Abstract
Introduction: Sleep deprivation affects cognitive performance and immune function, yet its mechanisms and biomarkers remain unclear. This study explored the relationships among gene expression, brain metabolism, sleep deprivation, and sex differences. Methods: Fluorodeoxyglucose-18 positron emission tomography measured brain metabolism in regions of interest, and RNA analysis of blood samples assessed gene expression pre- and post-sleep deprivation. Mixed model regression and principal component analysis identified significant genes and regional metabolic changes. Results: There were 23 and 28 differentially expressed probe sets for the main effects of sex and sleep deprivation, respectively, and 55 probe sets for their interaction (FDR-corrected p < 0.05). Functional analysis of genes affected by sleep deprivation revealed pathway enrichment in nucleoplasm- and UBL conjugation-related genes. Genes with significant sex effects mapped to chromosomes Y and 19 (Benjamini-Hochberg FDR p < 0.05), with 11 genes (4%) and 29 genes (10.5%) involved, respectively. Differential gene expression highlighted sex-based differences in innate and adaptive immunity. For brain metabolism, sleep deprivation resulted in significant decreases in the left insula, left medial prefrontal cortex (BA32), left somatosensory cortex (BA1/2), and left motor premotor cortex (BA6) and increases in the right inferior longitudinal fasciculus, right primary visual cortex (BA17), right amygdala, left cerebellum, and bilateral pons. Conclusion: Sleep deprivation broadly impacts brain metabolism, gene expression, and immune function, revealing cellular stress responses and hemispheric vulnerability. These findings enhance our understanding of the molecular and functional effects of sleep deprivation.
Journal Section:
Research Article
References
1.
Hafner
M
, Stepanek
M
, Taylor
J
, Troxel
WM
, van Stolk
C
. Why sleep matters-the economic costs of insufficient sleep: a cross-country comparative analysis
. Rand Health Q
. 2017
;6
(4
):11
.2.
Franzen
PL
, Siegle
GJ
, Buysse
DJ
. Relationships between affect, vigilance, and sleepiness following sleep deprivation
. J Sleep Res
. 2008
;17
(1
):34
–41
. 3.
Banks
S
, Dinges
DF
. Behavioral and physiological consequences of sleep restriction
. J Clin Sleep Med
. 2007
;03
(05
):519
–28
. 4.
Wu
JC
, Gillin
JC
, Buchsbaum
MS
, Hershey
T
, Hazlett
E
, Sicotte
N
, et al. The effect of sleep deprivation on cerebral glucose metabolic rate in normal humans assessed with positron emission tomography
. Sleep
. 1991
;14
(2
):155
–62
.5.
Mackiewicz
M
, Zimmerman
JE
, Shockley
KR
, Churchill
GA
, Pack
AI
. What are microarrays teaching us about sleep
. Trends Mol Med
. 2009
;15
(2
):79
–87
. 6.
Goel
N
. “Omics” approaches for sleep and circadian rhythm research: biomarkers for identifying differential vulnerability to sleep loss
. Curr Sleep Med Rep
. 2015
;1
:38
–46
. 7.
Cirelli
C
, Gutierrez
CM
, Tononi
G
. Extensive and divergent effects of sleep and wakefulness on brain gene expression
. Neuron
. 2004
;41
(1
):35
–43
. 8.
Wang
H
, Liu
Y
, Briesemann
M
, Yan
J
. Computational analysis of gene regulation in animal sleep deprivation
. Physiol Genomics
. 2010
;42
(3
):427
–36
. 9.
Hor
CN
, Yeung
J
, Jan
M
, Emmenegger
Y
, Hubbard
J
, Xenarios
I
, et al. Sleep-wake-driven and circadian contributions to daily rhythms in gene expression and chromatin accessibility in the murine cortex
. Proc Natl Acad Sci U S A
. 2019
;116
(51
):25773
–83
. 10.
Gaine
ME
, Bahl
E
, Chatterjee
S
, Michaelson
JJ
, Abel
T
, Lyons
LC
. Altered hippocampal transcriptome dynamics following sleep deprivation
. Mol Brain
. 2021
;14
(1
):125
. 11.
