40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice
The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A<sub>2A</sub> receptor (A<sub>2A</sub>R) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A<sub>2A</sub>R, and by the physical and functional A<sub>2A</sub>R-aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders.
Authors
- Zejun Wang (ORCID: https://orcid.org/0000-0003-4657-8812)
- Paula Agostinho (ORCID: https://orcid.org/0000-0001-5523-4945)
- Xiaohong Cai (ORCID: https://orcid.org/0000-0002-5762-4506)
- YouRu Wu (ORCID: https://orcid.org/0009-0007-5277-2079)
- Rodrigo A. Cunha (ORCID: https://orcid.org/0000-0003-2550-6422)
- Xuzhao Zhou (ORCID: https://orcid.org/0000-0002-4398-3495)
- Liliana Dias (ORCID: https://orcid.org/0000-0001-7032-5212)
- Zheng Wu (ORCID: https://orcid.org/0000-0002-2563-3387)
- Jiang‐Fan Chen (ORCID: https://orcid.org/0000-0002-0446-3956)
- Manli Jia
- Ruiliang Bai (ORCID: https://orcid.org/0000-0003-4246-5984)
- Wei Guo (ORCID: https://orcid.org/0000-0002-8560-6700)
- Chenlei Peng
- Yan He (ORCID: https://orcid.org/0000-0003-4357-4082)
- Ziyi Zhang (ORCID: https://orcid.org/0000-0002-2175-4931)
- Tao Xu (ORCID: https://orcid.org/0000-0003-2234-7737)
- Jia Qu (ORCID: https://orcid.org/0000-0001-6360-2568)
- Jiayi Jin (ORCID: https://orcid.org/0000-0003-3883-7386)
- Haoting Ge
- Xiaoting Sun
Institutions
- Zhejiang Chinese Medical University (CN)
- Wenzhou Medical University (CN)
- Affiliated Eye Hospital of Wenzhou Medical College (CN)
- Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University (CN)
- Zhejiang Lab (CN)
- Zhejiang University (CN)
- University of Coimbra (PT)
Publication Details
- Journal
- Cell Discovery
- Published
- 2024-08-05
- DOI
- https://doi.org/10.1038/s41421-024-00701-z
- Citations
- 46
- Primary Topic
- Cerebrospinal fluid and hydrocephalus
- Type
- article
- Field-Weighted Citation Impact
- 12.34
Funders
- Wenzhou Medical University
- National Natural Science Foundation of China
- Programa Operacional Regional do Centro
- State Key Laboratory of Ophthalmology
- Fundação para a Ciência e a Tecnologia
- Fundamental Research Funds for the Central Universities
- Natural Science Foundation of Zhejiang Province