40 Hz的光闪烁通过腺苷信号促进小鼠的淋巴流-动脉网

40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice

Nature 等信源发布 2024-08-06 11:55



可切换为仅中文







AbstractThe 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.

摘要淋巴淋巴系统越来越被认为是脑环境稳态的基础，因为它定义了脑实质中的脑脊液流动并消除了代谢废物。动物和人体研究揭示了调节淋巴系统的几个重要生理因素，包括睡眠，水通道蛋白-4和血液动力学因素。

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.

然而，我们对淋巴系统调节的理解是有限的，这阻碍了基于淋巴的衰老和神经退行性疾病治疗的发展。在这里，我们提供了来自荧光追踪，双光子记录和动态对比增强磁共振成像分析的证据，即40 Hz的光闪烁增强了淋巴管的流入和流出，而与麻醉和睡眠无关，这是由于星形胶质细胞水通道蛋白-4极化增加和血管舒缩增强所致。

Adenosine-A2A receptor (A2AR) 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 A2AR, and by the physical and functional A2AR–aquaporin-4 interaction in astrocytes.

腺苷-A2A受体（A2AR）信号传导作为40 Hz闪烁诱导的glymphatic血流增强的神经化学基础而出现，其基于脑液腺苷水平的增加，通过平衡核苷酸转运蛋白-2或A2AR的药理学或遗传失活以及星形胶质细胞中A2AR-水通道蛋白-4的物理和功能相互作用来消除增强的glymphatic血流。

These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders..

这些发现确立了40 Hz的光闪烁作为增强淋巴流的新型非侵入性策略，具有缓解脑部疾病的翻译潜力。。

IntroductionThe glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid (CSF) flow in the brain parenchyma and eliminates metabolic waste1. The glymphatic system involves CSF flowing into brain parenchyma along the perivascular space by the pulsatile arterial activity2, CSF-interstitial fluid (ISF) exchange through the polarized distribution of the water-permeable channel aquaporin-4 (AQP4) in astrocytic endfeet3,4, followed by a clearance efflux of the CSF and extracellular waste through the lymphatic system5.

。淋巴系统涉及脑脊液通过脉动动脉活动2沿着血管周围空间流入脑实质，脑脊液间质液（ISF）通过星形胶质细胞末端透水通道水通道蛋白-4（AQP4）的极化分布进行交换3,4，然后通过淋巴系统清除脑脊液和细胞外废物5。

The glymphatic clearance is mostly active during sleep6 and its disturbance or decreased function on aging7, leads to the accumulation of pathogenic proteins in the brain such as tau8,9, β-amyloid10, and α-synuclein11. The intertwined relationship of sleep, aging, glymphatic clearance, and accumulation of pathogenic proteins suggests that glymphatic failure is a critical step in the pathogenesis of a broad range of brain injuries/disorders and may represent a therapeutically targetable final common pathway.

glymphatic清除在睡眠期间最活跃6，其对衰老的干扰或功能降低7，导致大脑中致病蛋白如tau8,9，β-淀粉样蛋白10和α-突触核蛋白11的积累。睡眠，衰老，淋巴结清除和致病蛋白积累之间的交织关系表明，淋巴结衰竭是广泛脑损伤/疾病发病机制中的关键步骤，可能代表了治疗上可靶向的最终共同途径。

Recent studies have uncovered some physiological factors regulating the glymphatic system including sleep, AQP4, 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.High-frequency sensory stimulation is increasingly recognized as a promising non-invasive strategy to modulate brain function, affording benefits in various pathological conditions12,13,14.

最近的研究发现了一些调节淋巴系统的生理因素，包括睡眠，AQP4和血液动力学因素。然而，我们对淋巴系统调节的理解是有限的，这阻碍了基于淋巴的衰老和神经退行性疾病治疗的发展。高频感觉刺激越来越被认为是调节大脑功能的一种有前途的非侵入性策略，可在各种病理状况下提供益处12,13,14。

This is best heralded by the designation by the US FDA of combined visual and acoustic stimulation (GENUS) as a “breakthrough medical devise” for the treatment of A.