Liu
X
, Sun
J
, Ling
Z
, Dong
T
. Relationship between circadian rhythm-related genes and extracellular matrix: implications for sleep deprivation
. Sleep Breath
. 2024
;28
(2
):697
–705
. 12.
Le-Niculescu
H
, Kurian
SM
, Yehyawi
N
, Dike
C
, Patel
SD
, Edenberg
HJ
, et al. Identifying blood biomarkers for mood disorders using convergent functional genomics
. Mol Psychiatry
. 2009
;14
(2
):156
–74
. 13.
Luykx
JJ
, Olde Loohuis
LM
, Neeleman
M
, Strengman
E
, Bakker
SC
, Lentjes
E
, et al. Peripheral blood gene expression profiles linked to monoamine metabolite levels in cerebrospinal fluid
. Transl Psychiatry
. 2016
;6
(12
):e983
. 14.
Bhagar
R
, Le-Niculescu
H
, Roseberry
K
, Kosary
K
, Daly
C
, Ballew
A
, et al. Temporal effects on death by suicide: empirical evidence and possible molecular correlates
. Discov Ment Health
. 2023
;3
(1
):10
. 15.
Uyhelji
HA
, Kupfer
DM
, White
VL
, Jackson
ML
, Van Dongen
HPA
, Burian
DM
. Exploring gene expression biomarker candidates for neurobehavioral impairment from total sleep deprivation
. BMC Genomics
. 2018
;19
(1
):341
. 16.
Arnardottir
ES
, Nikonova
EV
, Shockley
KR
, Podtelezhnikov
AA
, Anafi
RC
, Tanis
KQ
, et al. Blood-gene expression reveals reduced circadian rhythmicity in individuals resistant to sleep deprivation
. Sleep
. 2014
;37
(10
):1589
–600
. 17.
Huang
Y
, Shen
C
, Zhao
W
, Shang
Y
, Wang
Y
, Zhang
HT
, et al. Genes associated with altered brain structure and function in obstructive sleep apnea
. Biomedicines
. 2023
;12
(1
):15
. 18.
Lim
J
, Dinges
DF
. Sleep deprivation and vigilant attention
. Ann N Y Acad Sci
. 2008
;1129
:305
–22
. 19.
Shelgikar
AV
, Chervin
RD
. Diagnostic tools for hypersomnias
. In: Kushida
CA
, editor. Encyclopedia of sleep
. Academic Press
; 2013
. p. 498
–505
. 20.
21.
Ringnér
M
. What is principal component analysis
. Nat Biotechnol
. 2008
;26
(3
):303
–4
. 22.
Ma
S
, Kosorok
MR
. Identification of differential gene pathways with principal component analysis
. Bioinformatics
. 2009
;25
(7
):882
–9
. 23.
Agrawal
B
, Boulos
S
, Khatib
S
, Feuermann
Y
, Panov
J
, Kaphzan
H
. Molecular insights into transcranial direct current stimulation effects: metabolomics and transcriptomics analyses
. Cells
. 2024
;13
(3
):205
. 24.
Fujisawa
K
, Shimo
M
, Taguchi
YH
, Ikematsu
S
, Miyata
R
. PCA-based unsupervised feature extraction for gene expression analysis of COVID-19 patients
. Sci Rep
. 2021
;11
(1
):17351
. 25.
Xu
Q
, Ni
S
, Wu
F
, Liu
F
, Ye
X
, Mougin
B
, et al. Investigation of variation in gene expression profiling of human blood by extended principle component analysis
. PLoS One
. 2011
;6
(10
):e26905
. 26.
Zuendorf
G
, Kerrouche
N
, Herholz
K
, Baron
C
. Efficient principal component analysis for multivariate 3D voxel-based mapping of brain functional imaging data sets as applied to FDG-PET and normal aging
. Hum Brain Mapp
. 2003
;18
(1
):13
–21
. 27.
Blazhenets
G
, Ma
Y
, Sörensen
A
, Rücker
G
, Schiller
F
, Eidelberg
D
, et al. Principal components analysis of brain metabolism predicts development of alzheimer dementia
. J Nucl Med
. 2019
;60
(6
):837
–43
. 28.
