15.3 Regulation of Sleep

Why Does Sleep Exist?

At first glance, the entire process of sleep seems maladaptive. While sleeping, organisms are not searching for food or mates and have reduced sensitivity to environmental stimuli, making them more vulnerable to predators or hazardous events. Despite this, almost all animals appear to sleep, even when they lack a central nervous system as is the case with Hydra (Kanaya et al., 2020). It therefore seems likely that sleep evolved in very primitive animals and gradually took on additional functions throughout the evolution of the animal kingdom.

In humans, sleep regulation can be modeled using the two-process model of sleep regulation. Process C refers to the circadian rhythms in the timing of sleep and wakefulness. There are endogenous rhythms to when you feel sleepy and when you feel most awake. For example, most of us feel fatigued and sleepy during the later hours of the evening, and we feel most alert in the morning hours. There is also a period of reduced alertness which occurs in the midafternoon. You may have experienced this as sleepiness after lunch. These cyclical rhythms in sleepiness and wakefulness are regulated by the circadian timekeeping system and the master clock found in the SCN. Process S refers to the homeostatic pressure to get restorative sleep. The more time it has been since you slept, the greater the pressure to fall asleep. After you have been awake for a while, a certain amount of sleep debt has accumulated, and you need a period of sleep to eliminate the debt. The interaction between these two processes determines the amount of sleep pressure at any given time and the likelihood of falling asleep.

Figure 15.12 Why we sleep

One major theory of the function of sleep is that sleep performs a restorative function, without which an animal’s performance is impaired in some fashion (Figure 15.12). In humans, when we don’t sleep, we feel tired and our ability to function is decreased on both physical and mental tasks. After sleeping, we feel better. There is significant evidence in support of this function at the behavioral, physiological, and molecular levels. Sleep deprivation impairs, among other things, cognitive function, tissue repair, attention to tasks, and even increases cancer risk.

One possible mechanism of the restorative function of sleep focuses on the neurotransmitter adenosine. Adenosine is released by neurons in response to excessive firing and metabolic exhaustion (Lovatt et al., 2012). During wakefulness, adenosine builds up in the brain, promoting sleepiness. It is then reduced during sleep. The impact of adenosine is counteracted by caffeine, giving coffee and other caffeinated beverages their ability to defer sleep onset. Caffeine has this effect by blocking action at the A2A adenosine receptor. This effect is temporary—once the caffeine wears off, a person is just as sleepy as if they had never had the caffeine.

Another possible mechanism for the restorative function of sleep is waste clearance. Metabolic waste products are removed from the brain at a higher rate during sleep than during wakefulness (Albrecht and Ripperger, 2018). One mechanism that clears this neural waste is known as the glymphatic system and this has been the subject of new and exciting research in neuroscience. In this system, cerebral spinal fluid (CSF) enters the brain then has an exchange with the brain tissue via the interstitial fluid. The byproducts of metabolism are collected and removed from the brain. The glymphatic system is active when animals are sleeping and it is largely quiet when animals are awake. Research has demonstrated that this rhythm in clearance is circadian in nature (Hablitz et al., 2020). Thus, sleep may serve as an active period when the brain is removing toxic waste (Jessen et al., 2015).

A second popular theory of sleep function is that it serves an energy conservation function. Energy usage is reduced during sleep, with the amount of savings varying from animal to animal. Animals spend a considerable amount of their energy budgets looking for food, and the reduction in energy usage during sleep could make a difference in evolutionary success. In fact, when we sleep our metabolism decreases by 10% (Sharma and Kavuru, 2010). Some species gain significant energy savings during sleep by reducing body temperature, but the reduction in muscle usage provides for significant savings. Many species also adopt sleeping postures that conserve heat, reducing the energy usage for body temperature homeostasis. At times when food is scarce, the reduction in metabolic rate during sleep could allow an animal to survive for a longer period of time than would otherwise be possible. While this theory is appealing, there are examples that do not support it. For example, some animals sleep a lot whereas others sleep very little. Lions and zebras both use relatively little energy; male lions do not hunt and grazing expends a small amount of energy. Yet lions sleep 15-18 hours a day and zebras sleep as little as 3-4 hours a day (Siegel 2005).

