Regulation of Sleep

Defining Sleep and Sleep States

Sleep is an unconscious state, characterized by reduced responsiveness and immobility. The purpose of sleep is hypothesized to be one of recovery and repair for cellular metabolism and neuronal networks in the brain. Whatever its function, sleep seems to be necessary.  There is homeostatic regulation of sleep:  if a person or animal is deprived of sleep, the body compensates by increasing sleep at the next opportunity.

A useful technique that has been used to further define different states of consciousness and sleep states is electroencephalography (EEG).  EEG involves the recording of small voltage changes on the surface of the scalp.  These voltage changes arise due to the summed activity of neurons beneath the recording electrode.

During the waking state, when an individual has his eyes open and his mind focused, one records a beta rhythm. The beta rhythm is characterized by low amplitude, high frequency oscillations. Low voltages are recorded during the beta rhythm because many neurons are firing independently, hence another term for this pattern of EEG is desynchronized. By contrast, synchronized neuronal activity produces EEG patterns with larger amplitude oscillations such as the alpha rhythm, which can be recorded when a subject is awake, but with his eyes closed and his mind drifting.

EEG recording has been used to characterize different stages of sleep. Sleep can be divided into two broad stages: REM sleep and NREM sleep.

REM stands for rapid eye movement, which is one characteristic of REM sleep. It is also a time of vivid dreaming.  A key physical characteristic is a nearly complete lack of skeletal muscle tone. With the exception of the extraocular muscles that move the eyes and the muscles required for breathing, skeletal muscles are inactive.

Another feature of REM sleep is a desynchronized EEG. Even though a person is deeply asleep during REM sleep, the brain activity recorded resembles that of an awake person. For this reason, REM sleep is sometimes referred to as paradoxical sleep.

All other stages of sleep are grouped into NREM sleep, which stands for non-REM. NREM sleep includes periods in which synchronized neuronal activity produces the characteristic EEG pattern known as the delta rhythm, with high amplitude, low frequency (about 4Hz) oscillations. The time periods during which the delta rhythm occurs are called slow wave sleep.

After falling asleep, a subject will first spend time progressing through different stages of NREM sleep. After about an hour, the subject will switch into REM sleep for some time, during which there might be vivid dreaming. In a typical night, a person will switch several times between NREM and REM sleep, with REM sleep periods becoming longer as the person approaches the time for waking.  The transitions between different states (waking, NREM sleep and REM sleep) are normally rapid and complete.


Brain Regions That Control Sleep and Arousal

brain regions controlling sleep and arousalThe figure at right is a sagittal section of the brain focusing in on the diencephalon and brainstem. The figure shows the location of some of the nuclei that are important for the regulation of sleep and arousal. Nuclei are labeled using abbreviations of their anatomical names. (OPTIONAL:  click here if you are interested in the actual names). This figure is a simplification, and doesn’t include, for instance, cholinergic nuclei that are active during arousal and REM sleep.

Several lines of evidence implicate these regions in the control of sleep and arousal.


neurotransmitter and activity tableThe table shows the particular neurotransmitters released by the neurons in the different nuclei, and the level of activity during sleep and arousal. “++” denotes a high level of activity, while “0” means that the neurons are quiet and not firing action potentials.


The basic model for the regulation of sleep and arousal is as follows. The arousal-promoting nuclei (LC, Raphe, and TMN; left side of figure below) make broad, diffuse connections to the entire cerebral cortex. The neurotransmitters released (norepinephrine, serotonin, and histamine) act on receptors that are G-protein coupled receptors (7 transmembrane domain proteins) that mediate slow postsynaptic potentials.  They work to promote wakefulness through general activation in the cerebral cortex.  Some of the arousal-promoting nuclei also have an inhibitory connection to the sleep-promoting nucleus, VLPO.  The VLPO (right side of figure below) releases GABA, the major inhibitory neurotransmitter in the brain. The VLPO makes direct inhibitory connections to all of the arousal-promoting nuclei, promoting sleep and turning off arousal systems during non-REM sleep.

arousal-promoting vs. sleep-promoting nuclei

mutual inhibitionNote that there is mutual inhibition between the sleep-promoting and arousal-promoting nuclei. This creates a system in which transitions from one state to another are full, rapid and efficient. For example, a small change that promotes wakefulness, will cause inhibition of VLPO, and thus reinforce a transition to waking through removal of the VLPO inhibition on arousal-promoting nuclei.

The importance of the orexin-releasing LHA nucleus has been recognized since the late 1990's, when it was determined that orexin played a role in the disorder narcolepsy. The LHA is active during arousal, and makes excitatory connections to all of the arousal-promoting nuclei. It is thought that the activity of the LHA helps to strengthen the awake state, and to prevent unwanted transitions between waking and sleep. When orexin is deficient in narcolepsy, these transitions are not prevented.

