Science of Sleep: How is Sleep Regulated?

The transition is nearly instantaneous—you're awake one moment, asleep the next. This alteration of consciousness involves a swift but complex interaction between various parts of the brain. Meet the sleep switch and learn about its function. 

Stable Wakefulness and Stable Sleep

In every 24-hour period, it is common for people to be continuously awake for about 16 hours and then almost continuously asleep for approximately 8 hours. A small number of brain cells are responsible for keeping us awake or asleep—some cells promote wakefulness and others promote sleep. The neurons that promote wakefulness inhibit those that promote sleep, and vice versa. This interaction normally leads to either a relatively stable period of wakefulness or a relatively stable period of sleep.

Although the brain's control of sleep and wakefulness is not entirely understood, scientists have pinpointed many areas of the brain involved in regulating these processes and have learned a great deal about how these areas function. For example, we now know that several areas in the brainstem and hypothalamus promote wakefulness by sending arousal signals to the cerebral cortex, the brain’s largest region. These signals come in the form of chemicals called neurotransmitters. When neurons in the arousal areas are active, the cortex remains activated and we stay awake.

One area of the brain that promotes arousal is the tuberomammillary nucleus (TMN). Here, neurons release histamine as one of their neurotransmitters. Interestingly, many "anti-histamine" medicines block this arousing signal and cause sleepiness. Other neurons produce a neurotransmitter called orexin (also known as hypocretin), which directly stimulates the arousal centers as well as the cerebral cortex itself.

Another area of the hypothalamus is responsible for shutting down the brain’s arousal signals and causing the transition to sleep. Neurons in a part of the hypothalamus called the ventrolateral preoptic nucleus (VLPO) connect directly to the many arousal-promoting centers. Rather than stimulating activity in these areas, signals from VLPO neurons inhibit their activity. By shutting down the arousal centers, the VLPO promotes sleep.

A "Flip-Flop Switch" Between Sleep and Wakefulness

The ability to remain in a stable period of sleep or wakefulness is a result of what scientists call "mutual inhibition" between the wake-promoting neurons and the sleep-promoting neurons. So, for example, the areas of the brain that maintain wakefulness by activating the cortex also inhibit VLPO neurons. Conversely, when VLPO neurons fire rapidly and induce sleep, they also inhibit activity in the arousal centers such as the TMN.

Transitions between these stable states of wakefulness and sleep occur relatively quickly, often in just seconds. Some researchers have compared the neurological mechanism that controls these rapid transitions to the "flip-flop switch" in an electrical circuit. In the brain, the mechanism that maintains stability through mutual inhibition is triggered by changes in factors such as the body's drive for sleep or the circadian alerting signal. When one of these forces becomes strong enough, it drives the transition to the opposite state. The same "flip-flop switch" analogy also describes the brain mechanisms involved in switching between rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep. However, different neurotransmitters and different groups of neurons in the brainstem are involved in the transitions between REM and NREM sleep.

Factors That Influence These Transitions

People generally require several minutes to calm down and relax enough to fall asleep, and the deepest stages of sleep typically occur 20 or more minutes after sleep onset. However, sleep onset and associated loss of consciousness can occur in an instant. This is particularly obvious in very tired people who can fall asleep at inconvenient and sometimes dangerous times, such as when driving a car. Similarly, waking up from sleep can occur very quickly, for example in response to an alarm clock, although it typically takes people much longer to become fully alert after awakening.

There are many internal factors (such as homeostatic sleep drive and circadian rhythms) and environmental factors (such as noise) that influence the likelihood of falling asleep or waking up. For example, a powerful sleep drive builds up with prolonged wakefulness and shifts the balance toward sleep. How this occurs is not precisely known, but adenosine is one of the chemicals thought to accumulate during prolonged wakefulness. When it does, it serves to induce sleep by inhibiting wake-promoting neurons. Interestingly, caffeine inhibits the actions of adenosine and therefore helps maintain wakefulness.

The timing of transitions between sleep and wakefulness are also tied closely to the body’s internal biological clock located in the suprachiasmatic nucleus (SCN). This tiny structure—made up of approximately 50,000 brain cells—receives light signals directly from the eye, through the optic nerve. Light resets the clock to correspond to the day-night cycle. In turn, the clock regulates the timing of dozens of different internal functions, including temperature, hormone release, and sleep and wakefulness. The SCN promotes wakefulness by producing a powerful alerting signal that offsets sleep drive. The SCN promotes sleep by turning off the alerting signal. In addition, the SCN actively maintains sleep throughout the night even after sleep drive has dissipated in the second half of the night.

