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Neuroanatomy and

neurobiology of sleepMary J. Morrell, Paolo Palange, Patrick Levy and Wilfried De Backer

The neurobiology of sleep

Sleep is a dynamic process involvingcomplex neural activation. In 1929 thepsychiatrist Hans Berger established thatbrain activity was different duringwakefulness and sleep by recording cortical

electrical potentials. He termed theserecordings electroencephalograms and bythe mid-1930s the cyclical patterns

associated with NREM sleep had beencategorised. The first observations of REMsleep occurred in the 1950s (Aserinsky et al.,1953). Understanding of the controlmechanisms of NREM and REM sleepcontinues to develop.

The neural regulation of wakefulness andarousal from sleep Neurons of the reticularactivating system are central to theregulation of wakefulness. Specifically, thereare two ascending pathways: one, a dorsalroute from the cholinergic laterodorsal andpedunculopontine tegmental nuclei,activates thalamic neurons to promote EEGactivity via glutamatergic thalamocorticalprojections (Saper et al., 2005). The ventralroute through the hypothalamus includesthe aminergic arousal system that originatesfrom the brainstem with serotonergic(dorsal raphe nuclei), noradrenergic (locuscoeruleus), histaminergic

(tuberomammillary nucleus) anddopaminergic (ventral periaqueductal grey)neurons (Horner, 2008). Cortical activationduring wakefulness is also influenced byorexinergic (hypocretin) neurons originatingin the hypothalamus, and cholinergicneurons from the basal forebrain (fig. 1a).During wakefulness these pathways allowsensory information to be transmitted toareas of the association cortex via thethalamic gate.

The neural regulation of NREM and REMsleep The transition between wakefulnessand sleep occurs through a process ofreciprocal inhibition between arousal- andsleep-promoting neurons by way of a flip-flop

Key points

N Wakefulness is maintained byactivation of the ascending reticularactivating system involving several

neurotransmitters includingglutamate, acetylcholine and themonoamines.

N NREM sleep onset is associated witha reduction in activation of theascending reticular activating systemand an increase in neural activitywithin the ventrolateral pre-optic area,anterior hypothalamus and basalforebrain.

N REM sleep is triggered by activation ofcholinergic neurons in thelaterodorsal and pedunculopontinetegmental nuclei. The suppression ofmotor activity in REM sleep isgenerated by glutamate-mediatedactivation of descending medullaryreticular formation.

N Cycles of NREM and REM sleepalternate throughout the night in a

predictable manner.

N Ageing is associated with difficulty inmaintaining sleep and more frequentarousals.

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a)

b)

Upperairway

1 Pineal2 Pons3 Medulla oblongata4 Spinal cord5 Pituitary6 Tuberomammillary

nucleus7 Preoptic area8 Hypothalamus9 Corpus callosum10 Cerebral cortex

11 Hippocampus12 Thalamus13 Midbrain14 Cerebellum

Upperairway

Upperairway

c)

Olfactorybulb

1

2 3

45

6

78

910

11

12

13

14

GABAergic

HistaminergicSerotonergic

Noradrenergic

CholinergicOrexinergic

Glutaminergic

Figure 1. a)Wakefulness-, b) NREM sleep- and c) REM sleep-generating neuronal systems in the rat brain.Descending projections to the respiratory and hypoglossal motor neurons in the medulla are also shown.Solid lines indicate active neuronal groups and projections, respectively. Dashed lines and decreasedsymbol size indicate suppressed activity. Lines terminating with an arrow indicate excitatory projections,lines terminating with an oval indicate inhibitory projections and lines terminating in a diamond indicatemixed excitatory and inhibitory projections for acetylcholine. The progressive suppression of hypoglossalmotor output to genioglossus muscle from wakefulness to NREM and REM sleep is illustrated by reducedline thickness. Figure adapted from Horner (2008), with permission from the publisher.

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switch (McGinty et al., 2000). This is anall-or-nothing process that prevents theoccurrence of intermediate conscious

states. At sleep onset, neurons in theventrolateral pre-optic area (VLPO),anterior hypothalamus and basal forebrainare activated and inhibit the arousalsystems detailed previously. In particular,the VLPO neurons containing theinhibitory neurotransmitters c-aminobutyricacid (GABA) and galanin, project to (andinhibit) the wake-promoting regions of theascending reticular system (Sherin et al.,1998) and the descending brainstemarousal neurons (fig. 1b).

REM sleep occurs with activation ofcholinergic neurons in the laterodorsal andpedunculopontine tegmental nuclei. Thischolinergic activation occurs whenwithdrawal of the aminergic arousal systems(noradrenergic neurons in the locuscoeruleus and serotonergic neurons in thedorsal raphe nuclei) produces disinhibition.This causes the release of acetylcholine,which triggers the increased neural activitythat is a feature of REM sleep. Suppressionof motor activity, the other marker of REMsleep, is generated by glutamate-mediatedactivation of descending medullary reticularformation relay neurons (fig. 1c). Theactivity of these neurons is inhibitory tospinal motor neurons via the release ofglycine and to a lesser extent GABA(Reinoso-Suarez et al., 2001).

The cycle of wakefulness and sleep Thetransition from wake to sleep can be difficultto determine as there are typically briefperiods of drowsiness with transient burstsof wakefulness before sleep consolidation.

NREM sleep is conventionally divided intothree or four stages according to theguidelines laid out by the American

Academy of Sleep Medicine in 2007. Thesestages approximately represent the depth ofsleep and are analysed using standardisedcriteria (see chapter 5).

