The Neurobiological Basis of Sleep and Sleep Disorders

Abstract

The functions of sleep remain a mystery. Yet they must be important since sleep is highly conserved, and its chronic disruption is associated with various metabolic, psychiatric, and neurodegenerative disorders. This review will cover our evolving understanding of the mechanisms by which sleep is controlled and the complex relationship between sleep and disease states.

Introduction: Defining and Measuring Sleep

As human beings, we sleep for approximately one-third of our lives, yet nobody knows why we do it, which molecular mechanisms are involved, or why sleep manifests as major changes in the brain’s electrical activity that are associated with unconsciousness. This condition is inherently dangerous, since it prevents animals from protecting themselves and from foraging for food. Therefore, it must serve important functions. This conclusion is underscored by the presence of sleep in all animals in which its essential features have been carefully sought (63) (FIGURE 1). The first of these features is rapidly reversible behavioral quiescence, which distinguishes sleep from seizure, coma, hibernation, and anesthesia. The second feature is reduced arousal. Empirically, this translates to reduced responsiveness to environmental stimuli, which distinguishes sleep from quiet wakefulness. The third feature is homeostatic regulation. This means that a set point exists for daily sleep, with deviations from this set point requiring compensation at a later time. Experimentally, this homeostatic property can be demonstrated by preventing an animal from sleeping and then observing a compensatory increase, or rebound, in sleep shortly afterward (23, 63).

FIGURE 1.

Core behavioral features of sleep

A: rapidly reversible quiescence can be demonstrated with a sufficiently strong stimulus, thus distinguishing sleep from seizure, coma, hibernation, and anesthesia. B: reduced arousal. A greater stimulus intensity is required to evoke a given behavioral response during sleep (red line) than during wakefulness (black line). C: the homeostatic nature of sleep is apparent from animals’ attempts to compensate for lost sleep. Black and red lines illustrate typical sleep cycles for control and sleep-deprived groups, respectively. Yellow bar indicates period of sleep deprivation. The next day, the sleep-deprived group sleeps more (i.e., rebounds) compared with the control.

Researchers have taken an additional approach to characterizing sleep in some animals. This approach involves using electrophysiological techniques, such as the electroencephalogram (EEG) to measure brain activity and the electromyogram (EMG) to measure skeletal muscle tension (22). These techniques have revealed the existence of two major sleep states in mammals, birds, and certain lizards (63). Non-rapid eye movement (NREM) sleep can be distinguished by slowing and synchronization of brain oscillations, whereas rapid eye movement (REM) sleep can be distinguished by brain desynchrony and muscle atonia (22). Importantly, both NREM and REM sleep states are also correlated with the essential behavioral features of sleep described above. Thus these behavioral features alone are considered to be sufficient to define sleep in animals in which electrophysiological recordings are particularly challenging, including fish and many invertebrates (63). Nonetheless, in some of these animals, such as fruit flies, crayfish, and worms, differences in brain activity have been confirmed between low and high arousal states (91, 93, 104), although in these organisms NREM and REM sleep states have not been observed, presumably because invertebrates lack the brain structures required for these phenomena.

Neuroanatomical Basis of Sleep Regulation

Although sleep involves changes in activity throughout the brain, this behavioral state is controlled by specific neural circuits. Mediators of external arousal cues include sensory neurons that project to the thalamus to promote waking (19, 63). In contrast, mediators of internal cues promote waking or sleep, depending on the source of the cue. This concept was elegantly first articulated in 1982, when researchers used EEG recordings of human subjects to tease apart the sleep/wake cycle into temporally distinct components. The results provided evidence for the first time that “two [internally driven] processes play a dominant role in sleep regulation: a sleep-dependent process (process S) and a sleep-independent circadian process (process C)” (17).

Process S represents the sleep-promoting, homeostatic component of sleep regulation. It rises with time spent awake and dissipates with time spent asleep, thus reflecting sleep need (FIGURE 2A) (17, 35). Since the needs fulfilled by sleep are unknown, process S is of great interest to neuroscientists and is being intensely studied using a variety of approaches. For example, process S can be approximated by measuring delta power, which is a mathematical transformation of the low-frequency EEG signature of the deepest stages of NREM sleep (6). Process S can also be approximated by measuring how much sleep the brain attempts to recover following a period of sleep deprivation. This so-called “rebound” manifests as a combination of increased depth and duration of sleep, with the relative changes in the two parameters varying with species. Despite great interest in process S, at the current time, neither its molecular nor its neuroanatomical basis has been identified.

