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SIRT6 Improves Hippocampal Neurogenesis Following Prolonged Sleep Deprivation Through Modulating Energy Metabolism in Developing rats

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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

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Acknowledgements

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Funding

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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  1. Junke Jia, Wanjiang Tao contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071, Hubei, China

    Junke Jia, Wanjiang Tao, Ting Chen, Qi Zhong, Jiahui Sun, Yutong Xu, Xiaokai Sui, Chang Chen & Zongze Zhang

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  1. Junke Jia
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Contributions

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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Correspondence to Chang Chen or Zongze Zhang.

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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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