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ACKNOWLEDGMENTS
I thank M. Nedergaard, R. Stickgold, and J. Voigts for discussions.
Funding:NIH grants R01-AG070135 and R01-AT011429, 1907
Trailblazer Award from 1907 Foundation, NARSAD Young Investigator
Award from the Brain and Behavior Research Foundation, Searle
Scholars Program, One Mind Rising Star Award, and Simons
Collaboration on Plasticity in the Aging Brain (no. 811231).Competing
interests:The author is a co-inventor on patent application
PCT/US20/27963,“Generating Imaging-Based Neurological State
Biomarkers and Estimating Cerebrospinal Fluid (CSF) Dynamics
Based on Coupled Neural and CSF Oscillations During Sleep,”and has
received speaking fees from Roche.

10.1126/science.abi8375

REVIEW

The translational neuroscience of sleep:

A contextual framework

Michael A. Grandner^1 *and Fabian-Xosé Fernandez^2

Sleep is entwined across many physiologic processes in the brain and periphery, thereby exerting

tremendous influence on our well-being. Yet sleep exists in a social-environmental context.

Contextualizing sleep health with respect to its determinants—from individual- to societal-level

factors—would enable neuroscientists to more effectively translate sleep health into clinical practice.

Key challenges and opportunities pertain to (i) recognizing and exploring sleep’s functional roles,

(ii) clarifying causal mechanisms in relation to key outcomes, (iii) developing richer model systems,

(iv) linking models to known contextual factors, and (v) leveraging advances in multisensory technology.

Meeting these challenges and opportunities would help transcend disciplinary boundaries such that

social-environmental considerations related to sleep would become an ever-greater presence in the clinic.

S

leep is generally defined as a naturally

recurring, reversible state of perceptual

disengagement, reduced consciousness,

and relative immobility, the propensity

of which is patterned by homeostatic and

circadian factors. Many studies have described

the neurophysiology that contributes to sleep

regulation, including the neuroanatomy of sleep

and arousal-promoting circuitry

( 1 ); the diffuse, interconnected

neurotransmitter systems that

transition between non–rapid

eye movement sleep (NREM),

REM sleep, and wakefulness ( 2 );

and the core molecular clock

mechanism and circadian pace-

maker activity within the brain

( 3 ). Additional work has de-

lineated how sleep serves as a

prerequisite for optimizing the

performance of critical biolog-

ical functions, including those

related to memory ( 4 ), waste

clearance from the brain ( 5 ), and

nutrient metabolism ( 6 ). Over

the past 70 years, sleep has been

increasingly conceptualized with

deference to these findings, pro-

moting an understanding of sleep as a set

of interrelated physiological processes some-

times devoid of greater biological and social-

environmental context.

Sleep is not just a collection of physiologic

processes that occur together at the intersection

of rest and activity and of circadian light-dark

rhythms. Sleep is a non-negotiable biological

state required for the maintenance of human

life. It is associated with behaviors, but sleep

itself is not a volitional behavior. It involves

physiologicprocessesbutismorethananamal-

gam of them. Sleep is a foundational aspect of

our biology—our need for sleep parallels those

for air, food, and water.

Total sleep deprivation results in death in

animal models ( 7 ). For obvious ethical reasons,

no previous scientific work has empirically

tested the amount of sleep dep-

rivation necessary to induce or-

gan failure and death in humans.

Prolonged sleep deprivation

in humans has been studied,

though. When sleep is curtailed,

sleep propensity increases, such

that individuals kept from sleep

for extended periods will fall

asleep faster and more deeply

when sleep is no longer restricted

( 8 ). Continued wakefulness for

several days results in the occur-

rence of involuntary sleep, where

individuals fall asleep even while

trying to stay awake. Although

there are no formal studies of

human mortality related to in-

lab sleep loss, there are many

reported cases in which sleep

propensity was sufficiently high to induce

involuntary sleep initiation, even during ac-

tivities when such an event would likely re-

sult in death (such as while driving a car) ( 9 ).

Thus, sleep is not a luxury for people with too

much free time; it is a biological necessity

whose many functions are increasingly the

interest of study.

Yet, modern society has a complicated rela-

tionship with sleep health. The drive for produc-

tivity has led to spoken and unspoken pressures

for minimizing sleep. Incentives can be both

direct (e.g., rewards for staying awake to per-

form tasks) or indirect (e.g., being perceived as

more industrious). Existing evidence suggests

that Americans trade sleep hours for work or

leisure hours ( 10 ) and that this trade-off is

568 29 OCTOBER 2021•VOL 374 ISSUE 6567 science.orgSCIENCE

(^1) Department of Psychiatry, University of Arizona College of
Medicine–Tucson, 1501 N. Campbell Ave., Suite AHSC
7326, Tucson, AZ 85724, USA.^2 Department of Psychology,
University of Arizona College of Science, 1503 E. University
Blvd., Room 507, Tucson, AZ 85721, USA.
*Corresponding author. Email: [email protected]
“Sleep is a
non-negotiable
biological state
required for
the maintenance
of human life....
our need for
sleep parallels
those for air,
food, and water.”
SLEEP