FIGURE 2.

Neuroanatomy of sleep control

A: two process model for control of the sleep/wake cycle by the circadian clock (process C) and the sleep homeostat (process S). The clock drives a cycling pattern of arousal with a period of ~24 h. Process S increases during waking until it exceeds a certain threshold, after which it discharges, leading to suppression of waking and initiation of sleep. B: wake-promoting loci in the mammalian brain, including neuromodulatory centers of the ascending reticular activating system. C: orexin neurons in the lateral hypothalamus excite wake-promoting loci to stabilize the waking state. D: GABAergic inhibition of wake-promoting loci and other unknown targets promotes sleep. Color-coded key: BF, basal forebrain; TC, thalamocortical relay neurons; LH, lateral hypothalamus; VTA, ventral tegmental area; LC, locus coeruleus; DR, dorsal raphe nucleus; VLPO, ventrolateral preoptic nucleus; ZI, zona inserta of the subthalamus; MO, medulla oblongata; LDT/PPT, laterodorsaltegmental and pedunculopontine nuclei. Glut, glutamate; ORX, orexin; HA, histamine; DA, dopamine; NA, noradrenaline; 5HT, serotonin; ACh, acetylcholine.

In contrast, process C represents the wake-promoting contribution of the circadian clock (FIGURE 2A) (17, 35), which is now a mechanistically well-understood phenomenon (see below). Although clocks have been identified in nearly all tissues and cell types, the circadian regulation of the sleep/wake cycle originates in the body’s master clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus (84, 107). The SCN receives photic input from the retina via the retinohypothalamic tract (RHT). Input from the RHT phase-shifts the endogenous oscillatory activity of the SCN, thus altering the timing of its synaptic output (84, 107). The SCN regulates some brain regions directly (i.e., monosynaptically) and other areas indirectly. Circadian regulation of hormonal release appears to entrain some peripheral endogenous clocks, whereas temperature and feeding act as entrainment cues in other cells (20, 97, 112).

Part of the lasting appeal of the so-called two-process model for sleep/wake control has been its ability to simply and accurately approximate sleep drive across a 24-h cycle as the difference between sleep-promoting process S and wake-promoting process C. Thus, despite proposed additional elaborations, the two-process model still serves as a major foundation for neuroanatomical and molecular underpinnings of sleep regulation (18).

It is unclear where and how the brain integrates external signals from sensory neurons and internal signals from the homeostat and the clock to determine which arousal state should prevail. However, additional important brain loci are known to help maintain sleep/wake states or the switching between them. The subset of these loci located in the brain stem are known as the ascending reticular activating system (ARAS) and include the dorsal raphe, the ventral tegmental area, the locus coeruleus, and the laterodorsal tegmental and pedunculopontine nuclei, which release serotonin, dopamine, noradrenaline, and acetylcholine, respectively (19, 63, 111) (FIGURE 2B). These neuromodulatory nuclei project through two major pathways to additional arousal-regulating loci in the forebrain. The dorsal pathway modulates the thalamus, which receives much sensory information before passing it on to the cortex for further processing. The ventral pathway extends to the basal forebrain, which also projects to the cortex. The ventral pathway leading through the basal forebrain also includes nodes in the lateral hypothalamus and the tuberomamillary nucleus that release orexin (also known as hypocretin) and histamine, respectively (19, 63, 111). The orexinergic neurons enhance activity in many arousal-promoting nuclei, thus stabilizing and enhancing waking (36, 110) (FIGURE 2C).