美国FDA将视觉和听觉联合刺激（GENUS）指定为治疗a的“突破性医学设计”，这最好地预示了这一点。

ReferencesIliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 4, 147ra111 (2012).Article

参考文献Siliff，J.J。等人。血管旁通路促进脑脊液流过脑实质并清除间质溶质，包括β淀粉样蛋白。科学。翻译。医学杂志4147RA111（2012）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mestre, H. et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat. Commun. 9, 4878 (2018).Article

Mestre，H。等人。脑脊液的流动是由动脉搏动驱动的，在高血压中会减少。国家公社。94878（2018）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mestre, H. et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. Elife 7, e40070 (2018).Article

Mestre，H。等人。啮齿动物大脑中水通道蛋白-4依赖性淋巴溶质转运。Elife 7，e40070（2018）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Gomolka, R. S. et al. Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation. Elife 12, e82232 (2023).Article

Gomolka，R.S。等人。水通道蛋白-4的丧失通过全脑间质液停滞导致淋巴系统功能障碍。Elife 12，e82232（2023）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).Article

Louveau，A。等人。中枢神经系统淋巴管的结构和功能特征。《自然》523337–341（2015）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013).Article

Xie，L.等人。睡眠驱动成人大脑的代谢物清除。科学342373-377（2013）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Kress, B. T. et al. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 76, 845–861 (2014).Article

Kress，B.T.等人。衰老大脑中血管旁清除途径的损伤。安。神经病学。76845-861（2014）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Iliff, J. J. et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J. Neurosci. 34, 16180–16193 (2014).Article

Iliff，J.J.等人。胶质通路功能受损促进创伤性脑损伤后的tau病理。J、神经科学。3416180-16193（2014）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Harrison, I. F. et al. Impaired glymphatic function and clearance of tau in an Alzheimer’s disease model. Brain 143, 2576–2593 (2020).Article

Harrison，I.F.等人在阿尔茨海默病模型中损害了淋巴功能和tau蛋白的清除。大脑1432576-2593（2020）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Feng, W. et al. Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer’s disease mouse model with suppression of glymphatic clearance. Alzheimers Res. Ther. 12, 125 (2020).Article

Feng，W。等人。小胶质细胞在阿尔茨海默病小鼠模型的早期阶段通过抑制淋巴清除来防止β淀粉样斑块的形成。阿尔茨海默病研究所。12125（2020）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lopes, D. M., Llewellyn, S. K. & Harrison, I. F. Propagation of tau and α-synuclein in the brain: therapeutic potential of the glymphatic system. Transl. Neurodegener. 11, 19 (2022).Article

Lopes，D.M.，Llewellyn，S.K。和Harrison，I.F。大脑中tau和α-突触核蛋白的传播：淋巴系统的治疗潜力。翻译。神经退行性变。11、19（2022年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540, 230–235 (2016).Article

Iaccarino，H.F。等人。γ频率夹带减弱淀粉样蛋白负荷并修饰小胶质细胞。《自然》540230–235（2016）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Martorell, A. J. et al. Multi-sensory gamma stimulation ameliorates Alzheimer’s-associated pathology and improves cognition. Cell 177, 256–271 (2019).Article

Martorell，A.J.等人。多感官伽玛刺激可改善阿尔茨海默病相关病理并改善认知。细胞177256-271（2019）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Adaikkan, C. et al. Gamma entrainment binds higher-order brain regions and offers neuroprotection. Neuron 102, 929–943 (2019).Article

Adaikkan，C。等人。γ夹带结合高阶大脑区域并提供神经保护。神经元102929-943（2019）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Chan, D. et al. Gamma frequency sensory stimulation in mild probable Alzheimer’s dementia patients: Results of feasibility and pilot studies. PLoS One 17, e0278412 (2022).Article

Chan，D.等人，《轻度阿尔茨海默病痴呆患者的伽玛频率感觉刺激：可行性和初步研究结果》。。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zheng, L. et al. Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity. Nat. Commun. 11, 3012 (2020).Article

Zheng，L.等人。节律性光闪烁通过增强突触前可塑性来挽救海马低伽玛射线并保护缺血神经元。国家公社。113012（2020）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Yang, X. et al. 40 Hz Blue LED relieves the gamma oscillations changes caused by traumatic brain injury in rat. Front. Neurol. 13, 882991 (2022).Article

Yang，X。等人。40 Hz蓝色LED减轻了大鼠创伤性脑损伤引起的伽马振荡变化。正面。神经病学。13882991（2022）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhou, X. et al. 40 Hz Light flickering promotes sleep through cortical adenosine signaling. Cell Res. 34, 214–231 (2024).Article

