Neurobiologic Mechanisms of Sleep and Wakefulness

Experimental studies in humans and animals led to the development of the two-process model, which accounts for the regulation of sleep and wake time. According to the model, sleep is regulated by two basic processes: a homeostatic process, which depends on the amount of prior sleep and wakefulness, and a circadian process, which is driven by an endogenous circadian pacemaker, generating near 24-hour cycles of behavior. An ultradian process within sleep is believed to control the alternation between REM and NREM sleep every 90 to 120 minutes. It is hypothesized that the interaction of homeostatic and circadian processes is responsible for helping humans to maintain wakefulness during the day and consolidated sleep at night.

Virtually all organisms have an absolute need to sleep. Human beings cannot remain awake voluntarily for longer than 2 to 3 days (12, 16). The homeostatic factor represents an increase in the need for sleep (sleep pressure) with increasing duration of prior wakefulness. The presence of the homeostatic factor is best demonstrated through sleep-deprivation studies. When a normal amount of sleep is reduced, the homeostatic drive is increased leading to increased sleep pressure and sleepiness during the day as well as increased deep sleep at night. When normal sleep is preserved, the homeostatic factor represents a basic increase in sleep propensity during waking hours. The pull of this drive builds up during wakefulness and reaches its peak at sleep time. Its strength declines during sleep, with the lowest point (nadir) on awakening in the morning. It is also useful to differentiate sleepiness from tiredness or fatigue. A tired or fatigued individual does not necessarily have a propensity to fall asleep given an opportunity to do so. A sleepy individual is not only anergic but will fall asleep given the opportunity to do so.

Human beings have an endogenous circadian pacemaker with an intrinsic period of slightly longer than 24 hours (17). Virtually all living organisms exhibit metabolic, physiologic, and behavioral circadian (i.e., about 24-hour) rhythms. The most obvious circadian rhythm is the human sleep-wake cycle. Examples of other circadian rhythms include the release of cortisol, thyroid stimulating hormone, and melatonin. Most mammalian tissues and organs contain mechanisms capable of expressing their function in accordance with the circadian rhythm. The “master biological clock,” which regulates sleep-wake and all other circadian rhythms, resides in the suprachiasmatic nuclei (SCN) of the hypothalamus. SCN are bilaterally paired nuclei located slightly above the optic chiasm in the anterior hypothalamus. Circadian clocks are normally synchronized to environmental cues by a process called entrainment. The process of entrainment of SCN cells is mediated through glutamate stimulating the N-methyl-d-aspartate (NMDA) receptor (18). Light hitting the retina activates the release of glutamate through the retinohypothalamic tract projecting to the SCN (19). In mammals, the light-dark cycle is the most potent entraining stimulus. The modulation of the SCN by both environmental cues and neurotransmitters/hormones is phase dependent. For example, when a patient is exposed to light at night it shifts the circadian clock back, whereas light exposure in the early morning shifts the clock forward (falling asleep earlier on the following night). Melatonin is effective in shifting the circadian clock only when given at dawn or at dusk but not during the daytime hours. Cholinergic activation of the muscarinic receptors affects the circadian clock only at night (20, 21).

Circadian information from the SCN is transmitted to the rest of the body after input from the hypothalamus. Thus, body-organ responses (e.g., sleep-wake cycle, core body temperature, the release of cortisol, thyroid-stimulating hormone, and melatonin) to the circadian rhythm are controlled by the SCN and modulated by the hypothalamus. The release of melatonin from the pineal gland, signaled by the circadian rhythm, peaks at dawn and dusk. The SCN contains melatonin receptors, and the circadian clock can be reset by melatonin through a feedback mechanism (17, 20, 22). In the absence of environmental cues (e.g., under conditions of sensory deprivation), the endogenous rhythmicity of a circadian pacemaker persists independent of the light-dark cycle (20, 23). The genes of the SCN cells, through transcription/translation, are responsible for maintaining the 24-hour clock. Experimental mutation of these genes in animals produces prolonged or shortened circadian periods, whereas in humans such mutations result in abnormal circadian rhythms (20). For example, polymorphisms in the PERIOD3 (PER3) gene have been linked to specific variations in the circadian rhythm. “Morning types” were more frequently homozygous for the PER35/5 (a genetic variant found in 10% of the population where the nucleotide coding sequence is repeated five times), and they were more susceptible to decline in executive function following sleep deprivation. Individuals homozygous for the PER34/4 (a genetic variant found in 50% of the population where the nucleotide coding sequence is repeated four times) were more likely to express an evening preference and less impacted by sleep deprivation (24).