The activities of particular brain stem neuromodulatory systems determine which combination of pathways will be activated, and consequently whether waking, REM sleep, or NREM sleep will ultimately result. For example, during waking, cholinergic and monoaminergic brain stem nuclei activate both the dorsal and the ventral pathways. As a result, the cortex is excited, and it can make sense of the external environment because the dorsal pathway maintains thalamic neurons in a firing mode that is conducive to throughput of sensory signaling (63). During REM sleep, cholinergic signaling continues to activate the ventral pathway and thus excites the cortex. However, monoaminergic signaling is simultaneously reduced, resulting in altered firing of thalamic neurons that filters out sensory signaling to the cortex (63). Cholinergic signaling during REM sleep also activates a descending pathway through the subcoeruleus nucleus that terminates with inhibition of motoneurons in the spinal cord, thus causing REM-specific muscle atonia (42). In contrast, during NREM sleep, cholinergic and monoaminergic signaling are both reduced, leading to dampened cortical excitation and heightened filtering of sensory information at the level of the thalamus (63).

The ARAS and the dorsal and ventral pathways to the cortex promote arousal during waking. But other brain loci have been proposed to suppress arousal. These include populations of GABAergic neurons within the cortex (45, 86), the brain stem (7, 8, 129), the ventrolateral preoptic nucleus (4), and other parts of the lateral hypothalamus (50, 60, 73, 124, 126), the basal forebrain (95, 136), and the subthalamus (76) (FIGURE 2D). When these various neuronal clusters are active, REM sleep or NREM sleep results, with switching between sleep states determined by an oscillatory circuit in the brain stem (7, 33, 52, 129, 130). Importantly, many of the sleep-promoting loci appear to form mutually inhibitory connections with arousal-promoting loci. This relationship has been likened to a flip-flop switch that favors rapid transitions and state stability (111).

Molecular Basis of Sleep Regulation

The functions of arousal circuits are determined by specific molecules expressed within those circuits. Therefore, at least some of those molecules must be required to initiate or maintain sleep/wake states. Identifying those molecules has been a goal of researchers interested in understanding sleep physiology and in treating sleep-related disorders. Unfortunately, the kinds of molecules that have been identified so far do not contribute to a coherent cellular function (FIGURE 3). This complexity has made it difficult to predict with any accuracy the identities of additional molecules that contribute to sleep regulation. Nonetheless, such molecules continue to be discovered, largely due to seven main approaches.

FIGURE 3.

Endogenous molecules that impact sleep and the approaches that led to their discovery

Only mammalian molecules are listed. Red, promotes waking; blue, promotes sleep; purple, promotes waking and sleep; asterisk, regulates sleep timing. Not listed: components of metabolic pathways for neurotransmitters, neurotransmitter receptors, and transporters. ^‡A gain-of-function mutation in NALCN decreases REM sleep but has no effect on total sleep duration (44). Loss-of-function mutations in the fly ortholog of NALCN, called narrow abdomen, increase sleep (64). Therefore, NALCN has been provisionally assigned a wake-promoting function.

Behavioral Pharmacology

Various drugs have well-established effects on arousal. The targets of these drugs thus inform our understanding of molecules that impact normal sleep and waking. Care must be taken in confirming such targets, however, since most drugs are selective rather than specific. As a result, a drug’s effects may be mediated by molecules other than an established target. For example, first-generation anti-histamines such as diphenhydramine are thought to promote sleep primarily by antagonizing histamine H1 receptors (67). As discussed above, histamine release by the tuberomamillary nucleus promotes waking. Thus it makes sense that antagonism of histaminergic signaling would promote sleep. However, first-generation anti-histamines also have off-target effects on structurally related muscarinic acetylcholine receptors. Since cholinergic signaling promotes arousal, antagonism of muscarinic receptors by early forms of anti-histamines also probably contributes to the soporific effects of these drugs (67). Other common sleep aids include barbiturates, benzodiazepine, and non-benzodiazepine hypnotics. These three classes of drugs potentiate signaling by GABA_A receptors (34), which is consistent with the arousal-suppressing effects of GABA discussed earlier.

