Sleep Mechanisms: Part II

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Neuroanatomy and physiology of sleep and wakefulness

It was thought that wakefulness is maintained by external and internal sensory stimulation of cerebral cortex and inhibition of sensory stimulation leads to sleep.

In 1949, Moruzzi and Magoun [] dramatically changed the existing concept of wakefulness and sleep. They discovered that stimulation of reticular formation maintains wakefulness even if sensory pathways are destroyed. The reticular formation is located in the brain stem and receives inputs from the ascending tracts, which are originated from spinal cord and brain stem. These ascending tracts give branches to the reticular formation and then pass to the thalamus. After relay in the thalamus, they reach the cerebral cortex. Lesion of the reticular formation causes a comatose state while ascending sensory pathways are intact.

It was later discovered that stimulation of the posterior hypothalamus produces EEG activation, while stimulation of the anterior hypothalamus promotes sleep. The pons, midbrain tegmentum, and the thalamus comprise the ascending reticular activating system. Steriade and McCarley 1990.

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It is believed that the thalamic inhibitory mechanism is responsible for transition from wakefulness to sleep. The sleep spindles are generated in the thalamus from onset of sleep. It is thought that spindle waves block activating input from the stem reticular system to the cerebral cortex at the thalamic level and as a result initiate and maintain sleep. B.M.Evans [] 2002.

The medullar reticular system also inhibits the midbrain activating reticular formation promoting sleep. Moruzzi, Magoun [] 1949.

Neurochemistry of sleep

Neural cell and synapses

A neural cell or neuron has many dendrites, which look like trees and serve for receiving information. One long processor - axon serves for output information. The body of neural cell and its dendrites are covered with thousand of synapses.

Through these synapses, the dendrites receive messages from the other neurons. These messages can inhibit or increase neuron activity. In the latter case, the neuron may generate action potential, which spreads along the axon.

An axon terminal forms a synapse, a structure comprised of axon terminal, presynaptic membrane, synaptic cleft and a postsynaptic membrane. Please see figure 1.

Synapse and Synaptic Transmission

Figure 1. Synaptic Transmission

The synapse contains vesicles with neurotransmitter. When action potential reaches the axon terminal, its membrane becomes permeable to Ca++ ions. Ca++ ions flow inside the terminal and cause vesicles to move to the presynaptic membrane and release a transmitter in the synaptic cleft. The transmitter molecules passively spread in the synaptic cleft and reach the postsynaptic membrane receptors. The transmitter binds to receptors and changes the potential of the postsynaptic membrane. The message is transferred to the next neuron.

There are many different neurotransmitters or neuromediators: norepinephrine, dopamine, serotonin, acetylcholine, gamma-aminobutiric acid (GABA), glutamine, etc. Transmitters can be inhibitory, excitatory or both, depending on receptor type.

Noradrenergic system (the locus coeruleus)

The locus coeruleus ("Blue spot") was discovered in 1786 by Félix Vicq-d'Azyr. .

It is located in the dorsolateral pons. In the 1960s it was discovered that the locus coeruleus is the major source of norepinephrine (noradrenalin) in the brain. Its neurons produce norepinephrine and send projections to the spinal cord, brainstem, midbrain, cerebellum, hippocampus, thalamus, and the cerebral cortex.

The locus coeruleus (LC) receive projections from many different brain regions, which release such a wide specter of neurotransmitters such as opiates, glutamate, GABA, serotonin, epinephrine. Aston-Jones G et al. 1991.

The suprachiasmatic nucleus, known as the circadian pacemaker, activates LC through the dorsomedial hypothalamus executing circadian regulation of arousal. Spontaneous activity of LC neurons depends on sleep-wake cycle. The highest neuronal activity, which is observed during wakefulness, is decreased during Non-REM sleep and absent during REM sleep. It is thought that LC is a part of activating system, which promotes cortical EEG arousal and hippocampal theta rhythm.

The Corticotropin-Releasing Factor (CRF), which is produced by neuroendocrine cells in the paraventricular nucleus of the hypothalamus and initiates adrenocorticotropin release from the anterior pituitary during stress, stimulates locus coeruleus neurons. LC plays major role not only in regulation of sleep-wakefulness, but also in stress related behavior.

