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ACKNOWLEDGMENTS
We thank V. Cazares, L. Roux, D. Almeida-Filho, and members of the
Girardeau lab for helpful comments on the manuscript. We apologize
to all authors whose studies we could not cite because of a focus
on the most recent literature and space restrictions. We acknowledge
that this selection of references does not reflect the highly incremental
and collaborative nature of scientific research.Funding:This work
was supported by an ATIP-Avenir grant; the Fyssen Foundation;
Emergence(s) Ville de Paris; a NARSAD Young Investigator Grant from
the Brain and Behavior Research Foundation and the Schlumberger
Foundation for Science and Education (G.G.); and the Medical
Research Council UK (MC_UU_00003/4; V.L.d.S.).Competing
interests:The authors declare no competing interests. This research
was funded in whole or in part by the Medical Research Council
UK (MC_UU_00003/4), a cOAlition S organization. The author will
make the Author Accepted Manuscript (AAM) version available under
a CC BY public copyright license.

10.1126/science.abi8370

REVIEW

The interconnected causes

and consequences of sleep in the brain

Laura D. Lewis*

Sleep is essential for brain function in a surprisingly diverse set of ways. In the short term, lack of sleep

leads to impaired memory and attention; in the longer term, it produces neurological dysfunction or

even death. I discuss recent advances in understanding how sleep maintains the physiological health of

the brain through interconnected systems of neuronal activity and fluid flow. The neural dynamics

that appear during sleep are intrinsically coupled to its consequences for blood flow, cerebrospinal fluid

dynamics, and waste clearance. Recognizing these linked causes and consequences of sleep has

shed new light on why sleep is important for such disparate aspects of brain function.

O

ur nightly sleep is critical for a wide

array of brain functions. Missing just a

single night of sleep results in memory,

mood, and attentional impairments the

next day ( 1 ); disrupted sleep across the

life span is linked to neurodegeneration ( 2 , 3 ).

These heterogeneous effects of sleep have posed

a puzzle in neuroscience: Why does this brain

state hold a unique role in supporting such

seemingly distinct aspects of brain function?

Decades of work have shown that sleep con-

tains distinct neural dynamics linked to cogni-

tion, such as slow waves in neural activity that

appear in non–rapid eye movement (NREM)

sleep ( 4 ). More recent discoveries have shown

that sleep is also a heightened state for waste

removal from the brain ( 5 , 6 ). Metabolic waste

products are transported out of brain tissue

( 7 ) via the interstitial fluid (ISF) and cerebro-

spinal fluid (CSF), and sleep plays a key role in

both waste regulation and flow of CSF in the

brain ( 8 , 9 ), which is essential for maintaining

neuronal health. These beneficial effects may

explain why we spend so many hours each day

asleep, as sleep’s role in basic housekeeping

for the brain implicates it in broad aspects of

neural function. But why is sleep linked to dis-

tinct fluid dynamics, and why does it play such

a profound role in maintaining brain function?

The control circuits that govern sleep

Sleep is controlled by large-scale arousal regu-

latory systems that can rapidly induce states of

sleep or wakefulness. Extensive circuit-based

investigations have recorded from and manip-

ulated individual brain regions and cell types

to identify their various roles in behavior.

This approach has been powerful, identify-

ing multiple regions in the hypothalamus,

brainstem, basal forebrain, and other subcor-

tical nuclei that control sleep states ( 10 ). Key

interacting circuits include the noradrenergic,

dopaminergic, cholinergic, and orexinergic sys-

tems, which can induce sleep-wake transitions

( 10 ). However, these findings have raised a new

question: Why do so many diverse nuclei play

decisive roles in whether an animal is sleep-

ing or awake?

One possibility is that the system is simply

unusually redundant; sleep is so important

that the brain contains multiple switches to

induce sleep states. However, a second and

perhaps more likely possibility is that these

circuits represent interacting components of

a larger system that induces the many distinct

features of sleep, including altered behavior,

oscillatory neural dynamics, modulated respi-

ratory and vascular physiology, and clearance.

Notably, the circuits that regulate sleep project

widely throughout the forebrain ( 10 ) as well as

to each other, so that activity within one sys-

tem inevitably influences the others. Further-

more, neuromodulators such as noradrenaline

and acetylcholine, which alter neuronal arousal

states, also have direct actions on the vasculature.

Low-frequency neural dynamics

emerge during sleep

During sleep, large-scale neural activity reor-

ganizes into distinctive, oscillatory patterns,

reflecting the wide-ranging reach of arousal

regulatory circuits throughout the thalamo-

cortical networks that generate EEG oscilla-

tions. These patterns have long been recognized

to define distinct stages of sleep, separating

NREM and REM. As sleep progresses into

NREM, many distinct EEG patterns appear,

including spindles (~11 to 14 Hz) and slow

waves, with distinct links to memory and cog-

nition ( 4 ). The increased low-frequency power

is referred to as slow wave activity, a catch-all

term that corresponds to 0.5 to 4 Hz EEG

power, and which can reflect several low-

frequency dynamics (Fig. 1A). These include

individual K-complexes (occurring seconds

or minutes apart), delta (1 to 4 Hz) waves, and

the slow (0.1 to 1 Hz) oscillations that group

and coordinate higher-frequency rhythms

( 11 , 12 ). K-complexes correspond to periods

564 29 OCTOBER 2021•VOL 374 ISSUE 6567 science.orgSCIENCE

Department of Biomedical Engineering, Boston University,

Boston, MA, USA, and Athinoula A. Martinos Center for

Biomedical Imaging, Massachusetts General Hospital,

Boston, MA, USA.

*Corresponding author. Email: [email protected]

SLEEP