Stimulants co-opt endogenous arousal-regulating mechanisms as well. For example, amphetamine and methamphetamine are thought to promote waking by enhancing cortical release of monoamines, especially dopamine (92). In contrast, caffeine is thought to promote waking by preventing the endogenous somnogen, adenosine, from stimulating excitatory adenosine A2 receptors in sleep-active neurons in the basal forebrain (19, 57, 74). Caffeine-insensitive adenosine signaling also appears to promote sleep. For example, adenosine A1 receptors inhibit wake-active neurons in the basal forebrain (10, 51) and brain stem (11, 103). Interestingly, increases in synaptically released adenosine in the basal forebrain correlate with time awake and thus sleep pressure in the cortex (100, 121) (but also see Ref. 16). As a result, adenosine signaling has been proposed to reflect homeostatic sleep drive. Although some studies have suggested that A2 receptors may mediate such signaling, increasing evidence suggests that neuronal A1 receptors are involved (14, 15, 100, 101, 120, 125), perhaps due to increased release of adenosine from astrocytes (14, 48, 113). Also consistent with its proposed function as an endogenous somnogen, adenosine is increased by the sleep-promoting factor prostaglandin D2 (58), whereas genetic manipulations that reduce adenosine also reduce sleep (96).

Circadian Clock Studies

Based on research from both flies and mice, we also know the molecular composition of the core circadian oscillator, a major regulator of the timing of arousal. In mammals, this oscillator utilizes the transcription factor CLOCK or its homolog NPAS2 and another transcription factor called BMAL1, which heterodimerize to activate transcription of clock-controlled genes (37, 84). Many of these genes control bodily functions at certain times of day. However, some of these genes function together with CLOCK/NPAS2::BMAL1 to allow the molecular clock to cycle. For example, the Period (Per) and Cryptochrome (Cry) translation products heterodimerize as PER::CRY to repress CLOCK/NPAS2::BMAL1. The net effects of this negative feedback loop are waxing and waning of CLOCK/NPAS2::BMAL1 activity and therefore cycling transcription of clock-controlled genes, including Per and Cry (37, 84, 122). In a second loop, CLOCK/NPAS2::BMAL1 upregulate transcription of Ror and Rev-erb α/β, which feed back to maintain appropriate transcription of Clock and Bmal1 (54). Other essential components of the molecular clock regulate the stabilities, interaction partners, and subcellular localizations of components of these loops (54, 122). The coordinate function of all of these core clock molecules leads to transcriptional [or, in some cases, indirect posttrancriptional (46)] cycling of downstream effector genes over a period of ~24 h. Since the clock regulates the timing of the sleep/wake cycle, it is not surprising that some core clock genes are also required for normal sleep timing and duration. For example, knockout of Clock or Npas2 causes a reduction in sleep (43, 89), and double knockouts of the two Cry homologs Cry1 and Cry2 cause an increase in sleep (132). The downstream transcriptional targets of these genes that are ultimately responsible for effects on arousal have yet to be identified.

Genetics of Sleep Disorders

A third approach to understanding the molecular basis of sleep regulation has been to identify families suffering from heritable sleep disorders, map the responsible genes, and confirm their identities by phenocopying disorders in mutant animal models. This approach has historically been very time-consuming, but it has also benefitted from circadian clock research, which has provided candidate genes to inspect for aberrations in patient populations. For example, patients with familial delayed sleep phase disorder (DSPD) typically wake up late in the morning and fall asleep late at night (65). This behavior has been mapped to a gain-of-function mutation in the gene encoding the core circadian clock gene Cry1 that causes its translation product to constitutively repress the circadian transcriptional activators CLOCK and BMAL1 (98). In contrast, patients with familial advanced sleep phase disorder (ASPD) typically wake up and fall asleep very early. Behavior in a subset of these patients has been mapped to loss-of-function mutations in another core circadian repressor, Per2, and in a kinase that controls PER2’s stability called CKIδ (49). Last, some naturally short sleepers rise early in the morning, like patients with ASPD, but exhibit normal timing of sleep onset in the evening. Some of these individuals have been shown to carry a mutation in Dec2, a clock-controlled repressor of various other cycling genes (53). Mice engineered with the same mutation have elevated levels of the wake-promoting neuropeptide orexin, and their excess sleep can be attenuated with an orexin receptor antagonist, suggesting that the DEC2 protein normally limits orexin levels to facilitate sleep (55). Rapid advances in whole-genome sequencing promise to accelerate progress in human sleep genetics in the near future.

