The story of circadian science began much later, in 1729, when a French astronomer noticed something curious: the leaves of the mimosa plant continued to open and close on a 24-hour rhythm—even in total darkness.¹ It was an early glimpse of something we now know: life on Earth is wired to anticipate the rhythm of light and dark.

In humans, that rhythm is coordinated by the brain’s master clock, a tiny structure called the suprachiasmatic nucleus (SCN). This master clock helps our bodies stay in sync with the 24-hour day—aligning everything from sleep to hormone release to body temperature.

But the biggest breakthroughs in circadian science came more recently. Thanks to advances in genetics—think of DNA as the body’s instruction manual—we’ve discovered the molecular gears that keep this clock ticking. In 2017, the Nobel Prize in Physiology or Medicine was awarded to three scientists for uncovering the biological mechanisms behind the circadian rhythm.² Their research showed that clock genes carry instructions for building clock proteins—proteins whose levels rise and fall in a daily cycle. They discovered that a protein called PER accumulates at night and breaks down during the day. These discoveries helped explain how plants, animals, and humans stay synchronized with Earth’s 24-hour cycle.

Today, thanks to their work, we understand more than ever how vital our biological clocks are to our health. Our circadian rhythm influences nearly every part of life: energy, hunger, metabolism, fertility, mood, and more. And when the clock is disrupted, the impacts ripple out—affecting sleep, blood sugar, and mood, and raising risks for conditions like insomnia, diabetes, and depression.

The more we learn, the clearer it becomes: understanding and protecting our body’s natural rhythms is essential for protecting our health.

An Evolving History of Sleep-Wake Control

The Two-Process Theory (Process S and Process C)

Have you ever wondered why it’s harder to fall asleep some nights than others? Or why pulling an all-nighter feels so exhausting? This theory helps explain it.

Sleep and circadian health are vital to our physical, mental, and cognitive well-being. And while sleep has been described in medical literature since ancient times—dating back to 400 BCE—our understanding of how and why we sleep continues to grow.

It wasn’t until about 40 years ago that scientists proposed a powerful idea: that two separate but connected processes regulate when we sleep and wake. This became known as the two-process theory, introduced by Borbély in 1982.³ According to this theory, our sleep-wake patterns are governed by:

• Process C—the circadian drive for arousal, shaped by our body’s internal clock, repeating roughly every 24 hours
• Process S—the homeostatic sleep pressure, the natural buildup of sleepiness the longer we’ve been awake

At its core, Process C keeps us aligned with the rhythms of day and night, while Process S tracks how long we’ve been awake—and how much our body needs rest.

The Two-Process Theory of Sleep-Wake Control

Figure Legend: The two-process theory provides a framework to help understand the interaction between two forces that regulate when we are awake, when we are sleepy, and when we fall asleep. Process S, the homeostatic process, is considered to be our sleep drive or pressure to return to sleep. This pressure grows based on how long we’ve been awake and is related to our overall typical sleep health (visualized as the purple line in the graph above). Process C, our circadian process, is the 24-hour cycle that, during the daytime, opposes our drive to fall asleep. In the evening, Process C begins to align with Process S, letting the sleep gate open and then allowing our sleep drive to put us to sleep. This is the main factor keeping us asleep until morning (shown as the orange line). 

Notice in the figure that the sleep pressure (Process S) is at its lowest after a full restful slumber, but from the moment we open our eyes to wake, the sleep pressure starts to build again. However, it is balanced for most of the day by Process C (and spoiler alert, orexin). It is not until we begin to produce melatonin in the evening, which reduces our circadian drive to be awake (Process C), that an optimal difference between our drive to be awake and desire to fall asleep coincide to say it is time for our nightly slumber. Our Process S puts us to sleep, while our melatonin keeps us asleep for the remainder of the night. For sleep to happen, there needs to be an optimal difference between these two forces—a moment when the “sleep gate” opens, making it easier to drift into rest.

For years, scientists thought these two processes worked independently. But newer research shows they are deeply connected, working together to orchestrate our daily dance between alertness and sleep. Their interplay shapes not only when we sleep, but how well we sleep—and how we feel when we wake.⁴

Understanding this partnership gives us a valuable framework for thinking about sleep, circadian rhythms, and the health conditions that arise when these processes fall out of sync. But science doesn’t stop here. We’re continuing to “color in the space between day and night,” building a richer picture of how sleep, wakefulness, and circadian health work together to support our lives.

As research continues, we’re learning more about how these rhythms shape our health—and how we can work with them, rather than against them, to support better sleep, stronger minds, and healthier bodies.

By understanding how these processes work, we can make choices that honor our body’s natural rhythms—unlocking better rest, sharper focus, and more energy each day.