References

• Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 2001; 24:726-31.
• Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. 2005; Nature. 437:1257–1263.
• Fuller PM, Saper CB, Lu J. The pontine REM switch: past and present. J Physiol. 2007: 584(Pt 3):735–41.

Nodding off throughout the day and night may be normal for cats, but the interaction of two systems ensures that most people enjoy extended periods of wakefulness and sleep each day. 

Sleep Drive

Nodding off at an inopportune moment can be embarrassing or even dangerous. And anyone who has experienced even a short bout of insomnia can attest to the frustration caused by the inability to sleep at a desired hour. These instances might happen more often if it weren't for two systems whose interaction governs wakefulness and sleep.

We have all experienced that undeniable drive to sleep. Staying up much later than usual, or rising after only a few hours of sleep and then attempting to stay alert and functional throughout the day, serve as an unpleasant reminder of the power of the sleep drive. And even when we feel alert and are unaware of our sleep drive, it is always present and growing while we're awake. In fact, the only true way to reduce rather than mask sleep drive is to sleep.

Scientists refer to sleep drive as a homeostatic system. Like body temperature or blood sugar, sleep is regulated internally. For instance, when body temperature falls, blood vessels constrict and we shiver; when blood sugar levels rise, the pancreas secretes insulin; and when we remain awake for an extended period of time, structures in the brain promote sleep. Furthermore, the duration and depth of our sleep vary according to the quantity and quality of sleep obtained previously.

With every waking hour there is a strengthening of the homeostatic sleep drive. This strengthening isn’t directly measurable as a quantity, but experts think that it is the result of the level of brain activity during wakefulness. One hypothesis suggests that the build-up in the brain of adenosine, a by-product of energy consumption by cells, promotes sleep drive. The fact that both adenosine and sleep drive increase during wakefulness and dissipate during sleep suggests a possible link between the two.

Awake and Asleep

Homeostatic sleep drive is not the only force involved in regulating the transition from wakefulness to sleep. If it were, catnapping throughout the day and night would likely be the norm rather than the exception. After just a few hours awake, we might nod off for an hour and then rise again, only to succumb to sleep just a few hours later. Instead, most of us remain awake—and alert—for 16 hours or more each day without respite. And despite the fact that our sleep drive increases with every hour of wakefulness, we are typically no sleepier at 8:00 p.m. than we are at 3:00 p.m.

Click on the interactive activity below to learn how sleep and wakefulness are regulated throughout the day.

Our relatively steady state of alertness over the course of a 16-hour day is due to what scientists call the circadian alerting system, a function of our internal biological clock. The clock, which is responsible for regulating a vast number of daily cycles, is found in a relatively small collection of neurons deep within the brain. Under normal conditions, the clock is highly synchronized to our sleep/wake cycle. When it is, the clock's alerting signal increases with every hour of wakefulness, opposing the sleep drive that is building at the same time. Only when the internal clock's alerting signal drops off does sleep load overcome this opposing force and allow for the onset of sleep.

Sleep Drive and Body Clock Through the Night

In the first half of the nightly sleeping period your sleep drive is still significant, and your alerting signal is declining rapidly. In normal circumstances, this means it is easy to maintain sleep. However, after approximately four hours of uninterrupted sleep the situation changes. Now that your sleep drive has decreased, the simple absence of an alerting signal is no longer sufficient to maintain sleep. At this point, the internal clock, which was promoting alertness during the day, begins to play an active role in sleep promotion by sending signals to parts of the brain that serve this function. In this way, the homeostatic sleep drive and the circadian system, when synchronized, interact to provide consolidated periods of both alertness and sleep.

Alertness, of course, varies for most people over the course of a day. For example, the grogginess that people often experience in the mid-afternoon, and commonly attribute to a heavy lunch or a dull meeting, is usually the result of a brief lull in the strength of the alerting signal. While sleep drive continues to climb, there is an hour or two each afternoon during which the alerting signal fails to keep pace, and alertness suffers as a result. Many cultures have incorporated this lull into their lives by making mid-afternoon naps, or siestas, part of the daily routine.

