Science - USA (2022-02-25)

816 25 FEBRUARY 2022 • VOL 375 ISSUE 6583

PHOTO: ENES EVREN/ISTOCKPHOTO.COM

science.org SCIENCE

By L aura H. Jacobson1,2,3 and Daniel Hoyer1,2,4

H

umans spend approximately one-third

of their lives asleep, but this is not dis-

tributed equally across their life span.

Sleep quantity and quality decline as

age advances, and insomnia and sleep

fractionation are common in older

people ( 1 , 2 ). Sleep is essential for vitality and

health. At any age, chronic sleep deprivation

causes a range of issues, including disrupted

cognition and memory ( 3 ). Correspondingly,

sleep complaints in older people are associ-

ated with increased risks of impaired physi-

cal and mental health and with mortality ( 4 ).

Beyond evidence of degenerating subcortical

nuclei in age-associated sleep disturbances

( 2 ), the underlying mechanisms remain un-

clear despite decades of awareness of the

problem and its consequences. On page 838

of this issue, Li et al. ( 5 ) report the hyper-

excitability of hypocretin neurons as a core

mechanism underlying sleep disruption in

aged mice, explaining why sleep is punctu-

ated by intruding wakefulness despite the

loss of wake-promoting neurons.

Hypocretins, neuropeptides that are also

called orexins, are produced by a few thou-

sand neurons located exclusively in the lat-

eral hypothalamus. These cells project widely

across the brain, providing dense, stimula-

tory innervation to wake-promoting nu-

clei, such as the adrenergic locus coeruleus,

histaminergic tuberomammillary nucleus,

serotonergic raphe nuclei, and basal fore-

brain cholinergic neurons ( 6 ). Hypocretin

neurons fire and release hypocretins during

wakefulness and become inactive with sleep.

Narcolepsy type 1 (NT1) is caused by the loss

of hypocretinergic neurons and is character-

ized by unstable sleep, wakefulness, and cata-

plexy (loss of muscle tone) ( 7 ). Accordingly,

hypocretin receptor antagonists, which block

hypocretin-induced wakefulness, produce a

more natural sleep architecture than clas-

sic hypnotics: benzodiazepines or “z-drugs”

(e.g., zolpidem), which activate inhibitory

g-aminobutyric acid type A (GABAA) recep-

tors, and sedative antidepressants and anti-

psychotics, which act by globally dampening

brain activity ( 8 ). Three dual orexin receptor

antagonists (DORAs) are now approved for

treating insomnia: suvorexant, lemborexant,

and daridorexant.

Li et al. report age-dependent decreased

hypocretin neuron density, which could be

expected to destabilize sleep-wakefulness, as

seen in NT1. Others have also observed de-

creased hypocretin neuron density with ag-

ing in various species, including humans ( 9 ).

However, the detailed analyses of remaining

hypocretin neurons by Li et al. provide a

deeper level of understanding of the underly-

ing mechanisms leading to disrupted sleep.

Using fiber photometry and calcium imag-

ing, Li et al. showed calcium peaks in hypo-

cretin neurons associated with wakefulness.

During the inactive (sleep dominant) phase,

these calcium transients were more frequent

and lower in amplitude in old versus young

mice and were associated with increased

wakefulness. This suggested a lower thresh-

old to arousal in aged hypocretin neurons

and increased hypocretin release. Indeed,

this was confirmed by the increased wakeful-

ness induced by optogenetic stimulation of

hypocretin neurons and their electrophysi-

ological hyperexcitability in aged mice.

Investigating possible causes of this in-

trinsic hyperexcitability, Li et al. discovered

a reduced expression of subunit 2 of the

KCNQ voltage-gated potassium channel.

Channels composed of KCNQ subunits 2

and 3 are responsible for M-currents, which

maintain the cell membrane potential below

the threshold for action potentials, inhibit-

ing neuronal activity. Li et al. found reduced

M-currents in aged hypocretin neurons, ex-

plaining their hyperactivity. By selectively

reducing KCNQ2/3 expression in hypocretin

neurons using CRISPR-Cas9 in young mice,

the authors mimicked aspects of hypocretin

neuron hyperexcitability and non–rapid eye

movement (NREM) sleep instability of old

mice. Characterized by slower electroen-

cephalographic (EEG) frequencies, NREM

sleep is associated with learning and memory

consolidation and is the most disrupted sleep

state with age ( 2 ). The KCNQ channel blocker

XE991 stimulated wakefulness in young mice,

whereas in old mice, the KCNQ2/3 channel

opener flupirtine improved NREM sleep

quantity and stability and, notably, enhanced

recognition memory. Increased NREM sleep

stability was also induced by treating aged

mice with the DORA MK6096.

Sleep is also disrupted in several neurode-

generative and neuropsychiatric diseases, in-

cluding anxiety, depression, autism, posttrau-

matic stress disorder, and Parkinson’s and

Alzheimer’s diseases. Li et al. show that de-

spite commonalities such as hypocretin neu-

ron loss and sleep-wakefulness fractionation

in aging and NT1 (but not cataplexy), the dis-

rupted sleep of older mice was mechanisti-

cally different from that of a mouse model of

NT1 (although resting membrane potential of

surviving hypocretin neurons was increased

in both aging and early stages of hypocretin

neuron loss in the NT1 mouse model, indicat-

ing some form of circuit-based compensation

in both). Given the severe hypocretin neu-

ron loss in advanced NT1, KCNQ2/3 channel

openers or hypocretin receptor antagonists

should not consolidate sleep in NT1 patients.

(^1) Florey Institute of Neuroscience and Mental Health,
Parkville, VIC, Australia.^2 Department of Biochemistry and
Pharmacology, School of Biomedical Sciences, Faculty of
Medicine, Dentistry and Health Sciences, The University of
Melbourne, Parkville, VIC, Australia.^3 Melbourne Dementia
Research Centre, The Florey Institute of Neuroscience
and Mental Health and The University of Melbourne,
Parkville, VIC, Australia.^4 Department of Molecular Medicine,
The Scripps Research Institute, La Jolla, CA, USA.
Email: [email protected]; [email protected]
Sleep quality declines with aging. In mice, wake-promoting hypocretin neurons, normally silent during sleep,
become hyperexcitable with age, resulting in intrusions of wakefulness into sleep. This discovery may lead to
new therapies to improve sleep in aging and related disorders.
NEUROSCIENCE
Losing sleep
with age
Hypocretin neuron
hyperexcitability underlies
disrupted sleep quality
associated with age
PERSPECTIVES
INSIGHTS