REVIEW
The inescapable drive to sleep:
Overlapping mechanisms of sleep and sedation
Nicholas P. Franks and William Wisden
Common human experience is that a long period without sleep is unsustainable, and it is also detrimental to
health and behavior. The powerful and primal urge to sleep after sleep deprivation is intense and seems
inescapable. The longer we stay awake, the more we feel the need to sleep, and however much we resist, we will
inevitably succumb. Although it is obvious what benefits derive from other common and strong physiological
drives, such as hunger, sex, and thirst, it is less obvious what drives us to sleep and what benefits accrue.
Understanding the biochemical or circuit basis for the sleep drive could enable the benefits of sleep to be
artificially stimulated with a new generation of sedative drugs.
W
hy do we sleep? The evolutionary ad-
vantages of remaining permanently
awake and alert seem so obvious that
sleep must provide some essential need.
Dolphins, fur seals, and whales alter-
nate their sleep in their cortical hemispheres
so that they can keep swimming: One half of
the brain“sleeps”while the other is awake ( 1 ).
This observation alone seems to highlight the
importance of sleep, at least for mammals. De-
spite intense research, why we sleep remains
one of the most baffling questions in neuro-
science. In this article, we discuss why we might
sleep, what mechanisms force us to sleep when
we are sleep deprived, and whether certain an-
esthetics and sedatives hijack this natural drive
to exert their effects on human consciousness.
Do we have to sleep and if so, why?
Although it is often stated that“all animals
sleep,”it is not obvious, or proven, that all types
of animals sleep or sleep in the same way or for
the same purpose. Nevertheless, it seems clear
that sleep is good for us humans and is in some
way restorative. Moreover, we know from per-
sonal experience that missing sleep is detrimen-
tal. In the short term, total sleep deprivation
decreases cognitive ability and mood ( 2 ). Twenty-
four hours of enforced wakefulness has a greater
detrimental effect on driving ability than con-
suming the legal limit for alcohol ( 3 ). There-
fore, something is clearly deteriorating in our
brain function when sleep is missing. What
about the long-term effects of sleep loss? A
recent study tracked nearly 8000 UK govern-
ment employees for 25 years, from middle age
through to their early seventies. The results
showed a higher dementia incidence in people
between 50 and 60 years of age who had been
chronically short sleepers (6 hours a night or
less, self-reported) ( 4 ). Thus, in the long term,
less sleep correlates with increased pathology.
Because we all experience sleep, there is a
common understanding of what the sleeping
state entails for us subjectively, which we are
comfortable extrapolating to other animals, at
least to other mammals. Sleep can be mea-
sured using the external electrical signatures
of brain and muscle ( 5 ) and can, in vertebrate
animals, be categorized as non–rapid eye move-
ment (NREM) and REM sleep, or at least NREM-
like and REM-like. However, depending on
species, these sleep states differ in their phys-
iological properties and timing ( 5 ). The detailed
properties of any one sleep state, electroenceph-
alographic (EEG) pattern, or calcium-oscillatory
activity are unlikely to be critical. Some other
common, as yet unknown, property of the sleep
stateisprobablythekeyingredientforwhy
sleep is essential. Much as birds and mammals
use different circuitry and brain organizations
to carry out cognitive tasks with high effective-
ness, sleep is likely to be an essential emergent
property regardless of how the brain is or-
ganized ( 6 ). The requirement for sleep could
originate at the cellular level, with neurons fa-
tiguing with time spent awake, analogous to
the metabolic fatigue of skeletal muscle with
exercise. But it is not obvious whether all parts
of the brain need to sleep; circuits that drive
breathing, for example, do not seem to rest.
Notwithstanding the many variations of
sleeping, is there a core reason to sleep that is
so fundamental that sleep is obligatory? Al-
though there are many activities that occur
during sleep but occur less often during waking,
few of these activities are likely to be the fun-
damental and primal reason that we must sleep.
A telling fact is that of the hundreds of mouse
mutants generated, no mutant mouse has yet
been discovered that does not exhibit NREM
sleep ( 7 ). Many mutations affect the depth of
NREM sleep or its timing (e.g., circadian mu-
tants), but so far all have NREM sleep ( 7 ). The
same picture emerges with circuit manipula-
tions. Lesions of sleep-promoting centers can
permanently reduce the amount of sleep in ro-
dents, yet some sleep always remains ( 8 – 10 ). So
far, no cell or circuit lesion has removed all sleep.So, what is sleep for? A widespread, but in
our view mistaken, belief is that if a detriment
in behavior or well-being can be identified as a
consequence of sleep deprivation, then this
provides evidence for the reason that we sleep.
However, it seems more likely that sleep pro-
vides some fundamental“housekeeping”or
metabolic functions that are necessary for a
healthy brain and body, so that there will be
multiple deficits of one sort or another that
arise when sleep is denied (Fig. 1A). By“house-
keeping,”we mean basic structural or meta-
bolic processes that are essential for the normal
functioning of the brain. The most important
constraint when considering what these func-
tions might be is that they cannot, apparently,
occur in the waking brain; restful waking does
not satisfy our need for sleep. Much like the
cleaning teams who move into empty offices
duringthenightandwhoseworkwouldbeal-
most impossible during the daytime bustle, some
essential and restorative process is underway
after we slip into sleep, when normal brain func-
tion is at least partly suspended. The need for un-
consciousness is perhaps the key thing to explain.
Mechanisms that stand out for being in-
compatible with consciousness would be those
that involve structural changes in the brain.
For example, the glymphatic hypothesis, that
NREM sleep allows the clearance of metabo-
lites from the brain ( 11 ), posits that the end feet
of astrocytes shrink to enhance glymphatic flow
( 11 ). Similarly, any remodeling of synapses to
rebalance network activity acquired during
wakefulness might preclude cognitive activity
or awareness and might only be possible“off-
line”( 12 ).Anotherfactortoconsideristem-
perature. During sustained NREM sleep, brain
neocortex temperature in mice drops by ~2°C
( 13 , 14 ) (Fig. 1B). In fact, specific hypothalamic
circuitry exists to cool the brain and simulta-
neously induce NREM sleep ( 15 ). It has been
proposed that a key function of sleep is to pre-
serve energy ( 16 ). For humans, however, this
temperature decrease with sleep would result
in only a modest saving in metabolic energy,
equivalent to about two slices of bread ( 16 ). A
lower temperature with sleep could nonethe-
less be required for an unknown restorative
process. This was first suggested >30 years ago
( 17 ) and might be linked to synaptic remodel-
ing. Cooling during NREM sleep induces the
expression of the cold-inducible RNA-binding
protein and RNA-binding motif protein 3 genes
( 13 ), and the proteins encoded by these genes
could be required for structural remodeling
(they are also induced in some hibernators).
Furthermore, cooling even by only a degree or
two would prolong inhibitory postsynaptic cur-
rentsbyaboutthesameextentasdomany
general anesthetics at sedative doses ( 18 ) (Fig.
1B); this would make normal cognition essen-
tially impossible, so a sleeping state would be
necessary for these processes to occur. Finally,SLEEP556 29 OCTOBER 2021•VOL 374 ISSUE 6567 science.orgSCIENCE
Department of Life Sciences and UK Dementia Research
Institute, Imperial College London, London SW7 2AZ, UK.
Correspondence: [email protected] (N.P.F.); w.wisden@
imperial.ac.uk (W.W.)