Abstract
Objective
Prolonged sleep deprivation is known to have detrimental effects on the hippocampus during development or in adulthood. Furthermore, it is well-established that sleep deprivation disrupts energy metabolism broadly. SIRT6 is a critical regulator of energy metabolism in both central and peripheral tissues. This study aims to investigate the role of SIRT6 in modulating hippocampal neurogenesis following sleep deprivation during development, and elucidate the underlying mechanism.
Methods
Male Sprague-Dawley rats, aged three weeks, were subjected to 2 weeks of sleep deprivation using the modified multiple platform method. Metabolomic profiling was carried out using the liquid chromatography–electrospray ionization-tandem mass spectrometry (LC‒ESI‒MS/MS). To investigate the role of SIRT6 in energy metabolism, the rats were administered with either the SIRT6-specific inhibitor, OSS128167, or SIRT6-overexpressing adeno-associated virus (AAV). Hippocampal neurogenesis was assessed by immunostaining with markers for neural stem cells (SOX2), immature neurons [doublecortin (DCX)] and newborn cells (BrdU). Sparse labeling of adult neurons was used to determine the density of dendritic spines in the dentate gyrus (DG). The Y-maze and novel object recognition (NOR) tests were performed to evaluate the spatial and recognition memory. SIRT6 expression was examined using immunofluorescence and western blotting (WB). The inhibition of SIRT6 was confirmed by assessing the acetylation of histone 3 lysine 9 (aceH3K9), a well-known substrate of SIRT6, through WB.
Results
Sleep deprivation for a period of two weeks leads to inhibited hippocampal neurogenesis, reduced density of dendritic spines in the DG, and impaired memory, accompanied by decreased SIRT6 expression and disrupted energy metabolism. Similar to sleep deprivation, administration of OSS128167 significantly decreased energy metabolism, leading to reduced neurogenesis and memory dysfunction. Notably, the abnormal hippocampal energy metabolism, neurogenetic pathological changes and memory dysfunction caused by sleep deprivation were alleviated by SIRT6 overexpression in the DG.
Conclusion
Our results suggest that SIRT6 plays a critical role in maintaining energy metabolism homeostasis in the hippocampus after sleep deprivation, promoting hippocampal neurogenesis and enhancing memory during development.
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Data Availability
All relevant data are within the paper. And all primary data in the manuscript are available upon reasonable request from the corresponding author.
Abbreviations
- AAV:
-
Adeno-associated virus
- NOR:
-
Novel object recognition
- DCX:
-
Doublecortin
- DG:
-
Dentate gyrus
- WB:
-
Western blotting
- LC‒ESI‒MS/MS:
-
Liquid chromatography–electrospray ionization-tandem mass spectrometry
- IH:
-
Immunohistochemistry
- IF:
-
Immunofluorescence
- PCA:
-
Principal component analysis
- TCA:
-
Tricarboxylic acid
- PPP:
-
Pentose phosphate pathway
- SD:
-
Sleep deprivation
- ATP:
-
Adenosine triphosphate
- AMP:
-
Adenosine monophosphate
- GMP:
-
Guanosine monophosphate
- CMP:
-
Cytidylate monophosphate
- IMP:
-
Inosine monophosphate
- UMP:
-
Uridine monophosphate
- G6P:
-
D-glucose-6-phosphate
- F6P:
-
D-fructose-6-phosphate
- GAP:
-
Glyceraldehyde-3-phosphate
- PEP:
-
Phosphoenolpyruvate
- Leu:
-
Leucine
- OXA:
-
Oxaloacetate (OXA)
- Glu:
-
Glutamate
- Arg:
-
Arginase
- R5P:
-
D-ribose-5-phosphate
- 3PG:
-
Glycerate-3P
- IGF-1:
-
Insulin-like growth factor 1
References
F., L.R.L. and C.M.W. L. Understanding the need for Sleep to Improve Cognition. Annu Rev Psychol. (2023) (74):27–57. https://doi.org/10.1146/annurev-psych-032620034127
Astill RG, Van D, Ijzendoorn MV et al (2012) Sleep, cognition, and behavioral problems in school-age children: a century of research meta-analyzed. Psychol Bull 1381109–1138. https://doi.org/10.1037/a0028204
Paruthi S, Brooks LJ, D’Ambrosio C et al (2016) Recommended amount of Sleep for Pediatric populations: a Consensus Statement of the American Academy of Sleep Medicine. J Clin Sleep Med 12785–786. https://doi.org/10.5664/jcsm.5866
Cope EC (2019) Gould Adult Neurogenesis, Glia, and the Extracellular Matrix. Cell Stem Cell 24690–705. https://doi.org/10.1016/j.stem.2019.03.023