A third theory is that sleep enforces inactivity during periods of time when an animal’s survival would be negatively impacted by active behaviors. Thus, animals with specialized adaptations for nocturnality sleep during the day, when they would be more vulnerable to predation, and diurnal animals dependent on vision are safer being inactive during the night. However, it is not clear whether sleep is really necessary to enforce this kind of behavior pattern, with the added cost of loss of responsiveness to sensory stimuli.

Finally, there is the idea that in animals with complex nervous systems sleep serves an important role in the growth, development, and plasticity of the brain, particularly as it relates to functions around learning and memory. As an example, sleep deprivation studies have confirmed that learning and memory are negatively impacted by insufficient sleep through effects on signaling in hippocampal neurons (see Chapter 18 Learning and Memory).

These theories are not mutually exclusive. It seems likely that sleep evolved in response to bioenergetic pressures that resulted from circadian rhythms of energy availability and took on additional functions as nervous systems developed and became more complex.

Stages of Sleep

There is a clear distinction between your activity levels during sleep when compared to being awake. However, getting a good night of sleep is not a uniform process where you lay immobile in bed and your brain becomes quiet. In reality, your brain and your body cycle through 4 different stages and the whole cycle can take about 90 minutes (Figure 15.14). You may experience 3-5 cycles per evening.

Figure 15.14 Hypnogram

The stages comprising a cycle can be divided into non-REM (3 stages) and REM sleep. Non-REM sleep (also referred to as NREM sleep) is characterized by large amplitude, slow oscillations on the EEG, representing synchrony of electrical activity in the cortex (Figure 15.13). Muscle tone is reduced and movement is limited (but not eliminated).

• Stage 1 non-REM sleep is a transitional stage that occurs as one moves from wakefulness into sleep. This period lasts less than 10 minutes and is considered the lightest stage of sleep because you are easily woken up during this stage.
• Stage 2 non-REM sleep is where the majority of your sleeping time is spent. Your body temperature drops, your breathing rate slows, and your brain electrical patterns exhibit sleep spindles (Figure 15.15). Spindles appear on the EEG as rapid and rhythmic bursts of activity. Spindles are associated with learning capacity. This period lasts about 25 minutes.
• Stage 3 non-REM sleep, or delta sleep, or slow wave sleep is a deeper sleep where it may be hard to wake up even if there are loud noises or stimuli in the environment. The body's breathing rate is slowed and muscles are relaxed. In the EEG, delta waves appear which are slow frequency and high amplitude waves of electrical activity (Figure 15.15). This is the deepest stage of sleep and is the critical stage for restorative sleep as it is a time when the body clears out waste, builds bone and muscle and the immune system is strengthened. Decreases in the amount of slow wave sleep is associated with more fatigue during the day. Importantly, this stage of sleep is critical for memory consolidation.

Figure 15.15 Sleep spindles and delta waves Image credit: Sleep spindles from EEG by MrSandman at English Wikipedia. Transferred from w to Commons by en., Public Domain, https://commons.wikimedia.org/w/index.php?curid=453178. Delta waves from EEG Public Domain, https://commons.wikimedia.org/w/index.php?curid=453193

Finally, about 90 minutes after you fall asleep you enter the REM sleep phase. Here your brain EEG has electrical activity that resembles wakefulness; as such, this stage is referred to as "paradoxical sleep". Despite brain activity that resembles the waking state, your muscles are immobilized, breathing is fast and irregular, and your eyes exhibit rapid movements. This stage can last 10 minutes in the first sleep cycle of the evening, but as the night progresses, you spend an increased amount of time in the REM portion of the sleep cycle, perhaps as long as 60 minutes by the end of the night. In a typical night of sleep, you do not progress through the sleep stages in order. Initially you may enter stage 1 through 4 in sequence before reaching REM sleep, but at the end of the night you may cycle between REM and stage 2 and stage 3 non-REM sleep.