Integrating Neurotransmitters and the Sleep Switch with Process C and Process S

As we continue our journey through the history of sleep and circadian science, our next stop is a review of two key pieces of the sleep puzzle from the late 1990s. Clifford Saper, MD, PhD, and his colleagues at Harvard put forth a key sleep concept, which they called the “sleep switch.”⁵ The other piece of the story is that two groups of scientists at two different universities simultaneously discovered a neuropeptide (a chemical messenger in the nervous system that modulates the effects of other chemical messengers called neurotransmitters). One group called this neuropeptide orexin,⁶ and the other group called it hypocretin.⁷ Same neuropeptide, just different names. To avoid confusion, we will use the term orexin in this discussion. Both groups were studying obesity, and they first identified the role of orexin in feeding behavior. This next part might become a bit challenging, so bear with us as we explain how this all fits together.

Let’s look first at the sleep switch. Saper described the sleep switch as being a flip-flop switch, which has its basis in electricity, where a circuit is wired so that when it is flipped in one direction, it’s on, and in the other direction, it’s off, and the electricity stops flowing.⁵ The same is true in the sleep switch. (You can also think of this switch as a teeter-totter that is either all the way up or all the way down–again, no in between.) Sitting on either side of the switch are chemicals produced in the brain, called neurotransmitters, that, along with Process C and Process S, help control our sleep and wake states and regulate rapid eye movement (REM) and non-REM (NREM) sleep.^5,8

On one side of the sleep switch is the ventrolateral preoptic nucleus or VLPO, where brain cells (or neurons) produce GABA, a sleep-promoting neurotransmitter. Then we have brain areas on the other side of the switch that contain neurons that produce wake-promoting neurotransmitters. Simply put, when you’re awake, certain parts of the brain send signals that keep you alert and stop the sleep system from working. When you’re asleep, a different part of the brain takes over and shuts down the wake system.^5,9

If you really want to get into the nitty-gritty, check out the table below, which shows the parts of the brain in which these wake-promoting neurotransmitters are primarily produced. This will be helpful in understanding the figures that are coming in a bit.

Before the discovery of orexin, the primary wake-promoting neurotransmitters were thought to include norepinephrine, dopamine, serotonin, and histamine. Norepinephrine is also called noradrenaline–you may be more familiar with its cousin, adrenaline, a hormone that your body produces in response to stress. Dopamine is sometimes called the happy or feel-good neurotransmitter because, in addition to promoting wakefulness, it is also involved in the brain’s reward system. Serotonin has several different functions in sleep, depending on which brain areas and which receptors are involved. It acts primarily as a wake-promoting neurotransmitter, but it also has a role in sleepiness. Serotonin is also involved in stabilizing mood. Though you may not be familiar with histamine itself, you likely have heard of antihistamines, medications that are used to treat allergies and that some people use as over-the-counter sleep aids. It makes sense that if antihistamines put you to sleep, histamines would keep you awake.

Now we know not only that these original neurotransmitters play roles in controlling sleep and waking, but that the more recently discovered neuropeptide, orexin, is vitally important. The story of how scientists discovered the role of orexin in sleep is fascinating. Over the early years after orexin was discovered, scientists found interesting results when they were looking at animal models of obesity. These animals not only ate too much, but also had what looked like sleep attacks (they would suddenly stop moving and appear to be dozing off). Through a number of coincidences, Mignot’s lab at Stanford University¹⁰ and Siegel’s at UCLA¹¹ discovered that dogs and people with narcolepsy have few if any orexin-producing neurons in their brains. This finding led to further research into the role of orexin in sleep in general. 

Low and behold, orexin has been discovered to be the key neuropeptide that sits at the balance point or fulcrum of the sleep switch, keeping the brain at a steady state of sleep or wakefulness. Produced in a part of the brain called the lateral hypothalamus–but with projections widely throughout the brain–orexin stimulates or activates those brain regions that create the neurotransmitters that are also involved in the control of sleep–the norepinephrine, dopamine, histamine, and serotonin that we talked about earlier. Orexin also stops REM sleep (the dreaming stage of sleep). Another brain chemical called melanin-concentrating hormone (MCH) does some of the same things as orexin, but unlike orexin, MCH is most active during REM sleep.^13,14 Not only do orexin and these neurotransmitters play a major role in sleep and wake, but they are also involved in emotion regulation, help build memories, and manage how the body uses energy. 

Figure legend: The flip-flop switch theory provides a framework that suggests that sleep and wake should be mutually exclusive, meaning they should not be able to occur at the same time. Using an illustration of a seesaw helps depict this idea and places “orexin” at the fulcrum or midpoint, thus providing the direction of sleep or wake status. The boxes on the left-hand side of these diagrams show the brain areas where the wake-promoting neurotransmitters are produced. LC, locus coeruleus; SN, substantia nigra; VTA, ventral tegmental area; DRN, dorsal medial nucleus; TMN, tuberomammilary nuclei. The names of the associated neurotransmitters are on the lines. The box on the right-hand side shows the ventrolateral preoptic nucleus (VLPO). A: WAKE When neurons in the VLPO are inhibited or turned off, the arousal centers in the brain are activated or turned on, resulting in wake. B: SLEEP When the VLPO is active or turned on, the arousal centers in the brain are inhibited or turned off, resulting in sleep. GABA, gamma-aminobutyric acid. Adapted from: Enhancing the management of hypersomnia: examining the role of the orexin system. Semin Neurol. 2025 May 12. doi:10.1055/a-2589-3825. Epub ahead of print.