Adenosine, which has been identified as a possible mediator of the homeostatic sleep process (enabling the transition from prolonged wakefulness to NREM sleep), is an endogenous sleep-producing substance (12, 20, 25–27). This breakdown product of adenosine triphosphate (ATP) mediates this transition by inhibiting arousal-promoting neurons of the basal forebrain. Adenosine accumulates in certain areas of the brain when neurons consume energy in the form of ATP during prolonged wakefulness. In animal studies, adenosine levels in the brain increased during sleep deprivation and returned to baseline during sleep. Caffeine is believed to promote wakefulness by blocking adenosine receptors (16, 28, 29). Other substances hypothesized to be involved in promoting sleep and contributing to the homeostatic factor includes proinflammatory cytokines (interleukin-1) (20, 21), prostaglandin D2, and growth hormone–releasing hormone (30).

Cholinergic neurons have a dual role: some promote sleep and others promote wakefulness. The serotonergic, noradrenergic, and histaminergic wakefulness-promoting neurons have a discharge pattern nearly opposite to that of the cholinergic sleep-promoting neurons. The discharge rate of serotonergic, noradrenergic, and histaminergic neurons is fastest during wakefulness, decreases during NREM sleep, and virtually stops firing during REM sleep. In addition, newly discovered peptides called hypocretins (also known as orexins) are thought to regulate wakefulness by interacting with histaminergic, aminergic, and cholinergic systems.

All drugs that cross the blood-brain barrier may affect sleep. Selective serotonin reuptake inhibitors, tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors suppress REM sleep. Acute withdrawal from these antidepressants is likely to produce a rebound increase in REM sleep. Barbiturates increase SWS and suppress REM. Benzodiazepines suppress SWS and do not affect REM. Psychostimulants, such as amphetamines and cocaine, increase sleep latency, fragment sleep, and suppress REM sleep (6, 12, 14).

Several theories attempt to explain the biological function of sleep, none of which is preeminent. One such theory posits that sleep serves a restorative function for the brain and body. Normal sleep is subjectively associated with feeling refreshed on awakening. REM sleep is associated with increased CNS synthesis of proteins and is critical for the CNS development of infants/young humans/animals. Growth-hormone secretion is increased while cortisol secretion is decreased during sleep. All of these facts can be used to support the restorative theory of sleep (37). Another theory of sleep function proposes that sleep has a central role in reinforcement and consolidation of memory. Sleep-deprivation experiments have highlighted the important role of REM sleep in memory function (37). Yet another theory suggests that sleep is important for thermoregulatory function. Experiments have demonstrated that total sleep deprivation results in thermoregulatory abnormalities, NREM sleep maintains thermoregulatory function, and REM sleep is associated with impaired thermoregulatory responses (shivering, sweating, and so forth) (37).

Since the mid-1950s, when REM sleep was identified, sleep research has focused on understanding the physiology of dreams. Most dreams (about 80%) occur during REM sleep and the remainder occurs during NREM sleep. REM sleep dreams are more complex, have more emotional valence, can be bizarre, and are easier to recall. NREM sleep dreams are more logical and realistic, but more difficult to recall possibly because awakening from NREM sleep leaves a person feeling more confused and disoriented than awakening from REM sleep. During REM sleep, neuronal signals originating from the brainstem are transmitted to the cerebral hemispheres and stimulate the cortical association areas to produce images that comprise our dreams.

Sleep is a vital, highly organized process regulated by complex systems of neuronal networks and neurotransmitters. Sleep plays an important role in the regulation of the CNS and body physiologic functions. Sleep architecture changes with age and is easily susceptible to external and internal disruption. The reduction or disruption of sleep can affect numerous functions varying from thermoregulation to learning and memory during the waking state.