In adults sleep is most often initiatedthrough NREM sleep and is marked bysynchronisation of EEG activity (for furtherdescription of the EEG that defines thestages of sleep see chapter 5). The overnightsleep patterns in a healthy young adult are

shown in figure 2. NREM predominatesearly in the night with episodes of REMsleep occurring in approximately 90-minintervals. The 90-min NREMREM cycle isrepeated approximately three to six timesduring the night, and the duration of REMsleep increases as the night progresses. Thepreferential occurrence of NREM sleep(particularly slow-wave sleep) early in thenight is coincidental with sleephomeostasis, while the predominance ofREM sleep later in the night is thought to beassociated with the circadian rhythm of corebody temperature.

Sleep cycles in ageing Sleep is essential forlife in humans. Total sleep deprivation over23 weeks impairs thermal regulation,energy balance and immune function,eventually causing death. The requirementsfor sleep vary with age. In infants, active(REM) sleep dominates in the first 12 months of life. After 3 months NREMsleep begins to dominate, and by 5 yrs ofage adult sleep stages are established. Thepercentage of REM sleep is reduced to adultlevels by 10 yrs of age.

AwakeREM

Stage 4

Stage 3Stage 2Stage 1

Hours of recording

1 2 3 4 5 60

Figure 2. A typical overnight sleep hypnogram illustrating the sleep cycles that occur overnight in a youngmale. REM sleep is seen approximately every 90 min and there are occasional brief arousals from sleep.


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In adults, optimal sleep duration varies.Sleep restriction to ,5 h a night causes areduction in psychomotor vigilance (Dingeset al., 1997), a decline in mood and

motivation and a worse performance onmemory tests. Increasing sleep opportunityup to 10 h a night improves cognitivefunction. Most estimates suggest that 7.58.5 h of sleep are required for optimalperformance.

Ageing influences sleep cycles, with olderpeople reporting that they experiencedifficulty in maintaining sleep and increasedawakenings (fig. 3). Morning preference also

increases with age (Taillard et al., 2004);however, this may be due to changing workschedules or variation in social activities, aswell as changes in the physiologicalrequirements for sleep (Dijk et al., 2000).The increased number of arousals per nightmay be a consequence of the decline in theneural systems that regulate sleep or an age-related change in the arousal thresholds toexternal stimuli. Interestingly, althougholder adults experience more awakening

during sleep, they do not seem to have anymore problems returning to sleep onceawake (Klerman et al., 2004).

By the age of 75 yrs there may be no deepsleep. The loss of the deep sleep with

increasing age may be due to a reduction inthe amplitude of delta waves detected onthe EEG recordings, meaning that stage 34sleep is not documented despite the

presence of delta waves. Alternatively,disrupted synchronisation of neuronalactivation may occur as a result of an age-related decline in the neural systems thatregulate sleep. An increase in the lightersleep partially compensates for the loss ofdeep sleep (Van Cauter et al., 2000) butthere is also a reduction in the number ofsleep spindles and K complexes. Theduration of REM sleep tends to remainconstant throughout adulthood (Landolt

et al., 1996), although a reduction in theproportion of REM sleep has been reportedby some (Van Cauter et al., 2000).

Further reading

N Aserinsky E, et al. (1953). Regularlyoccurring periods of eye motility, andconcomitant phenomena, during sleep.Science; 118: 273274.

N

Boselli M, et al. (1998). Effect of age onEEG arousals in normal sleep. Sleep; 21:361367.

N Dijk DJ, et al. (2000). Contribution ofcircadian physiology and sleep home-ostasis to age-related changes in humansleep. Chronobiol Int; 17: 285311.

N Dinges DF, et al. (1997). Cumulativesleepiness, mood disturbance, and psy-chomotor vigilance performance decre-ments during a week of sleep restricted to45 hours per night. Sleep; 20: 267277.

N Horner RL. (2008). Neuromodulation ofhypoglossal motoneurons during sleep.Respir Physiol Neurobiol; 164: 179196.

N Iber C, et al. (2007). The AASM Manualfor the Scoring of Sleep and AssociatedEvents: Rules, Terminology and TechnicalSpecifications. 1st Edn. Westchester,American Academy of Sleep Medicine.

N Klerman EB, et al. (2004). Older peopleawaken more frequently but fall backasleep at the same rate as younger

people. Sleep; 27: 793798.N Landolt HP, et al. (1996). Effect of age on

the sleep EEG: slow-wave activity andspindle frequency activity in young andmiddle-aged men. Brain Res; 738: 205212.

35

30

25

20

15

10

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0

Arousal/hourofs

leep

Age yrs

100 20 30 40 50 60 70 80

r=0.852

p

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N McGinty D, et al. (2000). The sleep-wakeswitch: a neuronal alarm clock. Nat Med;6: 510511.

N Reinoso-Suarez F, et al. (2001). Brainstructures and mechanisms involved inthe generation of REM sleep. Sleep MedRev; 5: 6377.

N Saper CB, et al. (2005). Hypothalamicregulation of sleep and circadianrhythms. Nature; 437: 12571263.

N Sherin JE, et al. (1998). Innervation ofhistaminergic tuberomammillary neuronsby GABAergic and galaninergic neurons

in the ventrolateral preoptic nucleus ofthe rat. J Neurosci; 18: 47054721.

N Taillard J, et al. (2004). Validation ofHorne and Ostberg morningness-eveningness questionnaire in a middle-aged population of French workers. J BiolRhythms; 19: 7686.

N Van Cauter E, et al. (2000). Age-relatedchanges in slow wave sleep and REMsleep and relationship with growth hor-mone and cortisol levels in healthy men.

JAMA; 284: 861868.


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