Regulating Sleep

When we are awake there are multiple brain areas that are actively responsible for keeping us in an awake state. However, you may not realize that when we are asleep our brains are not in an "off" state; instead, our brains remain engaged in active processes. While we sleep there are specific brain areas that are turned "on" to help regulate our sleep. During our waking period there are multiple brain areas, working together as part of the ascending arousal system, that secrete neurotransmitters which then maintain wakefulness (see Chapter 3 Basic Neurochemistry (Figure 15.16). The neurotransmitters that are secreted go to a sleep-promoting brain area to turn off its activity. This brain area, known as the ventrolateral preoptic area (VLPO, a region of the hypothalamus), communicates back to the wake-promoting system, and inhibits these structures in order to maintain a quiescent state. Thus, there is a brain area that promotes sleep, a second set of structures that promotes wakefulness, and these two systems inhibit one another. This is referred to as the flip flop switch.

Figure 15.16 Sleep circuitry

To be more specific, during wakefulness, in the brainstem, the locus coeruleus (LC) secretes norepinephrine and the raphe nuclei secretes serotonin. In the hypothalamus, the tuberomammillary nuclei (TMN) secrete histamine. Additionally, in the brainstem, near the pons are two groups of cells that secrete acetylcholine. These cells are located in the lateral dorsal tegmentum (LDT) and the pontine peduncular tegmentum (PPT). Together, these wake-promoting areas send projections through the rest of the brain to help maintain wakefulness. In contrast, there is a group of cells in the VLPO of the hypothalamus which promotes sleep. As mentioned above, there is a mutual inhibition between the sleep-promoting regions of the VLPO and the wake-promoting regions of the brainstem and hypothalamus. Specifically, the VLPO is inhibited by norepinephrine and serotonin via connections from LC and raphe nuclei; this occurs during wakefulness. The cells of the VLPO send neuronal projections containing the inhibitory amino acid GABA and the inhibitory neurotransmitter galanin to the aforementioned sleep-promoting brain areas. The VLPO thus inhibits these areas and as a result maintains sleep. These connections are diagrammed in Figure 15.17.

Figure 15.17 Reciprocal inhibitory connections of sleep areas Wake and sleep promoting regions inhibit each other.

Neuroscience across Species: Comparative Sleep

Adaptation to a variety of ecological niches has resulted in a wide range of sleep strategies and some unusual variations in sleep physiology. Just across mammals, sleep duration can vary from 4-20 hours per day, and length of time spent sleeping represents just one way in which sleep differs between species. Sleep may confer an advantage to remain quiet when predators are present, or to conserve energy for when food (prey) is abundant. For example, in sloths in the wild, predation appears to determine when they are sleeping and when they are awake (Voirin et al., 2014). The little brown bat sleeps for up to 20 hours a day, which might be due to the fact that its food source of moths and mosquitos is only present in a small window of time at dusk (Siegel, 2022).

Some mammals (whales, dolphins, fur seals, and sea lions) exhibit an unusual pattern of sleep called unihemispheric sleep. When in this state, one half of the brain is in a state of slow wave sleep at a time. Given the requirements of living in an aquatic environment, this makes sense: aquatic mammals must retain voluntary muscle control because they need to swim and surface to breathe, and maintain contact with conspecifics and be alert for threats. Behaviorally, the animals generally keep one eye open and one closed, with the open eye connected to the cerebral hemisphere that is awake. The open eye is usually the one directed towards other members of the group, rather than looking outward for threats, suggesting that these animals are utilizing unihemispheric sleep, in part, to maintain group cohesion. Unihemispheric sleep is also thought to occur in some birds and eared seals.

