Scientific Writing

Describe the neural circuitry underlying the sleep-wake cycle.

The sleep-wake cycle in mammals is the biological pattern of alternating periods of sleep and wakefulness. In mammals it is governed by the interaction of the homeostatic drive for sleep and the circadian rhythm. These systems work together to allow consolidation of sleeping and wakefulness; for example, it has been suggested that circadian stimulation of wakefulness increases throughout the day in order to oppose the wake-dependent increase in the homeostatic sleep drive, thus allowing a consolidated period of wakefulness during the day. Similarly, the circadian sleep drive may increase overnight to oppose the decreased in homeostatic sleep drive, allowing consolidated sleep. Whilst the homeostatic drive for sleep is clearly a significant influence on the sleep-wake cycle, it is poorly understood; in contrast, the circuitry responsible for circadian rhythmicity is much better understood. Investigation has also taken place into individual areas of the brain and types of neurons that are active during wakefulness and sleep; these will be discussed later.

The homeostatic drive for sleep is poorly understood, but can be conceptualised as a homeostatic pressure that builds during the waking period. One hypothesis for this is that adenosine plays a critical role (Porkka-Heiskanen et al., 1997). Adenosine is hypothesised to accumulate in the brain when awake and at specfic concentrations it may inhibit activity in the wake-promoting regions of the basal forebrain as well as potentially activating sleep-promoting ventrolateral preoptic area (VLPA) neurons (Saper et al., 2005). Other observations supporting this hypothesis include intracerebroventricular injections of adenosine promoting sleep, extracellular adenosine concentration increasing with prolonged waking and declining with sleep, and non-specific adenosine antagonists such as caffeine causing increased wakefulness. It has been shown, however, that accumulation of adenosine in the basal forebrain is not necessary for sleep drive (Blanco-Centurion et al., 2006); hence, the neural mechanisms underlying the homeostatic for sleep are still not understood.

The neural circuitry responsible for the influence of circadian rhythms on the sleep-wake cycle is somewhat better understood. The circadian rhythm is responsible for the cycle of physiological and behavioural changes that have evolved for animals to adapt to their environment. In mammals, the principal biological clock responsible for this is the suprachiasmatic nucleus (SCN), a paired nucleus located in the anterior hypothalamus above the optic chiasm. This has a intrinsic cycle of approximately twenty-four hours and is essential to biological rhythmicity; without the SCN this is lost. Importantly, the SCN is able to integrate various inputs to the circadian rhythm, including light-dark stimuli. This is essential to entrain the biological clock to a twenty-four hour light-dark cycle which can be critical in species that are adapted to be fully nocturnal or diurnal; without this circadian rhythm they would, for example, face increased predation. This integration of light-dark stimuli is possible due to the retinohypothalamic tract which provides input to the SCN from the retina; specifically, this is input from a photosensitive subset of retinal ganglion cells which contain melanopsin, a photopigment which is particularly sensitive to blue light. Significantly, this does not rely on visual photoreceptors or the visual processing centres of the brain, so individuals who are blind often retain this input to their circadian rhythm.

The SCN integrates this information and influences the sleep-wake cycle via its connections to a range of nuclei in the hypothalamus, including the dorsomedial nucleus (DMN) as well as diencephalic sites such as the midline thalamus and bed nucleus of the stria terminalis. Through these connections it affects the endocrine, autonomic and emotional state of the body; for example, it is likely involved in controlling melatonin levels, core body temperature (which decreases overnight) and cortisol levels (which rise sharply just before waking). One route that has been suggested for control of the sleep-wake cycle is regulation of the ventrolateral preoptic area (VLPA) of the hypothalamus via the DMN.

The VLPA is essential to control of sleep according to the ‘flip-flop’ model of sleep-wakefulness. In this, the VLPA acts to promote sleep, whilst the brain stem and forebrain arousal systems act to promote wakefulness; these areas mutually inhibit one another, leading to a self-reinforcing switch that provides a clear boundary between wakefulness and sleep. Lesions to the VLPA have been shown to reduce sleep time by more than 50% and cause increased waking during the sleep cycle and increased sleeping during the wake cycle; this supports the role of the VLPA in a switch system which contributes to consolidation of these aspects of the cycle. The mechanism that ‘tips the balance’ of this switch is unknown, as many neurochemical systems feed into these pathways; however, the input of the SCN is thought to be important in the circadian regulation of sleep. The SCN is certainly important to consolidate sleep during the night; disruption of the biological clock, for example in Alzheimers disease, causes night time wanderings that are a signficant issue for care of these individuals.

Orexin neurons have also been implicated in control of the sleep-wake cycle. They are one of the excitatory neurochemical systems that feed into this ‘flip-flop’ switch. They are stimulated by hunger signals from the arcuate neuropeptide Y neurons, which stimulate eating. In the short term, these neurons may be the cause of animals being active before meals, and more likely to sleep afterwards; this is obviously of evolutionary benefit in ensuring that animals seek out sufficient nutrition. In the longer term, food availability can also shape sleep-wakefulness cycles; for example, nocturnal animals become diurnal when food is only available during the day. This necessitates a neural link between the sleep-wake cycle and day-night cycle, as well as input from the food motivation systems of the brain.

Finally, various groups of neurons have been implicated in direct control of sleep-wakefulness. Two major contributors to the sleep-wake cycle are the brainstem modulatory neurotransmitter systems and the thalamus. Magoun and Moruzzi showed that electrically stimulating cholinergic neurons in the pedunculopontine region of the brainstem resulted in a state of wakefulness, whilst Walter Hess stimulated the thalamus with low frequency pulses in an awake animal, resulting in slow wave sleep. Further research has revealed various neurotransmitter roles; for example, noradrenaline and acetylcholine shift cells in the cortex and thalamus from an intrinsic burst firing mode to single spiking, which may cause transition from non-REM sleep to the waking state. In the intrinsic burst-firing mode the thalamus synchronises with the cortex, effectively disconnecting the cortex from processing external stimuli. Tonically active thalamic cells, however, allow thalamo-cortical neurons to transmit information to the cortex for processing.

In conclusion, the neural circuits underlying sleep still require further elucidation; whilst the roles of some regions such as the SCN are well established, the mechanisms involved in the homeostatic drive for sleep and the integration of various neural systems by the ‘flip-flop’ switch, for example, are still poorly understood. This is undoubtedly a difficult task as these mechanisms are highly complex, integrating external stimuli such as light with internal drives such as hunger and the unknown factor responsible for the homeostatic drive for sleep.

References

Blanco-Centurion, C., Xu, M., Murillo-Rodriguez, E. et al. (2006). Adenosine and sleep homeostasis in the basal forebrain. The Journal of Neuroscience, 26(31), 8092-8100.

Porkka-Heiskanen, T., Strecker, R. E., Thakkar, M. et al. (1997). Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science, 276(5316), 1265-1268.

Saper, C. B., Cano, G., Scammell, T. E. (2005). Homeostatic, circadian, and emotional regulation of sleep. The Journal of Comparative Neurology, 493, 92-98.