Another variation in alertness can be found near the end of the waking period, when the alerting signal is at its highest. Sleep experts refer to the period from 8:00 p.m. to 9:00 p.m. (for people who follow a fairly typical sleep/wake schedule) as the "forbidden hour for sleep" because most people find it next to impossible to fall asleep between these times.

A Delicate Balance

It is clear that synchronization of the sleep wake schedule and the internal clock is essential to an individual's ability to maintain sleep and wakefulness when desired. This has been shown conclusively in sleep research and is widely supported by anecdotal evidence from people who fly across time zones or work night shifts. Both of these activities desynchronize sleep and wake patterns from the internal clock's circadian rhythms and result in an alerting signal that is too low when an individual wishes to be awake and too high to allow for a consolidated period of sleep.

References

• Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci. 1995; 15:3526–38.
• Saper CB, Cano G, Scammell TE. Homeostatic, circadian, and emotional regulation of sleep. J Compar Neurol. 2005; 493:92-98.

A number of factors including the cups of coffee we drink, artificial lighting and air travel can alter when and how well we sleep by influencing the sensitive systems that regulate sleep and wakefulness.

Sleep in the Real World

The internal mechanisms that regulate our almost ceaseless cycles of sleep and wakefulness make up a remarkable system. However, a variety of internal and external factors can dramatically influence the balance of this sleep-wake system.

Changes in the structure and function of the brain during development can have profound, if gradual, effects on sleep patterns. The amount of sleep we obtain generally decreases and becomes more fragmented throughout our lifespan. These and other variations associated with age are covered at length in the essay Changes in Sleep with Age.

Other factors that affect sleep include stress and many medical conditions, especially those that cause chronic pain or other discomfort. External factors, such as what we eat and drink, the medications we take, and the environment in which we sleep can also greatly affect the quantity and quality of our sleep. In general, all of these factors tend to increase the number of awakenings and limit the depth of sleep.

Light's Effect

Light is one of the most important external factors that can affect sleep. It does so both directly, by making it difficult for people to fall asleep, and indirectly, by influencing the timing of our internal clock and thereby affecting our preferred time to sleep.

Light influences our internal clock through specialized "light sensitive" cells in the retina of our eyes. These cells, which occupy the same space as the rods and cones that make vision possible, tell the brain whether it is daytime or nighttime, and our sleep patterns are set accordingly.

Due to the invention of the electric lightbulb in the late 19th century, we are now exposed to much more light at night than we had been exposed to throughout our evolution. This relatively new pattern of light exposure is almost certain to have affected our patterns of sleep. Exposure to light in the late evening tends to delay the phase of our internal clock and lead us to prefer later sleep times. Exposure to light in the middle of the night can have more unpredictable effects, but can certainly be enough to cause our internal clock to be reset, and may make it difficult to return to sleep.

Jet Lag and Shift Work

Normally, light serves to set our internal clock to the appropriate time. However, problems can occur when our exposure to light changes due to a shift in work schedule or travel across time zones. Under normal conditions, our internal clock strongly influences our ability to sleep at various times over the course of a 24-hour period, as well as which sleep stages we experience when we do sleep.

Individuals who travel across time zones or work the night shift typically have two symptoms. One is insomnia when they are trying to sleep outside of their internal phase, and the other is excessive sleepiness during the time when their internal clock says that they should be asleep. Half of all night shift workers regularly report nodding off and falling asleep when they are at work. This should be seen as an important concern both for individuals and society, given that airline pilots, air traffic controllers, physicians, nurses, police, and other public safety workers are all employed in professions in which peak functioning during a night shift may be critical.

The effects of shift work and jet lag on sleep are covered in much greater detail in Jet Lag and Shift Work and You and Your Biological Clock.

Pain, Anxiety, and Other Medical Conditions

A wide range of medical and psychological conditions can have an impact on the structure and distribution of sleep. These conditions include chronic pain from arthritis and other medical conditions, discomfort caused by gastroesophageal reflux disease, pre-menstrual syndrome, and many others. Like many other sleep disruptions, pain and discomfort tend to limit the depth of sleep and allow only brief episodes of sleep between awakenings.