Forward Genetic Screens in Mammals

Identifying additional molecules involved in sleep regulation has been difficult for many reasons. In particular, such molecules have often been unpredictable, so some researchers have attempted to discover them by using unbiased screens for mutants that exhibit altered sleep phenotypes. In mammals, such screens are very time-consuming, labor-intensive, and expensive. For these reasons, only one forward genetic screen for sleep mutants has been successfully conducted in mice. So far, only two mutants have emerged from this screen. The first, called Sleepy, contains a splicing mutation in a kinase-encoding gene called Sik3 that causes increased NREM sleep by mechanisms that are not yet clear. The second sleep mutant, called Dreamless, appears to possess a gain-of-function mutation in a gene encoding the leak sodium channel NALCN. Consistent with the selective reduction in REM sleep that it causes, this mutant exhibits increased electrical activity in part of the brain stem oscillator responsible for shutting off REM sleep (44).

Studies in Genetically Tractable Invertebrates

The discovery that NALCN is required for mammalian sleep regulation was actually preceded by the discovery that an NALCN homolog called narrow abdomen stabilizes sleep and wake states in flies, with loss-of-function mutations leading to an increase in total sleep (64). These findings illustrate the power of invertebrate behavioral genetics when it comes to predicting the identities of novel mammalian sleep-regulating genes. In fact, although many genes have now been implicated in sleep regulation in flies (2), only a subset of these has been tested for homologous functions in mammals. One of these is the Shaker potassium channel. Loss-of-function mutations in Shaker lead to a near abolition of sleep in flies (30), and knockout of the mammalian Shaker homolog Kv1.2 also reduces sleep in mice (40). Shaker was identified in a forward genetic screen for sleep mutants (30). Molecules identified in such screens tend to have the most profound phenotypes. Other examples include sleep-promoting positive regulators of Shaker, such as Hyperkinetic (21) and Sleepless/Quiver (72, 135) [which also downregulates nicotinic acetylcholine receptors (134)]; the sleep-promoting E3 ubiquitin ligase insomniac (119); the sleep-promoting cyclin A (106), its regulator taranis (1) and regulator of cyclin A1 (106), and its likely effector cyclin-dependent kinase 1 (1); and the wake-promoting RNA-editing enzyme ADAR (105). Except for Shaker and its positive regulators, which reduce excitability, and to some extent for ADAR, which restricts prolonged presynaptic release of glutamate, the mechanisms by which these sleep-regulating molecules modify neuronal function are unknown.

Electrophysiological Studies Combined With Gene Knockouts

The genes described above illustrate another point: molecules that regulate excitability and synaptic physiology are highly represented among genes that have large effects on sleep. To some extent, this finding is expected, since excitability and synaptic transmission are essential to establishing and maintaining the properties of neural circuits. This idea has led several groups to identify ion channels known to contribute to the firing properties of arousal-controlling brain loci, genetically ablate the corresponding genes, and measure the resulting sleep phenotypes of mutant animals. As a result, it is now known that T-type calcium channels and Kv3-type potassium channels are required for burst firing of thalamic neurons that contribute to brain oscillations during NREM sleep (9, 12, 27, 41, 99). It seems likely that additional ion channels will emerge as essential to sleep/wake control as other arousal-regulating nuclei are characterized electrophysiologically and their underlying currents are manipulated in knockout studies.

Microarrays

Forward genetic screens offer the advantage of starting out with an established phenotype. However, mapping the responsible gene, then figuring out where and how it functions can be slow, expensive, and labor-intensive. An alternative screening approach that largely avoids these problems has been to use microarrays to identify genes that are differentially expressed during sleep and wake states. Such studies have demonstrated that, relative to extended waking, sleep causes upregulation of transcripts implicated in macromolecular biosynthesis and synaptic depression, and sleep causes downregulation of brain transcripts implicated in cellular stress responses, energy homeostasis, and synaptic potentiation (29, 31, 79, 81, 123).

Importantly, these patterns of altered gene expression are conserved among flies, birds, and mammals, suggesting that they reflect core rather than species-specific mechanisms (28). However, adrenalectomized mice show fewer changes in gene expression across the sleep/wake cycle (85). This result illustrates a major disadvantage of microarray studies over other approaches to identify molecules involved in sleep regulation; i.e., it is difficult to distinguish between transcriptional changes to stressful responses, which include extended waking and sleep disruption, and transcriptional changes to more specific mechanisms involved in sleep/wake control and function. Thus microarrays should be viewed as a starting point for formulating a hypothesis about general mechanisms. But demonstrating a causal relation between a gene and its role in sleep regulation requires validation, often by recapitulating a relevant phenotype using pharmacological or genetic ablation of the molecule in question. So far at least, data obtained by microarrays has not reached this stage.