Circadian Regulation of Sleep

A further factor involved in sleep regulation is that sleep follows a circadian rhythm. "Circadian" means "about a day". The suprachiasmatic nucleus (SCN) in the hypothalamus is the pacemaker that drives various circadian rhythms in the body. The SCN has an intrinsic pacemaker ability that is due to the activity of certain genes. We know this because circadian rhythms will persist even when subjects are kept in total darkness. Under normal conditions, input from the retina to the SCN entrains its pacemaker to the daily light-dark cycle. The SCN influences the sleep-wake cycle through indirect connections to the VLPO and LHA nuclei. The SCN also indirectly regulates secretion of the hormone melatonin by the pineal body.  Peak secretion of melatonin occurs in the dark, and it acts to reinforce the effects of the SCN on the sleep-wake cycle.

Drugs That Affect Arousal

Stimulants

Stimulants are used to treat excessive daytime sleepiness, as might occur in situations of sleep deprivation, or as part of a sleep disorder like narcolepsy. The most potent stimulants are drugs that increase the levels of dopamine, norepinephrine, and serotonin in the synaptic cleft. Examples are amphetamine and related compounds. These drugs increase neurotransmitter levels both by stimulating release as well as blocking reuptake. Amphetamine and related drugs have a strong potential for abuse because they also influence the brain’s reward system and produce feelings of euphoria.

The most prescribed stimulant today is the drug modafinil (Provigil). The mechanism of action of modafinil is unclear, although it also probably works to increase levels of dopamine and norepinephrine (and possibly also serotonin and histamine). Unlike other stimulants, it does not appear to affect the brain’s reward system, and so has much less potential for abuse.

A popular, widely used stimulant is caffeine. Caffeine has various pharmacological actions, but the one that is most likely involved in its action as a stimulant is that caffeine acts as an adenosine antagonist. Adenosine is a regulatory molecule released by neurons and glia, and it accumulates as a consequence of neuronal activity and metabolism. There is evidence to suggest that the accumulation of adenosine is what is responsible for sleep drive--the need for sleep that occurs after prolonged wakefulness.

Hypnotics

Sleep-promoting drugs are known as hypnotics.  Many of the hypnotic drugs have effects on GABA neurotransmission. Benzodiazepines are GABA potentiators, meaning they bind the GABA receptor at a site distinct from the ligand-binding site, and cause GABA to have an increased effect. Newer sleep drugs are known collectively as the “z-drugs”; examples are zolpidem (Ambien®), eszopiclone (Lunesta®), and zaleplon (Sonata®). These drugs are also GABA potentiators, although they are unrelated chemically to benzodiazepines. Their advantage over benzodiazepines is that they have a shorter half-life, and so are less likely to cause prolonged drowsiness.

A completely novel hypnotic called suvorexant (Belsomra®) was approved by the FDA in August of 2014. Suvorexant is an orexin antagonist, promoting sleep by blocking LHA stimulation of the arousal-promoting nuclei.

Two other types of sleep-promoting drugs work through entirely different mechanisms. Antihistamines such as diphenhydramine (Benadryl®) cause drowsiness by blocking histamine receptors (recall that the arousal-promoting TMN nucleus releases histamine as a neurotransmitter). Ramelteon (Rozerem®) is an agonist for melatonin, the hormone produced by the pineal body whose secretion is stimulated during darkness. Melatonin induces drowsiness, and works to coordinate the sleep-wake cycle with the dark-light cycle.

Gammahydroxybutyrate or GHB (Xyrem®) is a sleep-promoting drug that may increase GABA neurotransmission, or it may also bind to its own specific receptor. GHB has been approved specifically for the treatment of narcolepsy, to improve sleep consolidation.



Quick Quiz


Fill in Answer Correct False Correct Answer
1. Name the EEG pattern that is recorded when the subject is awake, alert, and with his eyes open.
2. During REM sleep, there is a nearly complete lack of _____________.
3. Name the nucleus that makes direct excitatory connections to the arousal-promoting nuclei.
4. What neurotransmitter is released by the neurons in this nucleus?
5. Name the nucleus that makes direct inhibitory connections to the arousal-promoting nuclei.
6. What neurotransmitter is released by the neurons in this nucleus?
7. "Z-drugs" enhance the effect of which neurotransmitter?
8. Which of the following might be taken during the day to prevent sleepiness in someone with narcolepsy? [benzodiazepine, zolpidem, antihistamine, modafinil, ramelteon]
9. Name the nucleus in the hypothalamus that is the pacemaker for circadian rhythms.
10. Caffeine is an antagonist for which of the following regulatory molecules? [acetylcholine, serotonin, norepinephrine, adenosine, GABA]


(Spelling must be correct)