Figure legend: The orexin system acts as the conductor of the orchestra, regulating sleep-wake, behavior, mood, the autonomic nervous system, and numerous other processes and systems throughout the body based on the information it is constantly receiving from these areas, carefully making adjustments in response. Adapted from Enhancing the management of hypersomnia: examining the role of the orexin system. Semin Neurol. 2025 May 12. doi:10.1055/a-2589-3825. Epub ahead of print.

Keeping the right balance of neurotransmitters is important for a healthy sleep-wake cycle. Changing the sleep schedule can affect how these chemicals are made, released, or used. For example, not getting enough sleep or having a sleep disorder can throw off the balance of these chemicals, which can raise the risk of developing problems like depression, memory issues, and diseases that affect how your body handles energy. Alternatively, when the neurotransmitters are out of balance, people can develop sleep problems. For example, people with type 1 narcolepsy have few, if any, orexin-producing cells and therefore have REM episodes that intrude into wakefulness and wake episodes that invade sleep. To learn more about narcolepsy, visit Sleep Disorders.

Circadian Rhythm

A discussion of sleep and health must also include a thorough review of the body’s rhythms and how they interact with all of the other factors involved in sleep and wake.¹⁵ The biological time structure of the human body includes not only circadian rhythm, but also ultradian and infradian rhythms. Ultradian rhythm lengths vary from less than a second to several hours. Examples of these rhythms include the cycles of sleep stages throughout the night, hormone release, digestion and metabolism, and neurotransmitters, among others. Infradian rhythms last longer than 24 hours. Examples of these rhythms include hibernation, migration, the menstrual cycle, and changes in mood with the seasons (seasonal affective disorder). 

The circadian rhythm, which lasts about 24 hours, involves a primary pacemaker–the SCN–that under typical conditions coordinates the period and phase of rhythms driven not only by light-dark exposure, but also other structures in the body.¹⁶

• Clocks in cells, tissue, and organs, all of which have a common mechanism and involve clock genes
• Melatonin, which is produced in the pineal gland, circulates throughout the body in the absence of artificial light. Although most people associate melatonin and light as what directs circadian rhythm, entrainment also plays a role in circadian rhythm.
• Oscillators of the left and right cerebral cortices 

Although normally thought of as intrinsic (that is, arising from within our bodies), the circadian rhythm can also synchronize to cues received from the environment (called zeitgebers—German for “time givers”). The most powerful of these zeitgebers is light, but the timing of eating, exercising, engaging in social interactions, and work schedules can also serve as zeitgebers. When our internal rhythms are in sync with our environments, a number of body or physiologic processes take place at somewhat standardized times, as shown in the figure below.

Sleep Hormones

Disturbed Sleep

Our bodies produce a number of hormones that fluctuate throughout the dark-light or sleep-wake cycle. Interactions between the sleep and circadian systems influence a number of these hormones, including growth hormone, melatonin, cortisol, leptin, and ghrelin.¹⁷ The clock genes regulate glucose and lipid metabolism. Disturbed sleep negatively affects hormone rhythms and metabolism. Disturbed sleep is associated with obesity, insulin insensitivity, diabetes, hormonal imbalance, and appetite dysregulation.

*Associated with increased sympathetic nerve activity and stress response.

When Circadian Rhythm Is Disrupted

As we have noted, there is a circadian timing to almost everything in the human body.¹⁸ The health consequences of irregular or disrupted circadian rhythms are therefore widespread, affecting almost every aspect of our body’s functioning. When the circadian rhythm is disrupted, overall health may be worsened because glucose and lipid metabolism are upset, the rhythms regulating melatonin and cortisol are reversed, and the rhythm of the clock genes is lost. Chronic jet lag and shift work have been shown to change the expression, phases, amplitudes, and rhythmicity of clock genes.^17,19

The following table illustrates some of the consequences when we live out of alignment with our circadian rhythm. 

*Late-night eating and irregular meal timing worsen these effects.

Knowing the impact of circadian misalignment on our overall health helps us to understand the importance of maintaining proper light exposure, keeping a consistent sleep schedule, and adjusting lifestyle factors to keep our circadian rhythm in alignment. When traveling across multiple time zones, the best way to adapt (or entrain) sleep-wake timing is to be exposed to sunlight in your new location. On the other hand, after working the night shift, avoid exposure to daylight on your way home and sleep in a completely dark room to allow you to sleep during the day, and no matter what time of the 24-hour period you sleep, keep in mind the principles of good sleep hygiene. For more information on the effects of circadian misalignment on health, check out Across the Body.