Boldrini M, Fulmore CA, Tartt AN et al (2018) Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22:589–599e5. https://doi.org/10.1016/j.stem.2018.03.015
Meerlo P, Mistlberger RE, Jacobs BL et al (2009) New neurons in the adult brain: the role of sleep and consequences of sleep loss. Sleep Med Rev 13187–194. https://doi.org/10.1016/j.smrv.2008.07.004
Guzman-Marin R, Suntsova N, Methippara M et al (2005) Sleep deprivation suppresses neurogenesis in the adult hippocampus of rats. Eur J Neurosci 22:2111–2116. https://doi.org/10.1111/j.1460-9568.2005.04376.x
Guzmán-Marín R, Suntsova N, Stewart DR et al (2003) Sleep deprivation reduces proliferation of cells in the Dentate Gyrus of the Hippocampus in rats. J Physiol 549563–571. https://doi.org/10.1113/jphysiol.2003.041665
Mirescu C, Peters JD, Noiman L et al (2006) Sleep deprivation inhibits adult neurogenesis in the hippocampus by elevating glucocorticoids. Proc Natl Acad Sci U S A 10319170–19175. https://doi.org/10.1073/pnas.0608644103
Akers KG, Cherasse Y, Fujita Y et al (2018) Concise Review: Regulatory Influence of Sleep and Epigenetics on adult hippocampal neurogenesis and cognitive and emotional function. Stem Cells 36969–976. https://doi.org/10.1002/stem.2815
Wadhwa M, Prabhakar A, Ray K et al Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation. J Neuroinflammation. 2017 (14):222. https://doi.org/10.1186/s12974-017-0998-z
Miller MA, Bates S, Ji C et al (2021) Systematic review and meta-analyses of the relationship between short sleep and incidence of obesity and effectiveness of sleep interventions on weight gain in preschool children. Obes Rev 22e13113. https://doi.org/10.1111/obr.13113
Nielsen LS, Danielsen KV (2011) Sorensen Short sleep duration as a possible cause of obesity: critical analysis of the epidemiological evidence. Obes Rev 12:78–92. https://doi.org/10.1111/j.1467-789X.2010.00724.x
Chandel NS, Jasper H, Ho TT et al (2016) Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat Cell Biol 18823–832. https://doi.org/10.1038/ncb3385
Ito K (2014) Suda metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 15243–256. https://doi.org/10.1038/nrm3772
Navarro Negredo P, Yeo RW (2020) Brunet Aging and rejuvenation of neural stem cells and their niches. Cell Stem Cell 27202–223. https://doi.org/10.1016/j.stem.2020.07.002
Karadzic V (2010) Mrsulja Deprivation of paradoxical sleep and brain glycogen. J Neurochem 1629–34. https://doi.org/10.1111/j.1471-4159.1969.tb10340.x
Noor E, Eden E, Milo R et al (2010) Central carbon metabolism as a minimal biochemical walk between precursors for biomass and energy. Mol Cell 39809–820. https://doi.org/10.1016/j.molcel.2010.08.031
Zhang L, Du J, Justus S et al (2016) Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration. J Clin Invest 1264659–4673. https://doi.org/10.1172/JCI86905
Zhong L, D’Urso A, Toiber D et al (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140280–293. https://doi.org/10.1016/j.cell.2009.12.041
Dominy JE Jr, Lee Y, Jedrychowski MP et al (2012) The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol Cell 48:900–913. https://doi.org/10.1016/j.molcel.2012.09.030
Kim H-S, Xiao C, Wang R-H et al (2010) Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metabol 12224–236. https://doi.org/10.1016/j.cmet.2010.06.009
Grootaert M, Finigan A, Figg N et al (2020) SIRT6 protects smooth muscle cells from Senescence and reduces atherosclerosis. Circ Res. https://doi.org/10.1161/CIRCRESAHA.120.318353
Zhang W, Wan H, Feng G et al (2018) SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature 560:661–665. https://doi.org/10.1038/s41586-018-0437-z
Ferrer CM, Alders M, Postma AV et al (2018) An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes Dev 32373–388. https://doi.org/10.1101/gad.307330.117
Zhao N, Chen QG, Chen X et al (2023) Intestinal dysbiosis mediates cognitive impairment via the intestine and brain NLRP3 inflammasome activation in chronic sleep deprivation. Brain Behav Immun 10898–117. https://doi.org/10.1016/j.bbi.2022.11.013
Manchanda S, Singh H, Kaur T et al (2018) Low-grade neuroinflammation due to chronic sleep deprivation results in anxiety and learning and memory impairments. Mol Cell Biochem 44963–72. https://doi.org/10.1007/s11010-018-3343-7
Pinotti M, Bertolucci C, Frigato E et al (2010) Chronic sleep deprivation markedly reduces coagulation factor VII expression. Haematologica 951429–1432. https://doi.org/10.3324/haematol.2010.022475