Toussaint
P-J
, Perlbarg
V
, Bellec
P
, Desarnaud
S
, Lacomblez
L
, Doyon
J
, et al. Resting state FDG-PET functional connectivity as an early biomarker of Alzheimer’s disease using conjoint univariate and independent component analyses
. Neuroimage
. 2012
;63
(2
):936
–46
. 29.
Clergue-Duval
V
, Questel
F
, Azuar
J
, Paquet
C
, Cognat
E
, Amami
J
, et al. Brain 18FDG-PET pattern in patients with alcohol-related cognitive impairment
. Eur J Nucl Med Mol Imaging
. 2020
;47
(2
):281
–91
. 30.
Van der Burg
E
, De Leeuw
J
. Nonlinear canonical correlation and some related techniques
. Multivariate Behav Res
. 1983
;18
(2
):155
–74
. 31.
Marini
F
, Linke
J
, Binder
H
. Ideal: an R/bioconductor package for interactive differential expression analysis
. bioRxiv
. 2020
. 32.
Irizarry
RA
, Hobbs
B
, Collin
F
, Beazer-Barclay
YD
, Antonellis
KJ
, Scherf
U
, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data
. Biostatistics
. 2003
;4
(2
):249
–64
. 33.
Sherman
BT
, Hao
M
, Qiu
J
, Jiao
X
, Baseler
MW
, Lane
HC
, et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update)
. Nucleic Acids Res
. 2022
;50
(W1
):W216
–21
. 34.
Huang
D
, Sherman
B
, Lempicki
R
. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
. Nat Protoc
. 2009
;4
(1
):44
–57
. 35.
Sauvet
F
, Arnal
PJ
, Tardo-Dino
PE
, Drogou
C
, Van Beers
P
, Erblang
M
, et al. Beneficial effects of exercise training on cognitive performances during total sleep deprivation in healthy subjects
. Sleep Med
. 2020
;65
:26
–35
. 36.
Hochstrasser
M
. Origin and function of ubiquitin-like proteins
. Nature
. 2009
;458
(7237
):422
–9
. 37.
Ryu
H-Y
, Hochstrasser
M
. Histone sumoylation and chromatin dynamics
. Nucleic Acids Res
. 2021
;49
(11
):6043
–52
. 38.
Constanze
B
, Cockerill
PN
. Chromatin mechanisms regulating gene expression in health and disease
. Madame curie bioscience Database [Internet]
. Austin (TX)
: Landes Bioscience
; 2000–2013
. Available from: https://www.ncbi.nlm.nih.gov/books/NBK45032/39.
National Center for Biotechnology Information (NCBI)
. SMCHD1 structural maintenance of chromosomes flexible hinge domain containing 1 [Homo sapiens (human)]
. Gene ID: 23347). 2024
. Retrieved August 1, 2024, from: https://www.ncbi.nlm.nih.gov/gene/2334740.
National Center for Biotechnology Information (NCBI)
. WASHC1 WASH complex subunit 1 [Homo sapiens (human)]
. Gene ID: 100287171). 2024
. Retrieved August 1, 2024, from: https://www.ncbi.nlm.nih.gov/gene/10028717141.
National Center for Biotechnology Information (NCBI)
. FKBP5 FKBP prolyl isomerase 5 [Homo sapiens (human)] (Gene ID: 2289)
. 2024
. Retrieved August 1, 2024, from: https://www.ncbi.nlm.nih.gov/gene/228942.
Li
P
, Wang
Y
, Liu
B
, Wu
C
, He
C
, Lv
X
, et al. Association of job stress, FK506 binding protein 51 (FKBP5) gene polymorphisms and their interaction with sleep disturbance
. PeerJ
. 2023
;11
:e14794
. 43.
Häusl
AS
, Brix
LM
, Hartmann
J
, Pöhlmann
ML
, Lopez
JP
, Menegaz
D
, et al. The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice
. Mol Psychiatry
. 2021
;26
(7
):3060
–76
. 44.
