Science - USA (2021-10-29)

the arousable NREM-like sleep induced by
dexmedetomidine ( 27 ). Propofol and isoflurane
both induce a sedative state ( 47 , 48 ), in part by
activating the lateral habenula, a midbrain nu-
cleus important for ensuring NREM sleep stabil-
ity ( 47 ). Selectively activating GABA neurons by
chemogenetics in the VTA also produces a par-
ticularly deep, sedative-like NREM state for 4 to
5 hours ( 9 ). The activation of these VTA GABAergic
neurons enhances isoflurane and sevoflurane
anesthesia ( 49 , 50 ), and their inhibition pro-
motes arousal from anesthesia ( 49 ). These VTA
GABA neurons are also needed for sleep ho-
meostasis ( 30 ). Therefore, these particular cells,
or a subset of them, could be a potential target for
new sedatives that provide restorative benefits.
What is the evidence that current sedatives
provide any restorative benefits? As many of
us have experienced, recovery from surgery or
a same-day procedure can be exhausting and
feels the opposite of restorative. However, the
trauma experienced during these operations
could easily overwhelm any beneficial restor-
ative benefits that the sedatives themselves
mightprovide.Moreimportantly,becausewe
do not know what these restorative benefits of
sleep are, we have no way of directly measur-
ing whether they accrue during sedation. In-
stead, we have to rely on other measures such
as the EEG delta power; however, as mentioned
above, this is more likely to correlate with sleep
depth rather than any restorative processes. An
additional confound is that many drugs will
affect the shape and timing of oscillations in the
EEG independently of what drives them. For

example, the anesthetics propofol and isoflurane

potentiate the actions of GABA at GABAAre-

ceptors ( 18 ), and this will reduce EEG frequency

independently of sleep. Therefore, a direct com-

parison between the EEG during sleep and

during sedation is not straightforward with

these drugs. A better approach is to determine

whether sedative drugs can“repay”sleep debt

after sleep deprivation. Some anesthetics can

repay NREM debt but few repay REM debt ( 51 ).

Even if current sedatives act on natural sleep

pathways, they certainly have other targets. The

receptors are not restricted to sleep-inducing

pathways. Moreover, the natural pattern of

NREM-REM cycles does not occur during se-

dation, so current drugs clearly do not exactly

mimic natural sleep. Therefore, until a drug is

developed that selectively acts on sleep path-

ways, we cannot be sure that the restorative ben-

efits of sleep can be provided artificially by drugs.

Conclusions

The overwhelming urge to sleep shapes the

lives of all humans. The most likely reason we

sleep is to allow fundamental housekeeping

processes to occur, and these processes require

an unconscious brain. The lower brain temper-

atures during sustained NREM sleep would

slow inhibitory postsynaptic currents by about

the same extent as sedatives and thus be incon-

sistent with consciousness. Multiple deficits in

brain function result if sleep is denied; the time

course of catching up on lost sleep implies an-

abolic or catabolic processes. Sleep need is

sensed locally by circuitry distributed through-

out the brain, and this circuitry eventually trig-

gers global sleep. In principle, drugs could be

developed that more selectively target the re-

storative properties of natural sleep.

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ACKNOWLEDGMENTS

We thank D.-J. Dijk (University of Surrey, UK) for helpful

discussion.Funding:Work in the Franks-Wisden laboratory is

funded by the Wellcome Trust (grants 107839/Z/15/Z and

107841/Z/15/Z) and the UK Dementia Research Institute (grant

UK DRI-5004).Competing interests:The authors declare no

competing financial interests.

10.1126/science.abi8372

SCIENCEscience.org 29 OCTOBER 2021•VOL 374 ISSUE 6567 559

Local sensing

of sleep need

Global induction

of sleep

Propofol Dexmedetomidine Deep NREM sleep

B

CTX

V TA

PO/BF

Raphe

Mouse brain

Time

awake

Time

awake

Time

awake

A

Fig. 3. Distributed circuitry senses local sleep need, which triggers global sleep, and sedatives hijack
some of these pathways.(A) Current data support a model in which there is distributed circuitry that
locally senses the need to sleep and then sleep is initiated globally, perhaps by the lateral hypothalamus
(red sphere). In addition to this circuitry that registers“tiredness,”signals from glia and muscle also
contribute to the sleep drive. (B) Overall brain activity in humans during deep NREM sleep is very similar to
that caused by general anesthetics and sedatives. Images show changes in regional cerebral blood flow
measured with positron emission tomography. Figure is adapted from ( 42 ) with permission under the
Creative Commons CC-BY license. BF, basal forebrain; CTX, neocortex; PO, preoptic hypothalamic area.