Individuals of all ages who experience stress, anxiety, and depression tend to find it more difficult to fall asleep, and when they do, sleep tends to be light and includes more REM sleep and less deep sleep. This is likely because our bodies are programmed to respond to stressful and potentially dangerous situations by waking up. Stress, even that caused by daily concerns, can stimulate this arousal response and make restful sleep more difficult to achieve.

Medications and Other Substances

Many common chemicals affect both quantity and quality of sleep. These include caffeine, alcohol, nicotine, and antihistamines, as well as prescription medications including beta blockers, alpha blockers, and antidepressants.

The pressure to sleep builds with every hour that you are awake. During daylight hours, your internal clock generally counteracts this sleep drive by producing an alerting signal that keeps you awake. The longer you are awake, the stronger the sleep drive becomes. Eventually the alerting signal decreases and the drive to sleep wins out. When it does, you fall asleep.

A chemical called adenosine, which builds up in the brain during wakefulness, may be at least partly responsible for sleep drive. As adenosine levels increase, scientists think that the chemical begins to inhibit the brain cells that promote alertness. This gives rise to the sleepiness we experience when we have been awake for many hours. Interestingly, caffeine, the world’s most widely used stimulant, works by temporarily blocking the adenosine receptors in these specific parts of the brain. Because these nerve cells cannot sense adenosine in the presence of caffeine, they maintain their activity and we stay alert.

If sleep does occur following the intake of caffeine, the stimulant’s effects may persist for some time and can influence the patterns of sleep. For instance, caffeine generally decreases the quantity of slow-wave sleep and REM sleep and tends to increase the number of awakenings. The duration of its effect depends on the amount of caffeine ingested, the amount of time before sleep that the person ingests the caffeine, the individual’s tolerance level, the degree of ongoing sleep debt, and the phase of the individual’s internal clock.

Alcohol is commonly used as a sleep aid. However, although alcohol can help a person fall asleep more quickly, the quality of that individual's sleep under the influence of alcohol will be compromised. Ingesting more than one or two drinks shortly before bedtime has been shown to cause increased awakenings—and in some cases insomnia—due to the arousal effect the alcohol has as it is metabolized later in the night. Alcohol also tends to worsen the symptoms of sleep apnea, which will further disrupt sleep in people with this breathing disorder.

Dozens of prescription drugs that are used to help control common disease symptoms may have varying effects on sleep. Beta blockers, which are used to treat high blood pressure, congestive heart failure, glaucoma, and migraines, often cause decreases in the amount of REM and slow-wave sleep, and are also associated with increased daytime sleepiness. Alpha blockers, which are also used to treat high blood pressure and prostate conditions, are linked to decreased REM and increased daytime sleepiness. Finally, antidepressants, which can decrease the duration of periods of REM sleep, have unknown long-term effects on sleep as a whole. Some antidepressants, from the class of drugs known as SSRIs, have been found to promote insomnia in some individuals.

The Sleep Environment

The bedroom environment can have a significant influence on sleep quality and quantity. Several variables combine to make up the sleep environment, including light, noise, and temperature. By being attuned to factors in your sleep environment that put you at ease, and eliminating those that may cause stress or distraction, you can set yourself up for the best possible sleep.

We’ve already noted that too much light at night can shift our internal clock and makes restful sleep difficult to achieve. To minimize this effect, nightlights in hallways and bathrooms can be used. As for noise, although background sounds may relax some people, the volume level must be low. Otherwise, increased frequency of awakenings may prevent transitions to the deeper stages of sleep. Research shows that the ideal temperature range for sleeping varies widely among individuals, so much so that there is no prescribed best room temperature to produce optimal sleep patterns. People simply sleep best at the temperature that feels most comfortable. That said, extreme temperatures in sleeping environments tend to disrupt sleep. REM sleep is commonly more sensitive to temperature-related disruption. For example, in very cold temperatures, we may be deprived entirely of REM sleep. Lastly, it is worth mentioning that the preferences of a spouse or bedmate may have a significant effect on sleep, especially when a partner's sleep and wake times vary, or if he or she snores or suffers from sleep-disordered breathing.

For tips on how to improve your sleep despite all of these factors, see the section Overcoming Factors That Interfere with Sleep.

You will find more about typical sleep patterns in Natural Patterns of Sleep.