Sleep-like states can also be measured in other organisms that do not have an SCN, such as fruit flies. In this versatile lab model, circadian rhythms are controlled by about 150 cells which are clustered into groups (reviewed by Dubowy and Sehgal, 2017). Together these groups function like the mammalian SCN. Further, these clusters also have differences in neurotransmitter expression, much like the different subregions of the SCN. Fruit flies have states of rest (quiescence) which resemble sleep. These periods of resting are circadian regulated and therefore occur rhythmically. Further, there is a homeostatic drive and flies can be deprived of this rest period after which they show sleep recovery periods. These recovery periods have longer and deeper sleep, indicating a potentially restorative function. Lastly, during the sleep period the fly requires a stronger stimulus to arouse it, much like you would require a stronger stimulus to get your attention when you were sleeping compared to when you were awake (Dubowy and Sehgal, 2017). This laboratory model has proven to be extremely useful in dissecting the genetic underpinnings of sleep, since the genes and behaviors underlying sleep are conserved.

Sleep qualities have been examined in humans from industrialized areas and compared to hunter-gatherer tribes that have little outside contact and no electricity (Siegel, 2022). Interestingly, in both types of cultures, humans do remain awake after the sun has set. In the tribal communities, humans remain awake for about 3 hours after dark, and further, they acquire about 7 hours of sleep a night. An additional interesting result is that there are relatively low reports of insomnia in individuals from hunter gatherer societies (2% compared to 10-30% in industrialized societies).

Ultimately, sleep can vary within or between species due to mating opportunities, season, food availability and predation. A comparative approach investigating sleep between various species, may lead to a common factor or factors which may determine why sleep is important.

Sex as a Biological Variable: Sex Differences in Sleep Variables

Polysomnography studies both at home and in the sleep lab indicate that women have better objective sleep quality when compared to men. Women fall asleep faster, stay asleep longer, have less wakefulness during their sleep period, and have a greater percentage of slow wave sleep than men. Women also tend to have an earlier bedtime and earlier wake time than men. Men have lighter sleep and spend more time in non-REM stages 1 and 2 and are more easily woken compared to women. Men have less slow wave sleep than do women. Some of these sex differences in sleep variables may be caused by changes in circulating gonadal hormones in males and females. For example, sleep changes and sleep complaints occur in women as they experience fluctuations in hormones such as occurs at the onset of puberty, across menstrual cycles, during pregnancy, and during menopause.

There are studies in men that examine the relationship of testosterone with sleep. Generally, we can suggest that low levels of testosterone are associated with reduced sleep; although not all reports support this conclusion. In healthy males, testosterone peaks around the time that REM sleep stage begins. If a male individual has fragmented sleep or sleep deprivation, then testosterone is reduced. Men with androgen deprivation therapy, which is a treatment for prostate cancer, report an increase in insomnia (Gonzalez et al., 2018). In a study of men 65 years old and older, there was a relationship between low levels of testosterone, increased waking during the night, and less time spent in the restorative slow wave sleep stage (Barrett-Conner et al., 2008). In contrast, high levels of testosterone replacement in older men or young men taking androgenic steroids have a decrease in the amount of total sleep (Liu et al., 2003).

There is still a relative lack of research into how and why sleep is regulated differently in women compared to men. Some of this lack of information may exist because of differences in how sleep is measured, how hormone profiles are determined, and males and females report sleep problems (Mallampalli and Carter, 2014). However, we can describe some consistent changes that are associated with ovarian hormones in sleep in healthy women (see Chapter 11 Sexual Behavior and Development). During the follicular phase of the menstrual cycle, estradiol is rising. When it reaches a threshold, it triggers a surge of luteinizing hormone and this is followed by ovulation. The period after ovulation is called the luteal phase and this is when progesterone begins to rise. One conclusion that can be made from the literature is that during the luteal phase women experience more awakenings during the night and there is a reduction in slow wave sleep (Baker and Driver, 2007). Furthermore, sleep spindles increase during the luteal phase. Some, but not all, studies have found that the amount of REM may be reduced, REM may start earlier, and there is increased slow wave sleep during the luteal phase. However, when the follicular phase is compared to the luteal phase, PSG studies have found no difference in the time it takes to fall asleep, the time spent awake after falling asleep, or sleep efficiency (time spent asleep/time spent in bed).

