40 Hz light flickering promotes sleep through cortical adenosine signaling  

作　　者：Xuzhao Zhou Yan He Tao Xu Zhaofa Wu Wei Guo Xi Xu Yuntao Liu Yi Zhang Huiping Shang Libin Huang Zhimo Yao Zewen Li Lingya Su Zhihui Li Tao Feng Shaomin Zhang Olivia Monteiro Rodrigo A.Cunha Zhi-Li Huang Kang Zhang Yulong Li Xiahong Cai Jia Qu Jiang-Fan Chen 

机构地区：[1]The Eye and Brain Center,State Key Laboratory of Ophthalmology,Optometry and Visual Science,Eye Hospital,Wenzhou Medical University,Wenzhou,Zhejiang,China [2]Oujiang Laboratory(Zhejiang Laboratory for Regenerative Medicine,Vision and Brain Health),School of Ophthalmology&Optometry and Eye Hospital,Wenzhou Medical University,Wenzhou,Zhejiang,China [3]State Key Laboratory of Membrane Biology,School of Life Sciences,Peking University,Beijing,China [4]Department of Pediatrics,The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University,Wenzhou,Zhejiang,China [5]Institute of Genomic Medicine,Wenzhou Medical University,Wenzhou,Zhejiang,China [6]Key Laboratory of Biomedical Engineering of Ministry of Education,Qiushi Academy for Advanced Studies,Zhejiang University,Hangzhou,Zhejiang,China [7]Faculty of Medicine,Macao University of Science and Technology,Taipa,Macao,China [8]CNC-Center for Neuroscience and Cell Biology,Faculty of Medicine,University of Coimbra,Coimbra,Portugal [9]Department of Pharmacology,School of Basic Medical Sciences,State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,and Institutes of Brain Science,Fudan University,Shanghai,China

出　　处：《Cell Research》2024年第3期214-231,共18页细胞研究（英文版）

基　　金：supported by the Science&Technology Initiative projects,the STI 2030-Major Project (2021ZD0203400 to J.-F.C.);the STI 2030-Major Project (2022ZD0208300 to Z.W.);the National Natural Science Foundation of China (82101556 to X.Z.,82151308 to J.-F.C,31970948 and 31600859 to W.G.,81971031 to Z.L,818700073 to X.C.,81971064 to Y.Z.);the Research Fund for International Senior Scientists (82150710558 to J.-F.C.);the Key Research Project (2023C03079 to J.-F.C.)from Zhejiang Provincial Administration of Science&Technology,the Natural Science Foundation of Zhejiang Province of China grant (LQ22H090013 to X.Z.);the Start-up Fund (OJQDSP2022007 to J.-F.C.)from the Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine,Vision and Brain Health);the Program Project from the State Key Laboratory of Ophthalmology,Optometry and Vision Science,Wenzhou Medical University (Jo1-20190101 to J.-F.C.)。

摘　　要：Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders.However,the lack of a neurochemical underpinning has hampered its therapeutic development.Here,we demonstrate that light flickering triggered an immediate and sustained increase(up to 3 h after flickering)in extracellular adenosine levels in the primary visual cortex(V1)and other brain regions,as a function of light frequency and intensity,with maximal effects observed at 40 Hz frequency and 4000 lux.We uncovered cortical(glutamatergic and GABAergic)neurons,rather than astrocytes,as the cellular source,the intracellular adenosine generation from AMPK-associated energy metabolism pathways(but not SAM-transmethylation or salvage purine pathways),and adenosine efflux mediated by equilibrative nucleoside transporter-2(ENT2)as the molecular pathway responsible for extracellular adenosine generation.Importantly,40 Hz(but not 20 and 80 Hz)light flickering for 30 min enhanced non-rapid eye movement(non-REM)and REM sleep for 2–3 h in mice.This somnogenic effect was abolished by ablation of V1(but not superior colliculus)neurons and by genetic deletion of the gene encoding ENT2(but not ENT1),but recaptured by chemogenetic inhibition of V1 neurons and by focal infusion of adenosine into V1 in a dose-dependent manner.Lastly,40 Hz light flickering for 30 min also promoted sleep in children with insomnia by decreasing sleep onset latency,increasing total sleep time,and reducing waking after sleep onset.Collectively,our findings establish the ENT2-mediated adenosine signaling in V1 as the neurochemical basis for 40 Hz flickering-induced sleep and unravel a novel and non-invasive treatment for insomnia,a condition that affects 20%of the world population.

关 键 词：SLEEP METABOLISM SUSTAINED 

分 类 号：R741[医药卫生—神经病学与精神病学]