Hausch
F
, Kozany
C
, Theodoropoulou
M
, Fabian
AK
. FKBPs and the Akt/mTOR pathway
. Cell Cycle
. 2013
;12
(15
):2366
–70
. 45.
Schwarz
DS
, Blower
MD
. The endoplasmic reticulum: structure, function and response to cellular signaling
. Cell Mol Life Sci
. 2016
;73
(1
):79
–94
. 46.
Balchin
D
, Hayer-Hartl
M
, Hartl
FU
. In vivo aspects of protein folding and quality control
. Science
. 2016
;353
(6294
):aac4354
. 47.
Lyons
LC
, Chatterjee
S
, Vanrobaeys
Y
, Gaine
ME
, Abel
T
. Translational changes induced by acute sleep deprivation uncovered by TRAP-Seq
. Mol Brain
. 2020
;13
(1
):165
. 48.
National Center for Biotechnology Information (NCBI)
. CH itchy E3 ubiquitin protein ligase [Homo sapiens (human)]
. (Gene ID: 83737). 2024
. Retrieved August 1, 2024, from: https://www.ncbi.nlm.nih.gov/gene/8373749.
Garbarino
S
, Lanteri
P
, Bragazzi
NL
, Magnavita
N
, Scoditti
E
. Role of sleep deprivation in immune-related disease risk and outcomes
. Commun Biol
. 2021
;4
(1
):1304
. 50.
National Center for Biotechnology Information (NCBI)
. GBP1 guanylate binding protein 1 [Homo sapiens (human)]
. (Gene ID: 2633). 2024
. Retrieved August 1, 2024, from: https://www.ncbi.nlm.nih.gov/gene/263351.
National Center for Biotechnology Information (NCBI)
. CYBB cytochrome b-245 beta chain [Homo sapiens (human)]
. (Gene ID: 1536). 2024
. Retrieved August 1, 2024, from: https://www.ncbi.nlm.nih.gov/gene/153652.
Klein
S
, Flanagan
K
. Sex differences in immune responses
. Nat Rev Immunol
. 2016
;16
(10
):626
–38
. 53.
Jamasbi
E
, Hamelian
M
, Hossain
MA
, Varmira
K
. The cell cycle, cancer development and therapy
. Mol Biol Rep
. 2022
;49
(11
):10875
–83
. 54.
Cheeseman
IM
, Chappie
JS
, Wilson-Kubalek
EM
, Desai
A
. The conserved KMN network constitutes the core microtubule-binding site of the kinetochore
. Cell
. 2006
;127
(5
):983
–97
. 55.
Hayward
DG
, Fry
AM
. Nek2 kinase in chromosome instability and cancer
. Cancer Lett
. 2006
;237
(2
):155
–66
. 56.
Chen
Y
, Riley
DJ
, Zheng
L
, Chen
PL
, Lee
WH
. Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is essential for faithful chromosome segregation
. J Biol Chem
. 2002
;277
(51
):49408
–16
. 57.
Satyanarayana
A
, Kaldis
P
. Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms
. Oncogene
. 2009
;28
(33
):2925
–39
. 58.
Chen
JS
, Lu
LX
, Ohi
MD
, Creamer
KM
, English
C
, Partridge
JF
, et al. Cdk1 phosphorylation of the kinetochore protein Nsk1 prevents error-prone chromosome segregation
. J Cell Biol
. 2011
;195
(4
):583
–93
. 59.
Mathieu
NA
, Paparisto
E
, Barr
SD
, Spratt
DE
. HERC5 and the ISGylation pathway: critical modulators of the antiviral immune response
. Viruses
. 2021
;13
(6
):1102
. 60.
Chen
W
, Li
ZY
, Huang
L
, Zhou
DH
, Luo
WQ
, Zhang
XF
, et al. Integrative bioinformatics analysis identifies DDX60 as a potential biomarker for systemic lupus erythematosus
. Dis Markers
. 2023
;2023
:8564650
. 61.