Zhou，X。等人。40 Hz的光闪烁通过皮质腺苷信号传导促进睡眠。Cell Res.34214–231（2024）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Soula, M. et al. Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer’s disease model mice. Nat. Neurosci. 26, 570–578 (2023).Article

Soula，M。等人。40赫兹光刺激不会在阿尔茨海默病模型小鼠中夹带天然伽马振荡。自然神经科学。。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Korkutata, M. & Lazarus, M. Adenosine A2A receptors and sleep. Int. Rev. Neurobiol. 170, 155–178 (2023).Article

Korkutata，M。＆Lazarus，M。腺苷A2A受体和睡眠。内景神经生物学评论。170155-178（2023）。文章

PubMed

Google Scholar

谷歌学者

Zhao, Z. A. et al. Perivascular AQP4 dysregulation in the hippocampal CA1 area after traumatic brain injury is alleviated by adenosine A2A receptor inactivation. Sci. Rep. 7, 2254 (2017).Article

Zhao，Z.A.等。腺苷A2A受体失活可缓解创伤性脑损伤后海马CA1区血管周围AQP4失调。科学。代表72254（2017）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Phillis, J. W. Adenosine and adenine nucleotides as regulators of cerebral blood flow: roles of acidosis, cell swelling, and KATP channels. Crit. Rev. Neurobiol. 16, 237–270 (2004).Article

Phillis，J。W。腺苷和腺嘌呤核苷酸作为脑血流的调节剂：酸中毒，细胞肿胀和KATP通道的作用。暴击。神经生物学评论。16237-270（2004）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Holstein-Rønsbo, S. et al. Glymphatic influx and clearance are accelerated by neurovascular coupling. Nat. Neurosci. 26, 1042–1053 (2023).Article

Holstein-Rønsbo，S。等人。神经血管耦合加速了淋巴流入和清除。自然神经科学。261042-1053（2023）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Munk, A. S. et al. PDGF-B is required for development of the glymphatic system. Cell Rep. 26, 2955–2969 (2019).Article

Munk，A.S。等人。PDGF-B是淋巴系统发育所必需的。Cell Rep.262955–2969（2019）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Pla, V. et al. A real-time in vivo clearance assay for quantification of glymphatic efflux. Cell Rep. 40, 111320 (2022).Article

Pla，V。等人。用于定量淋巴流出的实时体内清除测定。Cell Rep.40111320（2022）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Grozdanov, V. et al. Increased immune activation by pathologic α-synuclein in Parkinson’s disease. Ann. Neurol. 86, 593–606 (2019).Article

Grozdanov，V。等人在帕金森病中通过病理性α-突触核蛋白增加免疫激活。安。神经病学。86593-606（2019）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Hablitz, L. M. et al. Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci. Adv. 5, eaav5447 (2019).Article

Hablitz，L.M.等人。在麻醉下，小鼠的淋巴流入增加与高EEGδ功率和低心率相关。科学。Adv.5，eaav5447（2019）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Smith, A. J., Jin, B. J., Ratelade, J. & Verkman, A. S. Aggregation state determines the localization and function of M1- and M23-aquaporin-4 in astrocytes. J. Cell. Biol. 204, 559–573 (2014).Article

Smith，A.J.，Jin，B.J.，Ratelade，J。＆Verkman，A.S。聚集状态决定了星形胶质细胞中M1和M23-水通道蛋白-4的定位和功能。J、细胞。生物学204559-573（2014）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ciappelloni, S. et al. Aquaporin-4 surface trafficking regulates astrocytic process motility and synaptic activity in health and autoimmune disease. Cell Rep. 27, 3860–3872 (2019).Article

Ciappelloni，S。等人。水通道蛋白-4表面运输调节健康和自身免疫性疾病中的星形胶质细胞过程运动和突触活性。Cell Rep.273860–3872（2019）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Van Veluw, S. J. et al. Vasomotion as a driving force for paravascular clearance in the awake mouse brain. Neuron 105, 549–561.e5 (2020).Article

