OUTLOOK SLEEP THE ANATOMY OF SLEEP e ebb and flow of neurotransmitters switches our brains between sleep and wakefulness in carefully regulated cycles. By Mark Peplow.

Orexins Wake signals (branch 1): These peptides, THE BRAIN Neurons in the upper pons (1) produced in produce acetylcholine, which the lateral AWAKES activates areas of the thalamus (2)2 hypothalamus (5)5 , responsible for channelling signals reinforce the to the cerebral cortex arousal system. (3)3 — the site of consciousness.

THE ASCENDING A OUSAL SYSTEM Wake signals (branch 2): Neurotransmitters including noradrenaline, serotonin, histamine and dopamine are produced in the pons, hypothalamus (4)4 and other nearby regions. They prime the cerebral cortex to receive signals from the “Quote thalamus. black italic 10.5pt x 11pt over 5 or 6 lines 3 with 2 clear line spaces aboveWAKE SIGNALS and below”(B ANCH ) 6 2 THE BRAIN WAKE SIGNALS 5 8 (B ANCH 2) 4 TIRES 7



SLEEP SIGNALS Homeostatic control As the energy carrier adenosine triphosphate (ATP) breaks down, adenosine builds up and triggers neuron activity in the ventrolateral preoptic Shut down nucleus (VLPO) (6)6 . When VLPO neurons are activated, they release γ-aminobutyric acid (GABA) and galanin. These bind to receptors Circadian control in the hypothalamus and pons to inhibit the ascending The suprachiasmatic nucleus arousal system. (SCN) (7)7 is the brain’s master clock, containing neurons that re in a 24-hour cycle to inuence the VLPO. It is controlled by signals THE BRAIN from the retina during the day, and by melatonin from the SLEEPS pineal gland (8)8 at night.

 UPPE PONS 2 THALAMUS 3 CEEBAL COTEX 4 HYPOTHALAMUS 5 LATEAL HYPOTHALAMUS KEY 6 VENTOLATEAL PEOPTIC NUCLEUS (VLPO) 7 SUPACHIASMATIC NUCLEUS (SCN) 8 PINEAL GLAND

S2 | NATURE | VOL 497 | 23 MAY 2013 © 2013 Macmillan Publishers Limited. All rights reserved SLEEP OUTLOOK

THE PHASES OF SLEEP THE DECLINE OF SLEEP In a typical eight-hour sleep, the brain moves through dierent stages of electrical activity After a childhood lled with blissful slumber, in repeating cycles that last about 90 minutes. Rapid eye movement (REM) sleep is linked adulthood brings a decline in the quality and to distinctive electrical activity in the brain, and is often associated with dreaming. quantity of sleep.

20–25% of Schizophrenics lack Sleep abnormalities associated Awake Slow wave sleep REM total sleep short bursts of electrical with post-traumatic stress disorder time is REM activity during sleep include insu cient REM sleep High level of REM 24 sleep may help brain Awake Newborn HOURS development

REM Children spend more time in slow-wave sleep than adults, Stage 1 and the intensity of Child 24 this electrical activity

Light HOURS is linked to how well Stage 2 they learn Stages of sleep

Stage 3 Lack of slow-wave sleep can hamper Deep 24 learning ability Stage 4 Teenager HOURS Slow-wave sleep 23.00 00.00 01.00 02.00 03.00 04.00 05.00 06.00 07.00 declines as the Time ageing brain loses grey matter from the People with bipolar Slow-wave sleep Periods of REM medial prefrontal disorder wake more is crucial for memory lengthen at the Adult 24 cortex, with adults often and spend less consolidation and end of a sleep HOURS less able to lay down time in deep sleep learning new memories

THE D UGS OF SLEEP The most widely used insomnia drugs promote sleep by improving the binding of γ-aminobutyric acid (GABA) to chloride ions released by the ventrolateral preoptic nucleus (VLPO) to suppress the ascending arousal system.

Neuron Axon

Synaptic vesicle The most widely used sleep drugs Synaptic are non-benzodia- terminal zepines (Z-drugs) GABA such as zolpidem Chloride Older drugs, such

GABAA receptor as barbiturates and benzodiaze- pines, have worse Synaptic side-eects than terminal Z-drugs

Other insomnia drugs Antihistamines Orexinergics Binding increases suppress the ascending flow of chloride arousal system directly. Antidepressants A new class of drugs including suvorexant, which has had ions, reducing successful clinical trials neuron activity

23 MAY 2013 | VOL 497 | NATURE | S3 © 2013 Macmillan Publishers Limited. All rights reserved