Interestingly, changes in hormones such as occurs during menopause are associated with an increase in sleep complaints. As women transition through menopause, they have difficulty falling asleep and they have increased events of waking up during the night. This may be related to the decrease in estradiol and rise in follicular stimulating hormones which occurs at this time. However, some studies also found the speed at which these hormones changed also played a role (Baker et al., 2018). Additionally, women that take birth control report that this affects their sleep patterns. For example, they report more daytime sleepiness and insomnia (Bezarra et al., 2020). Relatively few studies have examined objective sleep measures in women on oral contraceptives. However, in one study, healthy women on oral contraceptives had disrupted sleep; they experienced less slow wave sleep and had a shorter latency to enter REM sleep (Burdick, Hoffmann, and Armitage, 2002).

There are also sex differences in sleep disorders. Insomnia can be defined as difficulty falling asleep and staying asleep, waking up too early, and having poor sleep quality. Insomnia is common in the general population with an estimate that approximately 30% of the population reports at least one insomnia symptom (Sateia et al., 2000). There is a striking difference in men and women with respect to the occurrence of insomnia: women are nearly twice as likely to report insomnia compared to men, and the risk of reporting insomnia increases with age. In fact women have a 40% greater risk for insomnia in their lifetime compared to men (Mong and Cusmano, 2016). This predisposition for women to have insomnia has been found consistently across studies. Interestingly, the sex difference in the number of complaints about poor sleep and insomnia in women begins at puberty, suggesting that ovarian hormones may be playing a role in this perception.

There are self-reported sleep disruptions that occur during the menstrual cycle, pregnancy, postpartum period, and when women are experiencing the transition to menopause. Sleep disturbances can have a significant impact on quality of life, mood, and health thus identifying how they may occur could lead to therapies. We have already discussed the findings that sleep is more disrupted in the luteal phase of the menstrual cycle. In pregnant women, subjective data indicates total sleep time increases in the first trimester but is dramatically reduced in the third trimester. Women in the last trimester also have more nighttime awakenings (Salari et al., 2021). This disrupted sleep is related, in part, to discomfort due to an increase in pain or decrease in bladder volume. However, treating insomnia in the third trimester can help alleviate postpartum depression (Khazaie et al., 2013). Objective measures of sleep using polysomnography confirmed that sleep variables are changed in pregnant women. Pregnant women had less total sleep, a longer latency to fall asleep, more awakenings, and less slow wave sleep. In the initial postpartum period sleep was significantly disrupted with total sleep time at night being reduced but there was an increase in daytime napping. As the postpartum period progresses, however, sleep quality does improve somewhat. Clearly, there are many factors influencing sleep during pregnancy including the dramatic shift in hormones, the physical discomfort experienced, and the needs of a newborn.

In menopausal women, the decline in sleep quality is one of the most common and problematic symptoms that women report. In this population, declining concentrations of estradiol and rising levels of follicular stimulating hormone are associated with more frequent awakenings and reduced sleep quality. While endocrine changes are likely playing a role in the sex differences seen in insomnia prevalence in all stages of life, we cannot rule out the influence of other factors including aging, quality of health, anxiety, depression, and hot flashes.

In conclusion, there is evidence that sleep in healthy individuals is regulated in part by circulating gonadal hormones and changes in hormones across the lifespan may contribute to sex differences observed in insomnia.