Van Veluw，S.J.等人。血管舒缩作为清醒小鼠大脑血管旁清除的驱动力。神经元105549-561.e5（2020）。文章

PubMed

Google Scholar

谷歌学者

Drew, P. J. Neurovascular coupling: motive unknown. Trends Neurosci. 45, 809–819 (2022).Article

Drew，P.J。神经血管耦合：动机未知。趋势神经科学。45809-819（2022）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Williams, S. D. et al. Neural activity induced by sensory stimulation can drive large-scale cerebrospinal fluid flow during wakefulness in humans. PLoS Biol. 21, e3002035 (2023).Article

。《公共科学图书馆·生物学》。21，e3002035（2023）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Iliff, J. J. et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J. Neurosci. 33, 18190–18199 (2013).Article

Iliff，J.J.等人。脑动脉搏动驱动小鼠大脑中的血管旁CSF间质液交换。J、神经科学。3318190–18199（2013）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mitchell, J. B., Lupica, C. R. & Dunwiddie, T. V. Activity-dependent release of endogenous adenosine modulates synaptic responses in the rat hippocampus. J. Neurosci. 13, 3439–3447 (1993).Article

Mitchell，J.B.，Lupica，C.R。＆Dunwiddie，T.V。内源性腺苷的活性依赖性释放调节大鼠海马的突触反应。J、神经科学。。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Chang, C. P., Wu, K. C., Lin, C. Y. & Chern, Y. Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases. J. Biomed. Sci. 28, 70 (2021).Article

Chang，C.P.，Wu，K.C.，Lin，C.Y。＆Chern，Y。腺苷稳态失调在脑部疾病中的新兴作用，特别关注神经退行性疾病。J、生物医学。科学。28，70（2021）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wu, Z. et al. Neuronal activity-induced, equilibrative nucleoside transporter-dependent, somatodendritic adenosine release revealed by a GRAB sensor. Proc. Natl. Acad. Sci. USA 120, e2212387120 (2023).Article

Wu，Z。等人。通过GRAB传感器揭示的神经元活动诱导的平衡核苷转运蛋白依赖性体树突状腺苷释放。程序。纳特尔。阿卡德。科学。美国120，e2212387120（2023）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Plagemann, P. G. & Woffendin, C. Species differences in sensitivity of nucleoside transport in erythrocytes and cultured cells to inhibition by nitrobenzylthioinosine, dipyridamole, dilazep and lidoflazine. Biochim. Biophys. Acta 969, 1–8 (1988).Article

Plagemann，P.G。＆Woffendin，C。红细胞和培养细胞中核苷转运对硝基苄基硫代肌苷，双嘧达莫，地拉西普和利多拉嗪抑制敏感性的物种差异。生物化学。生物物理。Acta 969，1-8（1988）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Ahn, H. S. et al. Effects of selective inhibitors on cyclic nucleotide phosphodiesterases of rabbit aorta. Biochem. Pharmacol. 38, 3331–3339 (1989).Article

Ahn，H.S.等人。选择性抑制剂对兔主动脉环核苷酸磷酸二酯酶的影响。生物化学。药理学。383331-3339（1989）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Chiang, H. L. et al. The critical role of equilibrative nucleoside transporter-2 in modulating cerebral damage and vascular dysfunction in mice with brain ischemia-reperfusion. Pharm. Res. 40, 2541–2554 (2023).Article

Chiang，H.L.等人。平衡核苷转运蛋白-2在调节脑缺血再灌注小鼠脑损伤和血管功能障碍中的关键作用。Pharm.Res.402541–2554（2023）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Cunha, R. A. How does adenosine control neuronal dysfunction and neurodegeneration? J. Neurochem. 139, 1019–1055 (2016).Article

Cunha，R.A。腺苷如何控制神经元功能障碍和神经变性？J、神经化学。1391019-1055（2016）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Rasmussen, M. K., Mestre, H. & Nedergaard, M. The glymphatic pathway in neurological disorders. Lancet Neurol. 17, 1016–1024 (2018).Article

Rasmussen，M.K.，Mestre，H。＆Nedergaard，M。神经系统疾病中的淋巴通路。柳叶刀神经学。171016-1024（2018）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Gao, Y., Liu, K. & Zhu, J. Glymphatic system: an emerging therapeutic approach for neurological disorders. Front. Mol. Neurosci. 16, 1138769 (2023).Article

