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

作　　者：Jinpiao Zhu Chang Chen Zhen Li Xiaodong Liu Jingang He Ziyue Zhao Mengying He Binbin Nie Zili Liu Yingying Chen Kuanpin Su Xiang Li Juxiang Chen Hongbing Xiang Fuqiang Xu Kangguang Lin Zongze Zhang Jie Wang 

机构地区：[1]Department of Anesthesiology,Brain Research Center,Department of Neurosurgery,Zhongnan Hospital,Wuhan University,Wuhan,Hubei Province,China [2]Department of Anesthesiology and Pain Medicine,Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei Province,China [3]Department of Anesthesia and Intensive Care,Peter Hung Pain Research Institute,The Chinese University of Hong Kong,Hong Kong Special Administration Region,China [4]Key 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 [5]Key Laboratory of Nuclear Radiation and Nuclear Energy Technology,Institute of High Energy Physics,Chinese Academy of Sciences,Beijing,China [6]The 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 [7]Mind-Body Interface Research Center(MBI-Lab),China Medical University Hospital,Taichung,Taiwan,China [8]An-Nan Hospital,China Medical University,Tainan,Taiwan,China [9]Department of Neurosurgery,Changhai Hospital,Naval Medical University,Shanghai,China [10]Department of Affective Disorders,The Affiliated Brain Hospital of Guangzhou Medical University,Guangzhou,Guangdong Province,China [11]Institute of Neuroscience and Brain Diseases,Xiangyang Central Hospital,Affiliated Hospital of Hubei University of Arts and Science,Xiangyang,Hubei Province,China [12]University of Chinese Academy of Sciences,Bei

出　　处：《Neural Regeneration Research》2023年第11期2449-2458,共10页中国神经再生研究（英文版）

基　　金：National Natural Science Foundation of China,Nos.81771160 (to ZZ),81671060 (to CC),31970973 (to JW),21921004 (to FX);Translational Medicine and In terdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University,No.ZNJC201934 (to ZZ)。

摘　　要：Sleep benefits the restoration of energy metabolism and thereby suppo rts 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 excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp 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 co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed 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 Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression 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.

关 键 词：chronic sleep deprivation cognitive impairment functional connectivity glutamatergic neurons metabolic kinetics neuronal-astrocytic glucose metabolism prelimbic cortex REM sleep Sirt6 synaptic function 

分 类 号：R338[医药卫生—人体生理学]