Kempermann G (2015) Activity dependency and aging in the regulation of adult neurogenesis. Cold Spring Harb Perspect Biol 7https://doi.org/10.1101/cshperspect.a018929
Zager A, Andersen ML, Ruiz FS et al (2020) Effects of acute and chronic sleep loss on immune modulation of rats. Am J Physiol Regul Integr Comp Physiol 293R504–R509. https://doi.org/10.1152/ajpregu.00105.2007.-Sleep
Albani SH, McHail DG and T.C. Dumas Developmental studies of the hippocampus and hippocampal-dependent behaviors: insights from interdisciplinary studies and tips for new investigators. Neurosci Biobehav Rev. 2014 (43):183–190. https://doi.org/10.1016/j.neubiorev.2014.04.009
Antunes M (2012) Biala the novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 1393–110. https://doi.org/10.1007/s10339-011-0430-z
Parenti MD, Grozio A, Bauer I et al (2014) Discovery of novel and selective SIRT6 inhibitors. J Med Chem 57:4796–4804. https://doi.org/10.1021/jm500487d
Fiorentino F, Mai A (2021) Rotili Emerging Therapeutic potential of SIRT6 modulators. J Med Chem 649732–9758. https://doi.org/10.1021/acs.jmedchem.1c00601
Callahan PM, Terry AV Jr, Peitsch MC et al (2021) Differential effects of alkaloids on memory in rodents. Sci Rep 119843. https://doi.org/10.1038/s41598-021-89245-w
Golderman V, Ben-Shimon M, Maggio N et al (2022) Factor VII, EPCR, aPC modulators: novel treatment for neuroinflammation. J Neuroinflammation 19:138. https://doi.org/10.1186/s12974-022-02505-y
Eckel-Mahan K (2013) Sassone-Corsi metabolism and the circadian clock converge. Physiol Rev 93107–135. https://doi.org/10.1152/physrev.00016.2012.-Circadian
Goyal MS, Hawrylycz M, Miller JA et al (2014) Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. Cell Metab 19:49–57. https://doi.org/10.1016/j.cmet.2013.11.020
Kanfi Y, Naiman S, Amir G et al (2012) The sirtuin SIRT6 regulates lifespan in male mice. Nature 483218–221. https://doi.org/10.1038/nature10815
Jiang F (2019) Sleep and early Brain Development. Annals of Nutrition and Metabolism. 7544–54. https://doi.org/10.1159/000508055
Navarro-Sanchis C, Brock O, Winsky-Sommerer R et al Modulation of adult hippocampal neurogenesis by Sleep: impact on Mental Health. Front Neural Circuits. 2017 (11):74. https://doi.org/10.3389/fncir.2017.00074
Kent BA (2017) Mistlberger Sleep and hippocampal neurogenesis: Implications for Alzheimer’s disease. Front Neuroendocrinol 4535–52. https://doi.org/10.1016/j.yfrne.2017.02.004
Lucassen PJ, Scheper W (2009) Van Someren Adult neurogenesis and the unfolded protein response; new cellular and molecular avenues in sleep research. Sleep Med Rev 13183–186. https://doi.org/10.1016/j.smrv.2008.12.004
Roffwarg HP, Muzio JN (1966) Dement Ontogenetic development of the human sleep-dream cycle. Science 152604–619. https://doi.org/10.1126/science.152.3722.604
Dragos N, Kristin MP, Ülkü VRG et al (2018) A bdnf-mediated push-pull plasticity mechanism for synaptic clustering. Cell Rep 242063–2074. https://doi.org/10.1016/j.celrep.2018.07.073
Sen T (2016) Sen isoflurane-induced inactivation of CREB through histone deacetylase 4 is responsible for cognitive impairment in developing brain. Neurobiol Dis 96:12–21. https://doi.org/10.1016/j.nbd.2016.08.005
Kayser MS, Yue Z, Sehgal A A critical period of sleep for development of courtship circuitry and behavior in Drosophila. Science. 2014 (344):269–274. https://doi.org/10.1126/science.1250553
Bertrand SJ, Zhang Z, Patel R et al (2020) Transient neonatal sleep fragmentation results in long-term neuroinflammation and cognitive impairment in a rabbit model. Exp Neurol 327113212. https://doi.org/10.1016/j.expneurol.2020.113212
Petit JM, Eren-Kocak E, Karatas H et al (2021) Brain glycogen metabolism: a possible link between sleep disturbances, headache and depression. Sleep Med Rev 59101449. https://doi.org/10.1016/j.smrv.2021.101449
Kanazawa LKS, Vecchia DD, Wendler EM et al (2016) Quercetin reduces manic-like behavior and brain oxidative stress induced by paradoxical sleep deprivation in mice. Free Radic Biol Med 9979–86. https://doi.org/10.1016/j.freeradbiomed.2016.07.027
Camandola S (2017) Mattson Brain metabolism in health, aging, and neurodegeneration. EMBO J 361474–1492. https://doi.org/10.15252/embj.201695810
Johnson ECB, Dammer EB, Duong DM et al (2020) Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med 26769–780. https://doi.org/10.1038/s41591-020-0815-6