Gao，Y.，Liu，K。＆Zhu，J。淋巴系统：一种新兴的神经系统疾病治疗方法。正面。分子神经科学。161138769（2023）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Parkinson, F. E. et al. Molecular biology of nucleoside transporters and their distributions and functions in the brain. Curr. Top. Med. Chem. 11, 948–972 (2011).Article

Parkinson，F.E.等人，《核苷转运蛋白的分子生物学及其在大脑中的分布和功能》。货币。顶部。医学化学。11948-972（2011）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Chen, S. J. et al. Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema. Proc. Natl. Acad. Sci. USA 111, 13199–13204 (2014).Article

Chen，S.J.等人。缺氧引起的促肾上腺皮质激素释放因子受体1型和水通道蛋白-4的过度活化引起脑水肿。程序。纳特尔。阿卡德。科学。美国11113199–13204（2014）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang, W. et al. Gamma frequency entrainment rescues cognitive impairment by decreasing postsynaptic transmission after traumatic brain injury. CNS Neurosci. Ther. 29, 1142–1153 (2023).Article

Wang，W。等人。伽玛频率夹带通过减少创伤性脑损伤后的突触后传递来挽救认知障碍。中枢神经系统神经科学。他们。291142-1153（2023）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Shen et al. A critical role of the adenosine A2A receptor in extrastriatal neurons in modulating psychomotor activity as revealed by opposite phenotypes of striatum and forebrain A2A receptor knock-outs. J. Neurosci. 28, 2970–2975 (2008).Article

Shen等人。纹状体和前脑A2A受体敲除的相反表型揭示了纹状体外神经元腺苷A2A受体在调节精神运动活动中的关键作用。J、神经科学。282970–2975（2008）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Shen, H. Y. et al. Adenosine A2A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation. PLoS One 8, e80902 (2013).Article

Shen，H.Y.等人。纹状体谷氨酸能末端和GABA能神经元中的腺苷A2A受体反向调节精神刺激作用和DARPP-32磷酸化。PLoS One 8，e80902（2013）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Gonçalves, F. Q. et al. Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer’s disease depends on increased formation of ATP-derived extracellular adenosine. Neurobiol. Dis. 132, 104570 (2019).Article

Gonçalves，F.Q。等人。早期阿尔茨海默病的β-淀粉样蛋白模型中的突触和记忆功能障碍取决于ATP衍生的细胞外腺苷的形成增加。神经生物学。。132104570（2019）。文章

PubMed

Google Scholar

谷歌学者

Matos, M. et al. Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia. Biol. Psychiatry 78, 763–774 (2015).Article

。生物精神病学78763-774（2015）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wei, C. J. et al. Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain. Biol. Psychiatry 75, 855–863 (2014).Article

Wei，C.J.等人。前脑纹状体和纹状体外腺苷A2A受体对恐惧反应的调节。生物精神病学75855-863（2014）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Simões, A. P. et al. Adenosine A2A receptors in the amygdala control synaptic plasticity and contextual fear memory. Neuropsychopharmacology 41, 2862–2871 (2016).Article

Simões，A.P.等人。杏仁核中的腺苷A2A受体控制突触可塑性和情境恐惧记忆。神经精神药理学412862-2871（2016）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhao, Y., Zhou, Y. G. & Chen, J. F. Targeting the adenosine A2A receptor for neuroprotection and cognitive improvement in traumatic brain injury and Parkinson’s disease. Chin. J. Traumatol. 27, 125–133 (2024).Article

Zhao，Y.，Zhou，Y.G.＆Chen，J.F.靶向腺苷A2A受体，用于创伤性脑损伤和帕金森病的神经保护和认知改善。下巴。J、创伤。。文章

PubMed

Google Scholar

谷歌学者

Rebola, N., Lujan, R., Cunha, R. A. & Mulle, C. Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses. Neuron 57, 121–134 (2008).Article

Rebola，N.，Lujan，R.，Cunha，R.A。＆Mulle，C。腺苷A2A受体对于海马苔藓纤维突触中NMDA EPSC的长时程增强至关重要。神经元57121-134（2008）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Costenla, A. R. et al. Enhanced role of adenosine A2A receptors in the modulation of LTP in the rat hippocampus upon ageing. Eur. J. Neurosci. 34, 12–21 (2011).Article

