticular activating system and other systems passing through the midbrain. It modifies midbrain spindle activity and through its widespread projections to the cerebral cortex is able to integrate and synchronize cortical activity. Synchronization of cortical activity initiates and maintains the state of NREM sleep. It effectively disconnects the cerebral cortex from brainstem and other influences, although this is reversible through the mechanism of arousal.
The thalamus not only protects the cortex from other incoming electrical impulses, so that it is deafferented or sensorily deprived, but also, through its GABA-secreting neurones, it inhibits brainstem centres that are capable of leading to an arousal. It also influences REM sleep through its projections to the LDT/PPT.
Although the thalamic arousal inhibiting mechanism responsible for NREM sleep has a global projection to the cerebral cortex there are also specific thalamic effects during NREM sleep, for instance on primary sensory areas [19].
Cerebral cortex
The cerebral cortex is an extensive heterogeneous structure, which has correspondingly complex effects on the initiation, maintenance and cessation of sleep.
The cerebral cortex is responsible for most aspects of the adaptive sleep–wake drive, and it enables the homeostatic and circadian influences on sleep to be more precisely adjusted to optimize responses to environmental changes. Cortical synchronization during NREM sleep is essential for the maintenance of this state, but its activity during REM sleep is more similar to that during wakefulness than to that during NREM sleep.
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