Connections Between Sleep and Disease

Disturbances in circadian functions and sleep have long been associated with metabolic, psychiatric, and neurodegenerative disorders. However, increasing evidence suggests that such disturbances may not always be secondary symptoms but may in fact contribute to the etiology and severity of disease states (FIGURE 4). In some cases, the causal relation can be traced to dysregulation of one or more neurotransmitter systems that control arousal, or to a disruption in circadian timing of sleep (see above). In other cases, however, the relation is unclear, in part because the mechanisms underlying sleep regulation and sleep-related disorders are poorly understood. Below is a list of common types of these disorders and a brief description of how they impact or are impacted by the circadian and sleep systems.

FIGURE 4.

Interaction between sleep and disorders of the nervous system

Many disorders disrupt sleep (arrow from green to blue circle). In other cases, low sleep exacerbates existing health problems (arrow from blue to yellow circle). Positive feedback may exist between poor-quality sleep and still other disorders (bidirectional arrow between blue and pink circles).

Insomnia

People suffering from insomnia have trouble falling asleep, staying asleep, or feeling refreshed following sleep (5). Up to 10% of adults are afflicted with insomnia severely enough for it to be referred to as a chronic disorder, and at least another 40% of the population is estimated to suffer from its symptoms intermittently (87). Its causes are multivariate, but ultimately they lead to hyperactivity of subcortical arousal-promoting neural circuits during sleep (94). The American College of Physicians recommends cognitive behavioral therapy, which involves a combination of mental exercises and healthy sleeping habits as a primary approach to treating insomnia (102). Non-benzodiazepines are a common alternative that function by elevating inhibitory GABAergic signaling, thus suppressing arousal. More recently, orexin receptor antagonists have also been approved for treatment of insomnia (56).

Although insomnia is moderately heritable, specific genetic risk factors for it are largely unknown (75). One exception is fatal familial insomnia (FFI), a rare autosomal dominant disease caused by a specific mutation in the prion protein gene PRNP. Symptoms of FFI initially include insomnia and autonomic dysfunctions (e.g., tachycardia), followed by progressive cognitive and motor impairment, and finally death. These symptoms result from neuronal and astrocytic cell death in brain regions through which PRNP rapidly spreads, including the thalamus, a known locus for control of sleep (77).

Narcolepsy

Patients with narcolepsy exhibit excessive daytime sleepiness associated with frequent intrusions of REM sleep into the waking state. Narcolepsy is also often accompanied by cataplexy, which is a temporary state of paralytic muscle weakness whose onset is triggered by positive emotions such as excitement or laughter. During these periods of paralysis, patients are conscious of the world around them. Thus the cataplectic state of narcolepsy has been described as a hybrid between REM paralysis and the waking state (24). Patients with narcolepsy have trouble maintaining complete wakefulness for more than a few hours at a time, and they have disrupted nighttime sleep as well, thus leading to the characterization of narcolepsy as a wake and sleep maintenance disorder. Narcolepsy is caused by reduced signaling involving the neuropeptide orexin, possibly due to autoimmune destruction of the neurons that produce it (138). Treatments include stimulants such as amphetamine to facilitate monoamine release and thus increase wakefulness during the day, hypnotics to promote sleep at night and thus reduce daytime sleepiness, and anti-depressants that reduce REM sleep drive and cataplexy (13).

Metabolic Disorders and Obesity

Thirty percent of the U.S. workforce reports sleeping 6 h or less per night (78), which is significantly less than the 7–8 h recommended by the American Academy of Sleep Medicine (128). These statistics are particularly concerning considering that reduced sleep quality and quantity increase the risk of weight gain and Type 2 diabetes (25, 26, 59). Although the reasons for this relation are unproven, several studies provide plausible explanations. For example, restricted sleep has been reported to increase food consumption and plasma levels of leptin, a hunger-promoting hormone, while lowering levels of ghrelin, a satiety-promoting hormone (90, 115, 116, 118). The underlying mechanisms by which sleep restriction might lead to such molecular changes are unknown.