Costella，A.R.等人。腺苷A2A受体在衰老后大鼠海马LTP调节中的增强作用。Eur.J.Neurosci。34,12-21（2011）。文章

PubMed

Google Scholar

谷歌学者

Shin, H. K., Park, S. N. & Hong, K. W. Implication of adenosine A2A receptors in hypotension-induced vasodilation and cerebral blood flow autoregulation in rat pial arteries. Life Sci. 67, 1435–1445 (2000).Article

Shin，H.K.，Park，S.N。＆Hong，K.W。腺苷A2A受体在大鼠软脑膜动脉低血压诱导的血管舒张和脑血流自动调节中的意义。生命科学。671435-1445（2000）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Iliff, J. J., D’Ambrosio, R., Ngai, A. C. & Winn, H. R. Adenosine receptors mediate glutamate-evoked arteriolar dilation in the rat cerebral cortex. Am. J. Physiol. 284, H1631–H1637 (2003).CAS

Iliff，J.J.，D'Ambrosio，R.，Ngai，A.C。＆Winn，H.R。腺苷受体介导大鼠大脑皮层中谷氨酸诱发的小动脉扩张。Am.J.Physiol。284，H1631–H1637（2003）。中科院

Google Scholar

谷歌学者

Murdock, M. H. et al. Multisensory gamma stimulation promotes glymphatic clearance of amyloid. Nature 627, 149–156 (2024).Article

Murdock，M.H。等人。多感觉γ刺激促进淀粉样蛋白的淋巴清除。自然627149-156（2024）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Cunha-Reis, D., Fontinha, B. M., Ribeiro, J. A. & Sebastião, A. M. Tonic adenosine A1 and A2A receptor activation is required for the excitatory action of VIP on synaptic transmission in the CA1 area of the hippocampus. Neuropharmacology 52, 313–320 (2007).Article

Cunha-Reis，D.，Fontinha，B.M.，Ribeiro，J.A。＆Sebastião，A.M。VIP对海马CA1区突触传递的兴奋作用需要强直性腺苷A1和A2A受体激活。神经药理学52313-320（2007）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Benveniste, H. & Nedergaard, M. Cerebral small vessel disease: a glymphopathy? Curr. Opin. Neurobiol. 72, 15–21 (2022).Article

？货币。奥平。神经生物学。72，15-21（2022）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Peters, M. E. & Lyketsos, C. G. The glymphatic system’s role in traumatic brain injury-related neurodegeneration. Mol. Psychiatry 28, 2707–2715 (2023).Article

Peters，M.E。＆Lyketsos，C.G。淋巴系统在创伤性脑损伤相关神经变性中的作用。摩尔精神病学282707-2715（2023）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Chen, J. F. et al. A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J. Neurosci. 19, 9192–9200 (1999).Article

Chen，J。F。等人。A2A腺苷受体缺陷减轻小鼠短暂局灶性脑缺血引起的脑损伤。J、神经科学。19192-9200（1999）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Spuentrup, E. et al. Metallic renal artery MR imaging stent: artifact-free lumen visualization with projection and standard renal MR angiography. Radiology 227, 897–902 (2003).Article

Spuentrup，E。等。金属肾动脉MR成像支架：投影和标准肾MR血管造影的无伪影管腔可视化。放射学227897-902（2003）。文章

PubMed

Google Scholar

谷歌学者

Smith, S. M. et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23, S208–S219 (2004).Article

Smith，S.M.等人。功能和结构MR图像分析和FSL实现的进展。神经影像23，S208–S219（2004）。文章

PubMed

Google Scholar

谷歌学者

Hablitz, L. M. et al. Circadian control of brain glymphatic and lymphatic fluid flow. Nat. Commun. 11, 4411 (2020).Article

Hablitz，L.M.等人。脑淋巴和淋巴液流动的昼夜节律控制。国家公社。114411（2020）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Matiello, M., Schaefer-Klein, J., Sun, D. & Weinshenker, B. G. Aquaporin 4 expression and tissue susceptibility to neuromyelitis optica. JAMA Neurol. 70, 1118–1125 (2013).Article

Matiello，M.，Schaefer-Klein，J.，Sun，D。＆Weinshenker，B.G。水通道蛋白4的表达和组织对视神经脊髓炎的易感性。JAMA Neurol。701118-1125（2013）。文章