Hypocretin (Orexin)

Recently, a neuropeptide called hypocretin/orexin, which has an important role in the sleep regulation, was identified independently by two groups of scientists. De Lecca et al. [] 1998. Sakurai T et al. [] 1998. The cells producing hypocretin/orexin are located in the dorso-lateral hypothalamus. These cells send their excitatory projections to the cholinergic pontine reticular formation, the spinal cord, locus coeruleus, dorsal raphe nuclei, amygdale, and basal forebrain.

The hypocretins are thought to play a primary role in the control of sleep and wakefulness as well as attention, learning, memory, feeding-energy regulation and modulation of pain at all levels of spinal cord. Ebrahim I.O. et al. []2002

Human narcolepsy, a disorder, which is characterized by excessive daytime sleepiness, with irresistible sleep attack or cataplexy (a sudden loss of muscle tone) , links to an 85-95% decrease of hypocretin neurons. Hypocretin neurons stimulate noradrenergic, serotonergic and histaminergic neurons promoting wakefulness and their activity decreases during Non-REM sleep. The other authors suggest that hypocretin neurons increase activity of acetylcholinergic neurons during active waking and REM sleep. Kiyashchenko L. et al. [] 2002.

Serotonergic System (The Raphe nuclei)

The raphe nuclei are located in the brain stem and send projection to almost every area of the brain." In order from the caudal to the rostral, the raphe nuclei are known as the nucleus raphe obscurus, the raphe magnus, the raphe pontis, the raphe pallidus, the nucleus centralis superior, nucleus raphe dorsalis, nuclei linearis intermedius and linearis rostralis "


The dorsal raphe nucleus (DRN) contains the largest pool of serotonergic neurons in the brain. The raphe sends predominantly inhibitory serotonergic projections to the dentate gyrus and moderate projections to Ammon's horn regions of the hippocampus. These projections end on the hippocampal interneurons. Microinjections of the 5-HT1a receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in median raphe increases anxiety. This compound inhibits serotonergic neurons in the median and dorsal raphe.

The microinjection of the 8-OH-DPAT in median raphe increases the hippocampal theta rhythm amplitude and the movement velocity of the freely behaving rats. Nitz D.A., McNaughton B.L. 1999. The dorsal raphe sent major projections to the dorsolateral pons which promotes REM sleep. The microinjections of the 8-OH-DPAT in the dorsal raphe increases REM sleep.

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The limbic cortical and diencephalic structures control the activity of the median and dorsal raphe serotonergic neurons by modulation of GABAergic neurons in the raphe nuclei. Varga et al. 2001, 2003. The activity of serotonergic neurons of the dorsal raphe nuclei decreases from waking through slow wave sleep to REM sleep, while the activity of the GABAergic neurons increases. The GABAergic neurons in the raphe nuclei may decrease the ascending serotonergic output by direct inhibition of serotonergic neurons or increase it by inhibition of GABA interneurons.

The serotonergic ascending pathway inhibits hippocampal theta rhythm and causes desynchronization of EEG. The GABA interneurons also inhibit glutamatergic projections from median raphe to the limbic theta rhythm generators. The blockade of the GABA receptors activates the glutamatergic pathway and promotes theta rhythm. Li et al. 2005.

Lesions in the centralis superior raphe (CeSR) and reticularis pontis nuclei (RPN) in cats decrease slow wave sleep (SWS) and parodoxal sleep (PS) and increase wakefulness. Drowsiness was increase during the light "day time" phase but not during the dark phase.

It is known that the circadian rhythm may be controlled by changes in serotonin concentration by an endogenous pacemaker (the suprachiasmatic nucleus) and by the light. The present study supports the concept of possible control of sleep - wakefulness cycle by the raphe nuclei. Arpa J et al. 1998.

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It is known that morphine increases the release of serotonin in DRN by inhibiting GABAergic projections to DRN, which imply participation of DRN in morphine addiction. The nucleus raphe magnus (NRM) and dorsal raphe nucleus (DRN) are involved in central modulation of pain by descending inhibitory pathways to spinal cord. Cucchiaro G. et al.[] 2005

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