Sleep Apnea

Another contributing factor to metabolic disorders is the prevalence of obstructive sleep apnea (OSA), a type of sleep-disordered breathing that afflicts ~15% of adults (137). OSA is caused by repeated collapse of the upper airway, which results in bouts of intermittent hypoxia. To compensate, patients undergo repeated brief arousals, resulting in poor-quality sleep and subsequent daytime sleepiness. These repeated cycles also upregulate the sympathetic nervous system and production of reactive oxygen species (ROS). Although the underlying molecular mechanisms are not well-understood, elevated sympathetic tone, ROS, and sleep fragmentation are known to increase the risk of inflammation and metabolic dysfunction, including obesity (71, 83).

Restless Leg Syndrome

Another common sleep disorder is restless leg syndrome (RLS), which is characterized by a strong urge to move one’s legs at night that is exacerbated by lack of movement. Although RLS can be secondary to other disorders, primary (or idiopathic) RLS has a strong genetic component that allows it to exist on its own. Based on multiple genome-wide association studies, six genes have been implicated in primary RLS. However, their molecular functions appear to be diverse and unrelated, and alleles for high risk of RLS are excluded from their coding regions (61, 109). Drugs that elevate levels of dopamine in the brain are first-line treatment options for RLS, suggesting that dysfunction arises from disrupted dopamine signaling in patients. However, attempts to correlate risk for RLS with variants of genes involved in dopamine function have so far proven unsuccessful (38, 69). Thus the molecular mechanisms that contribute to RLS continue to remain elusive.

Depression

Disrupted sleep is a common symptom of depression and a major risk factor for suicide (3, 70). Paradoxically, however, sleep deprivation is sometimes used as a temporary way to treat depression (133). Debate continues as to the possible causal relation between these two health problems. However, it seems likely that both involve altered monoaminergic signaling. For example, many antidepressants that elevate synaptic levels of serotonin and/or noradrenaline also cause or exacerbate symptoms of insomnia (131). Depending on other symptoms, some physicians may thus opt to supplement treatment of patients suffering from both depression and insomnia with sedatives, at least in the short-term, or with antidepressants that have sedative properties of their own (62, 131). In patients for whom insomnia is not a problem, compounds in the latter category may be avoided since they can lead to oversedation. These examples illustrate that the desired effect on sleep may be an important consideration when selecting the optimal type of pharmacotherapy for treatment of depression.

Neurodegenerative Diseases

Poor sleep quality and excessive daytime sleepiness unrelated to medications and comorbidities are common symptoms among patients with Parkinson’s disease (PD) and Alzheimer’s disease (AD). These symptoms are often reported very early in disease progression, thus suggesting a mechanistic relation to the earliest stages of the diseases (82, 114). In PD, it has been hypothesized that excessive daytime sleepiness is secondary to loss of wake-promoting dopaminergic neurons during disease progression (138). However, in AD, sleep/wake dysfunction may have a more causal relation to the development of the disease state. In AD, amyloid beta (Aβ) and phosphorylated tau protein are believed to contribute to disease pathology. Notably, extracellular accumulation of Aβ peaks during the waking period and reaches a nadir during sleep, with sleep deprivation exaggerating and sleep-promoting drugs ameliorating these effects (68). Still other studies have shown that sleep deprivation exacerbates tau pathology and loss of synapses (39, 108). Although the specific mechanisms by which disrupted sleep might contribute to AD pathology are unknown, one possibility is that extended waking promotes Aβ plaque formation. In support of this hypothesis, Aβ release is upregulated by synaptic activity (32, 66), which is generally higher during waking than during sleep (127). In humans, short sleep duration and poor sleep quality are also correlated with elevated Aβ load (117). Thus disrupted sleep may be a proxy for disease progression. Since neurodegeneration during AD also contributes to disrupted sleep, it has been suggested that the bidirectional relationship between poor-quality sleep and AD leads to a vicious cycle that exacerbates both conditions (47, 80, 88).

Concluding Remarks

The pace of discovery of new sleep-regulating molecules and brain loci continues at a rapid pace. Because of the growing recognition that sleep is not just affected by but also contributes to disease states, these discoveries present new opportunities to intervene in many common, and in some cases tragically debilitating, health problems. These discoveries also illustrate the growing synergy between basic research and the rapidly evolving field of sleep medicine.