John
SP
, Sun
J
, Carlson
RJ
, Cao
B
, Bradfield
CJ
, Song
J
, et al. IFIT1 exerts opposing regulatory effects on the inflammatory and interferon gene programs in LPS-activated human macrophages
. Cell Rep
. 2018
;25
(1
):95
–106.e6
. 62.
Irwin
MR
, Carrillo
C
, Olmstead
R
. Sleep loss activates cellular markers of inflammation: sex differences
. Brain Behav Immun
. 2010
;24
(1
):54
–7
. 63.
Dou
DR
, Zhao
Y
, Belk
JA
, Zhao
Y
, Casey
KM
, Chen
DC
, et al. Xist ribonucleoproteins promote female sex-biased autoimmunity
. Cell
. 2024
;187
(3
):733
–49.e16
. 64.
Zielinski
MR
, Systrom
DM
, Rose
NR
. Fatigue, sleep, and autoimmune and related disorders
. Front Immunol
. 2019
;10
:1827
. Article 1827. 65.
Murphy
M
, Huber
R
, Esser
S
, Riedner
BA
, Massimini
M
, Ferrarelli
F
, et al. The cortical topography of local sleep
. Curr Top Med Chem
. 2011
;11
(19
):2438
–46
. 66.
Gujar
N
, Yoo
SS
, Hu
P
, Walker
MP
. The unrested resting brain: sleep deprivation alters activity within the default-mode network
. J Cogn Neurosci
. 2010
;22
(8
):1637
–48
. 67.
Bélanger
M
, Allaman
I
, Magistretti
PJ
. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation
. Cell Metab
. 2011
;14
(6
):724
–38
. 68.
Senyilmaz
D
, Virtue
S
, Xu
X
, Tan
CY
, Griffin
JL
, Miller
AK
, et al. Regulation of mitochondrial morphology and function by stearoylation of TFR1
. Nature
. 2015
;525
(7567
):124
–8
. 69.
Bastian
TW
, Rao
R
, Tran
PV
, Georgieff
MK
. The effects of early-life iron deficiency on brain energy metabolism
. Neurosci Insights
. 2020
;15
:2633105520935104
. 70.
Ghemrawi
R
, Khair
M
. Endoplasmic reticulum stress and unfolded protein response in neurodegenerative diseases
. Int J Mol Sci
. 2020
;21
(17
):6127
. 71.
Upadhyay
A
, Joshi
V
, Amanullah
A
, Mishra
R
, Arora
N
, Prasad
A
, et al. E3 ubiquitin ligases neurobiological mechanisms: development to degeneration
. Front Mol Neurosci
. 2017
;10
:151
. 72.
Courtland
JL
, Bradshaw
TW
, Waitt
G
, Soderblom
EJ
, Ho
T
, Rajab
A
, et al. Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans
. Elife
. 2021
;10
:e61590
. 73.
Jang
WE
, Park
JH
, Park
G
, Bang
G
, Na
CH
, Kim
JY
, et al. Cntnap2-dependent molecular networks in autism spectrum disorder revealed through an integrative multi-omics analysis
. Mol Psychiatry
. 2023
;28
(2
):810
–21
. 74.
Davies
AK
, Itzhak
DN
, Edgar
JR
, Archuleta
TL
, Hirst
J
, Jackson
LP
, et al. AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A
. Nat Commun
. 2018
;9
(1
):3958
. 75.
Wahle
T
, Prager
K
, Raffler
N
, Haass
C
, Famulok
M
, Walter
J
. GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network
. Mol Cell Neurosci
. 2005
;29
(3
):453
–61
. 76.
Seaman
MN
. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer
. J Cell Biol
. 2004
;165
(1
):111
–22
. 77.
Huuskonen
MT
, Wang
Y
, Nikolakopoulou
AM
, Montagne
A
, Dai
Z
, Lazic
D
, et al. Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C
. J Exp Med
. 2022
;219
(1
):e20211372
. 78.
Shahid
A
, Wilkinson
K
, Marcu
S
, Shapiro
CM
, editors. STOP, THAT and One Hundred Other Sleep Scales
. Springer Science + Business Media
; 2012
. © 2025 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2025
You do not currently have access to this content.
