Science - USA (2020-09-04)

SCIENCE sciencemag.org 4 SEPTEMBER 2020 • VOL 369 ISSUE 6508 1165

GRAPHIC: A. KITTERMAN/

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reflect an adaptive response to misalign-

ment in females.

Studies in animal models have shown that

sex hormones are not required to maintain

circadian rhythms but can affect their ampli-

tude and response to photic stimuli. Female

mice in which the estrogen receptor 1 (Esr1)

gene is deleted show fractured behavioral

rhythms and blunted phase delays produced

by light pulses given in the early active phase

of the day. By contrast, light pulses given

late in the active phase increase phase ad-

vances compared with that of controls ( 11 ).

This suggests that estrogen consolidates be-

havioral rhythms in female mice and could

facilitate the faster entrainment to phase

shifts observed in female mice. The same

study showed that Esr1 deletion did not af-

fect phase shifting in males, but that wild-

type males showed smaller phase shifts than

those of females when exposed to light early

in the active phase.

Gonadectomy in male mice deconsolidates

behavioral rhythms and enhances the phase

shift produced by light in the early active but

not the late active phase. Thus, testosterone

may restrain the phase-shifting effect of light

( 12 ). Nonreproductive factors are also perti-

nent to the sexual dimorphism in circadian

rhythmicity. For example, female mice en-

trained to an 8-hour phase shift in 6 days,

whereas males took 10 days to adapt ( 13 ).

This difference disappeared in the absence of

Liver X Receptor a (Lxra), with male mice in

which Lxra is deleted showing significantly

faster entrainment than that of wild types.

This may be due to the impact of Lxra dele-

tion on corticosterone rhythms, which affect

reentrainment. It is not well understood how

sex hormones influence rhythmicity directly

in the SCN because whole-body deletion of

the receptors or removal of sex organs oblit-

erates signaling across the entire organism.

Sexual dimorphism in the SCN should be

revisited by using single-cell transcriptomics

and SCN-targeted deletions of estrogen and

androgen receptors.

The repeated pattern of dimorphic rhyth-

micity observed in humans and animal mod-

els suggest that these differences are not

attributable simply to societal pressures on

either sex. Consistent with the findings that

female mice show enhanced entrainment to

phase shifts, studies in rodents have shown

that females tend to be more resistant to

genetic and environmental circadian disrup-

tion. In ClockD19/D^19 mutant mice, in which

mutation of the Clock protein interferes with

transcriptional regulation by the BMAL1-

CLOCK heterodimer and leads to lengthen-

ing of the circadian period, females do not

develop any detectable cardiac dysfunction

until 21 months of age, despite male ClockD19/D^19

mice showing cardiac hypertrophy and dys-

function after 12 months ( 14 ). However, in

ovariectomized ClockD19/D^19 mice, cardiometa-

bolic function was impaired relative to ovari-

ectomized controls by 8 months of age, high-

lighting the protective effect of estrogen.

One possible reason for the resilience to

circadian disruption in females relates to

their biological imperative. Resistance to the

negative consequences of circadian disrup-

tion coupled with improved sleep, even when

experiencing nocturnal disturbances, may

facilitate their adaptation to frequent noc-

turnal awakenings over a sustained period,

given their predominant role in nurturing

offspring. The early-activity chronotypes seen

in women before menopause also align with

those in children.

Circadian rhythms are influenced by sex,

and this interaction is remolded throughout

life. In the healthy state, females often show

higher-amplitude oscillations with an ear-

lier peak in gene expression. Dimorphism

can also shape the response to circadian

misalignment and the downstream conse-

quences of disruptions to normal rhythms.

A chronic disruption to human circadian

rhythms is shiftwork, which is associated

with cardiometabolic disease and cancer.

Studies have sought to clarify whether this

risk is affected by sex ( 15 ), but the results are

constrained by a lack of longitudinal data.

There are large differences in the rhythmic

regulation of the liver transcriptome be-

tween males and females, but it is unknown

whether other organs show similar differ-

ences or how faithfully this translates to

protein expression and function. In humans,

well-controlled, longitudinal analyses of the

impact of misalignment will be necessary to

address the hypothesis that females are more

resilient than males to the disruption of cir-

cadian function caused by shiftwork and re-

peated long-distance travel. j

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11. M. S. Blattner, M. M. Mahoney, J. Biol. Rhythms 28 , 291
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12. I. N. Karatsoreos et al., Endocrinology 152 , 1970 (2011).


13. C. Feillet et al., PLOS ONE 11 , e0150665 (2016).


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    ACKNOWLEDGMENTS
    We gratefully acknowledge funding from the Volkswagen
    Stiftung. G.A.F. is a senior adviser to Calico Laboratories.

10.1126/science.abd4964

Shell

Core

Shell

Core

Intergeniculate

leafet

Circulation

Estrogen

Te s t o s t e r o n e

Circulation

Estrogen

Te s t o s t e r o n e

SCN

Peripheral

tissue

clocks

Time

Behavior

Time

Behavior

High amplitude Moderate amplitude

Dorsal

raphe

nuclei

Median

raphe

nuclei

Intergeniculate

leafet

Retinohypothalamic

tract

SCN

Dorsal

raphe

nuclei

Female Male

Median

raphe

nuclei

Sex hormone receptors in the circadian network

The patterning of estrogen receptors (purple) and androgen receptors (green) throughout the circadian

network varies between males and females. The suprachiasmatic nucleus (SCN) signals to peripheral organs,

many of which also have circadian oscillations in sex hormone receptors. Circulating estrogen and testosterone

are also likely to affect the SCN in a sexually dimorphic, rhythmic fashion. This dimorphism is manifested at the

behavioral level through higher-amplitude rhythms in female activity patterns compared with that of males.

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