Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (11): 2449-2458.doi: 10.4103/1673-5374.371370

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Overexpression of Sirt6 ameliorates sleep deprivation induced-cognitive impairment by modulating glutamatergic neuron function

Jinpiao Zhu1, #, Chang Chen1, #, Zhen Li2, Xiaodong Liu3, Jingang He4, Ziyue Zhao4, Mengying He1, Binbin Nie5, Zili Liu6,  Yingying Chen1, Kuanpin Su7, 8, Xiang Li1, Juxiang Chen9, Hongbing Xiang2, Fuqiang Xu4, 6, Kangguang Lin10, *, Zongze Zhang1, *,  Jie Wang4, 11, 12, *   

  1. 1Department of Anesthesiology, Brain Research Center, Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, China; 2Department of Anesthesiology and Pain Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; 3Department of Anesthesia and Intensive Care, Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administration Region, China; 4Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Wuhan, Hubei Province, China; 5Key Laboratory of Nuclear Radiation and Nuclear Energy Technology, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China; 6The Brain Cognition and Brain Disease Institute (BCBDI), NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, Guangdong Province, China; 7Mind-Body Interface Research Center (MBI-Lab), China Medical University Hospital, Taichung, Taiwan, China; 8An-Nan Hospital, China Medical University, Tainan, Taiwan, China; 9Department of Neurosurgery, Changhai Hospital, Naval Medical University, Shanghai, China; 10Department of Affective Disorders, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China; 11Institute of Neuroscience and Brain Diseases; Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei Province, China; 12University of Chinese Academy of Sciences, Beijing, China
  • Online:2023-11-15 Published:2023-05-04
  • Contact: Jie Wang, PhD, jie.wang@wipm.ac.cn; Zongze Zhang, MD, PhD, zhangzz@whu.edu.cn; Kangguang Lin, MD, PhD, klin@gzhmu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81771160 (to ZZ), 81671060 (to CC), 31970973 (to JW), 21921004 (to FX); and the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University, No. ZNJC201934 (to ZZ).

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Abstract: Sleep benefits the restoration of energy metabolism and thereby supports neuronal plasticity and cognitive behaviors. Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes. The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation (CSD). We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex (PrL). We then assessed cerebral functional connectivity (FC) using resting-state functional MRI, neuron/astrocyte metabolism using a metabolic kinetics analysis; dendritic spine densities using sparse-labeling; and miniature excitatory postsynaptic currents (mEPSCs) and action potential (AP) firing rates using whole-cell patch-clamp recordings. In addition, we evaluated cognition via a comprehensive set of behavioral tests. Compared with controls, Sirt6 was significantly decreased (P < 0.05) in the PrL after CSD, accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus, piriform cortex, motor cortex, somatosensory cortex, olfactory tubercle, insular cortex, and cerebellum. Sirt6 overexpression reversed CSD-induced cognitive impairment and reduced FC. Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4 and GABA2 synthesis, which could be fully restored via forced Sirt6 expression. Furthermore, Sirt6 overexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons. These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network, neuronal glucose metabolism, and glutamatergic neurotransmission. Thus, Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.

Key words: chronic sleep deprivation, cognitive impairment, functional connectivity, glutamatergic neurons, metabolic kinetics, neuronal-astrocytic glucose metabolism, prelimbic cortex, REM sleep, Sirt6, synaptic function