Kerloch T, Clavreul S, Goron A et al (2019) Dentate granule neurons generated during Perinatal Life Display distinct morphological features compared with later-born neurons in the mouse Hippocampus. Cereb Cortex 293527–3539. https://doi.org/10.1093/cercor/bhy224
Lu Y, Liu B, Ma J et al (2021) Disruption of Circadian Transcriptome in Lung by Acute Sleep Deprivation. Front Genet 12664334. https://doi.org/10.3389/fgene.2021.664334
Wisor JP, Pasumarthi RK, Gerashchenko D et al (2008) Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel electroencephalographic differences among mouse strains. J Neurosci 287193–7201. https://doi.org/10.1523/JNEUROSCI.1150-08.2008
S., M., O.-S. R., A.-A. L., et al. Coupling circadian rhythms of metabolism and chromatin remodelling. Diabetes, obesity & metabolism. 2015 (Suppl 1):17–22. https://doi.org/10.1111/dom.12509
Finkel T, Deng CX (2009) Mostoslavsky recent progress in the biology and physiology of sirtuins. Nature 460587–591. https://doi.org/10.1038/nature08197
Tennen RI, Berber E (2010) Chua Functional dissection of SIRT6: identification of domains that regulate histone deacetylase activity and chromatin localization. Mech Ageing Dev 131185–192. https://doi.org/10.1016/j.mad.2010.01.006
Masri S, Rigor P, Cervantes M et al (2014) Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism. Cell 158659–672. https://doi.org/10.1016/j.cell.2014.06.050
Mostoslavsky R, Chua KF, Lombard DB et al (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 124:315–329. https://doi.org/10.1016/j.cell.2005.11.044
Schwer B, Schumacher B, Lombard DB et al (2010) (107):21790–21794 Neural sirtuin 6 (sirt6) ablation attenuates somatic growth and causes obesity. Proc. Natl. Acad. Sci. U. S. A. https://doi.org/10.1073/pnas.1016306107
Roichman A, Elhanati S, Aon MA et al (2021) Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nat Commun 123208. https://doi.org/10.1038/s41467-021-23545-7
Tang Q, Gao Y, Liu Q et al (2020) Sirt6 in pro-opiomelanocortin neurons controls energy metabolism by modulating leptin signaling. Mol Metab 37100994. https://doi.org/10.1016/j.molmet.2020.100994
Glasser MF, Goyal MS, Preuss TM et al (2014) Trends and properties of human cerebral cortex: correlations with cortical myelin content. NeuroImage 93:165–175. https://doi.org/10.1016/j.neuroimage.2013.03.060
Almeida AS, Soares NL, Sequeira CO et al (2018) Improvement of neuronal differentiation by carbon monoxide: role of pentose phosphate pathway. Redox Biol 17:338–347. https://doi.org/10.1016/j.redox.2018.05.004
Yeh CY, Asrican B, Moss J et al (2018) Mossy cells control adult neural stem cell quiescence and maintenance through a dynamic balance between Direct and Indirect Pathways. Neuron 99:493–510e4. https://doi.org/10.1016/j.neuron.2018.07.010
Schilit Nitenson A, Manzano Nieves G, Poeta DL et al (2019) Acetylcholine regulates olfactory Perceptual Learning through Effects on adult neurogenesis. iScience. 22544–556. https://doi.org/10.1016/j.isci.2019.11.016
Austad SN, Ballinger S, Buford TW et al (2022) Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer’s disease. Acta Pharm Sin B 12511–531. https://doi.org/10.1016/j.apsb.2021.06.014
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This study was supported by the Science and Technology Development Fund Guided by Central Government (2022BGE236 to Zongze Zhang), and the National Natural Science Foundation of China (81671060 to Chang Chen and 81901109 to Ting Chen).
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J.J.: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; W.T.: collection and assembly of data, data analysis, and manuscript writing; T.C.: data interpretation and financial support; Q.Z., J.S., Y.X. and X.S.: collection and assembly of data, data analysis and interpretation; C.C.: conception and design, manuscript writing, and financial support; Z.Z.: manuscript writing, supervision, and financial support.
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Jia, J., Tao, W., Chen, T. et al. SIRT6 Improves Hippocampal Neurogenesis Following Prolonged Sleep Deprivation Through Modulating Energy Metabolism in Developing rats. Mol Neurobiol 61, 883–899 (2024). https://doi.org/10.1007/s12035-023-03585-4
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DOI: https://doi.org/10.1007/s12035-023-03585-4