Sleep - What Sleep Is, How Sleep Works, Why Do We Sleep, How Sleep Can Go Wrong

HOW SLEEP WORKS

NEUROLOGICAL MECHANISMS OF SLEEP

The processes of sleep and wakefulness are mediated by networks of neurons in the brain (image from Wikipedia)
The processes of sleep and wakefulness are mediated by networks of neurons in the brain (image from Wikipedia)
Neurons (nerve cells) in the brain and brainstem produce a variety of nerve-signalling chemicals called neurotransmitters in different parts of the brain. These neurotransmitters in turn act on different groups of neurons in various parts of the brain, which control whether we are asleep or awake. As we have seen in the earlier section on the Two-Process Model of Sleep Regulation, the timing of the activation of these various different processes results from the interaction between the increasing homeostatic drive to sleep and the changing influence of our internal circadian clock.

In general, when the alerting areas of the brain are most active, they send arousal signals to the cerebral cortex (the outer layer of the brain that is responsible for learning, thinking, and organizing information), while at the same time inhibiting activity in other areas of the brain that are responsible for promoting sleep, resulting in a period of stable wakefulness. When the sleep-promoting areas of the brain are most active, on the other hand, they inhibit activity in areas of the brain responsible for promoting wakefulness, resulting in a period of stable sleep.

It used to be thought that the brain had a specific "sleep centre" (in the hypothalamus) and a separate "wakefulness centre" (in the reticular activating system in the brainstem), but more recent research has indicated that the situation is actually substantially more complicated than that: wakefulness actually appears to be regulated by a whole network of redundant structures in the brainstem, hypothalamus and basal forebrain, and is not centred in any one part of the brain.

The ventrolateral preoptic nucleus (VLPO) promotes sleep by inhibiting activity in the brain's arousal centres (image from Healthy Sleep)
The ventrolateral preoptic nucleus (VLPO) promotes sleep by inhibiting activity in the brain's arousal centres (image from Healthy Sleep)
The ventrolateral preoptic nucleus (VLPO or VLPN) of the hypothalamus is one area of the brain that is particularly involved in the switch between wakefulness and sleep. Neurons in this small area help to promote sleep by inhibiting activity in areas of the brainstem that maintain wakefulness. Likewise, in a process of "mutual inhibition", during waking hours, those areas of the brain that are active in maintaining wakefulness by stimulating the cerebral cortex also work to inhibit the neurons of the VLPO.

For this reason, the VLPO is often referred to as the sleep switch”, although this is really a gross simplification. In fact, several different simultaneous and interactive processes are involved - some of which are described below - and there is as yet no single unifying theory that describes all their interactions. It sometimes seems that the more we discover about the complex physiological and neurological mechanisms of sleep and wakefulness, the more complications and interactions come to light, and the more questions arise.

A whole cocktail of neurotransmitters are involved in driving wakefulness and sleep, including histamine, dopamine, norepinephrine, serotonin, glutamate, orexin and acetylcholine, among others. While none of these neurotransmission processes is individually necessary, they all appear to contribute in some way. Histamine in particular is sometimes referred to as the “master” wakefulness-promoting neurotransmitter, exhibiting high activity during wakefulness, decreasing activity during non-REM sleep, and its lowest levels during REM sleep (which is why histamine-blocking antihistamine medications cause drowsiness and increase non-REM sleep). Serotonin activity promotes wakefulness, increases sleep-onset latency (the length of time it takes to fall asleep) and decreases REM sleep. Acetylcholine activity in the reticular activating system of the brainstem stimulates activity in the forebrain and cerebral cortex, encouraging alertness and wakefulness, although it also appears to be active during REM sleep. Dopamine activity sometimes seems to promote wakefulness and sometimes sleep (it is also involved in the process of dreaming), so its role is still far from clear.

Orexin (hypocretin) is an important chemical in promoting wakefulnes (image from Nature Medicine)
Orexin (hypocretin) is an important chemical in promoting wakefulness (image from Nature Medicine)

Another important chemical in the sleep-wake cycle is orexin (also called hypocretin), a neurotransmitter that regulates arousal, wakefulness and appetite. Orexin is only produced by some 10,000-20,000 neurons in the hypothalamus region of the brain, although axons from those neurons extend throughout the entire brain and spinal cord. Activation of orexin triggers wakefulness, while low levels of orexin at night serve to drive sleep. A deficiency of orexin results in sleep-state instability, leading to many short awakenings and mixed-up REM and non-REM sleep states typical of sleep disorders like narcolepsy.

