Volume 34, No 3, Mar 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 3, March 2024: 214-231   |  Open Access

ORIGINAL ARTICLES

40 Hz light flickering promotes sleep through cortical adenosine signaling

Xuzhao Zhou^1,2,† , Yan He^1,† , Tao Xu^1,† , Zhaofa Wu^3,† , Wei Guo¹ , Xi Xu⁴ , Yuntao Liu¹ , Yi Zhang^2,5 , Huiping Shang¹ , Libin Huang¹ , Zhimo Yao¹ , Zewen Li¹ , Lingya Su¹ , Zhihui Li¹ , Tao Feng⁶ , Shaomin Zhang⁶ , Olivia Monteiro⁷ , Rodrigo A. Cunha⁸ , Zhi-Li Huang⁹ , Kang Zhang^1,7,* , Yulong Li³ , Xiaohong Cai^4,* , Jia Qu^1,2,* , Jiang-Fan Chen^1,2,*

¹The Eye and Brain Center, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
²Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
³State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
⁴Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
⁵Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
⁶Key Laboratory of Biomedical Engineering of Ministry of Education, Qiushi Academy for Advanced Studies, Zhejiang University, Hangzhou, Zhejiang, China
⁷Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau, China
⁸CNC-Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
⁹Department 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
^†These authors contributed equally: Xuzhao Zhou, Yan He, Tao Xu, Zhaofa Wu
Correspondence: Kang Zhang(kang.zhang@gmail.com)Xiaohong Cai(caixh839@sina.com)Jia Qu(jia.qu@163.com)Jiang-Fan Chen(chenjf555@gmail.com)

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.

https://doi.org/10.1038/s41422-023-00920-1

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