When sleep is called for, the normal signals of wakefulness are interrupted at the thalamus, which serves as the “gatekeeper” to the cerebral cortex (the furrowed outer layer of the brain where most conscious activity takes place), effectively disconnecting the cortex from most internal and external signals. It is largely the thalamus that imparts the regular slow brain waves of deep slow-wave sleep to the cortex, rather than the more unsynchronized cortical firing typical of the waking state and REM sleep. It has been shown that a damaged thalamus seriously interferes with sleep, and there is a very rare sleep disorder called fatal familial insomnia (FFI) in which malformed proteins called prions attack the sufferer’s thalamus, which effectively makes sleep impossible and which is in fact quite as fatal as its name suggests.

REM sleep in particular is regulated in a very specific part of the pons region of the brainstem, where a population of neurons are selectively active during REM sleep, even if disconnected from practically all of the rest of the brain. At the same time as acetylcholine neurotransmitters activate this part of the brainstem, two other areas in the pons are simultaneously inhibited in order for REM sleep to occur. Inhibitory signals are also sent from the pons to the spinal cord to bring about the temporary atonia or muscle paralysis that is characteristic of REM sleep. As a result of this, the release of neurotransmitters such as norepinephrine, serotonin and histamine, which normally stimulate motor neurons to create muscle activity, is completely shut down. The switching between non-REM and REM sleep during each sleep cycle is regulated by several complex interactions between various “REM-on” and “REM-offneurons, employing different neurotransmitters in various different regions of the mid-brain and hind-brain, all of which are necessary for the various characteristics of REM sleep to play out.

As described in the section on Sleep-Wake Homestasis, the homeostatic pressure to sleep is largely regulated by a neurotransmitter and neuromodulator called adenosine, which builds up throughout the day, and acts to inhibit many of the processes associated with wakefulness. During the night, after the body has received a certain amount of restorative non-REM sleep, adenosine levels start to decline. At this point, the systems responsible for wakefulness start to become more active (i.e. become less inhibited by adenosine), and conditions gradually become more favourable to awakening.

Small cell-signalling protein molecules called cytokines (such as interleukin and interferon, among others) are also involved in this process to some extent. Cytokines are chemicals produced by our immune systems while fighting an infection, but they are also are powerful hypnogenic chemicals, which is why infectious diseases like the flu tend to make us feel sleepy. It is thought that sleep may help the body conserve energy and other resources that the immune system needs to mount an attack on diseases.

Melatonin is naturally synthesized in the body from seratonin (image from Best Sleep Aids)
Melatonin is naturally synthesized in the body from seratonin (image from Best Sleep Aids)
Another neurotransmitter, serotonin, is also released in the brain throughout the day, which has the effect of stimulating a particular area in the hypothalamus, which in turn inhibits a different part of the same organ, all of which has the effect of encouraging sleep. Even more importantly, serotonin is used by the body to produce yet another hormone, melatonin, sometimes called the “ sleep hormone”, which is a major regulator our biological or circadian clock.

Melatonin is converted from serotonin in the pineal gland in the brain, under directions from the body's internal circadian clock (it can also be bought over the counter as a sleep medication). Melatonin production increases in the evening, chemically causing drowsiness and helping to lower body temperature, and then decreases back to its normal negligible daytime levels by the early morning. It is thought that melatonin secretion regulates the sleep-wake cycle, not by promoting sleep actively, but by inhibiting the circadian alerting system in the suprachiasmatic nucleus. Melatonin actually feeds back to the suprachiasmatic nucleus in order to regulate its own production.

Melatonin production is inhibited by light (and therefore stimulated by lack of light, or darkness), and so it effectively provides a kind of internal representation of the external light conditions. In non-equatorial regions, it also encodes the seasons to some extent, as night length changes throughout the year, which some animals use in their mating practices. However, it is not completely clear what exact sleep function melatonin carries out, especially considering that nocturnal animals like rats and hamsters also secrete melatonin at night, which is their active phase, suggesting that melatonin itself may not have any direct effect on sleep or alertness.

Towards the end of the night, the secretion of the stress hormone cortisol begins to increase in preparation for the anticipated stress of the day, usually capped by a particularly large increase (up to 50%) about 20-30 minutes after waking, known as the cortisol awakening response.