PubMed

Google Scholar

谷歌学者

Zhang, C. et al. A large, switchable optical clearing skull window for cerebrovascular imaging. Theranostics 8, 2696–2708 (2018).Article

Zhang，C.等人。用于脑血管成像的大型可切换光学清除颅骨窗口。Theranostics 82696-2708（2018）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Matos, M., Augusto, E., Agostinho, P., Cunha, R. A. & Chen, J. F. Antagonistic interaction between adenosine A2A receptors and Na+/K+-ATPase-alpha2 controlling glutamate uptake in astrocytes. J. Neurosci. 33, 18492–18502 (2013).Article

Matos，M.，Augusto，E.，Agostinho，P.，Cunha，R.A。＆Chen，J.F。腺苷A2A受体与Na+/K+-ATPase-alpha2之间的拮抗相互作用控制星形胶质细胞中谷氨酸的摄取。J、神经科学。3318492-18502（2013）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kasymov, V. et al. Differential sensitivity of brainstem versus cortical astrocytes to changes in pH reveals functional regional specialization of astroglia. J. Neurosci. 33, 435–441 (2013).Article

Kasymov，V。等人。脑干与皮质星形胶质细胞对pH变化的不同敏感性揭示了星形胶质细胞的功能区域特化。J、神经科学。33435-441（2013）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ciruela, F. et al. Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. J. Neurosci. 26, 2080–2087 (2006).Article

Ciruela，F。等人。腺苷A1-A2A受体异聚体对纹状体谷氨酸能神经传递的突触前控制。J、神经科学。262080-2087（2006）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Download referencesAcknowledgementsWe acknowledge grants from the National Key R&D Program of China (2022YFE0210100 to J-F.C.), the Science & Technology Initiative STI2030-Major Projects (2021ZD0203400 to J-F.C.; 2022ZD0206000 to R.B.), the National Natural Science Foundation of China (82101556 to X.Z.; 82151308 to J-F.C.; 31970948 and 31600859 to W.G.), the Fundamental Research Funds for the Central Universities (K20230156 to R.B.), the Natural Science Foundation of Zhejiang Province of China grant (LQ22H090013 to X.Z), the Research Fund for International Senior Scientists (82150710558 to J-F.C), the Start-up Fund (OJQDSP2022007 to J-F.C) from Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Program Project from the State Key Laboratory of Ophthalmology, the Optometry and Vision Science, Wenzhou Medical University (J01-20190101 to J-F.C), the Key Research Project (2023C03079 to J-F.C) from Zhejiang Provincial Administration of Science & Technology, the State Key Laboratory of Ophthalmology, Optometry and Vision Science (2023ZY1011 to J.Q.), Centro 2020 (CENTRO-01-0246-FEDER-000010 to R.A.C.) and by Fundação para a Ciência e Tecnologia (FCT, POCI-01-0145-FEDER-031274, UIDB/04539/2020 to R.A.C.).

下载参考文献致谢我们感谢中国国家重点研发计划（2022YFE0210100授予J-F.C.）、科学技术倡议STI2030重大项目（2021ZD0203400授予J-F.C.；2022ZD0206000授予R.B.）、国家自然科学基金（82101556授予X.Z.；82151308授予J-F.C.；31970948和31600859授予W.G.）、中央大学基础研究基金（K20230156授予R.B.）、中国浙江省自然科学基金（LQ22H090013授予X.Z），国际资深科学家研究基金（82150710558至J-F.C），瓯江实验室启动基金（OJQDSP2022007至J-F.C）（浙江再生医学、视觉和大脑健康实验室），温州医科大学眼科、视光学和视觉科学国家重点实验室计划项目（J01-20190101至J-F.C），浙江省科技厅重点研究项目（2023C03079至J-F.C），眼科，验光和视觉科学国家重点实验室（2023ZY1011至J.Q.），Centro 2020（Centro-01-0246-FEDER-000010至R.A.C.）和Fundação para Ciência e Tecnologia（FCT，POCI-01-0145-FEDER-031274，UIDB/04539/2020至R.A.C.）。

L.D. was under receipt of an FCT fellowship (SFRH/BD/147159/2019). We thank Drs. Yuanguo Zhou, Jianhong Zhu and Yi Zhang for critical reading, discussion, and suggestions to improve the manuscript. We thank Miss Jidian Ye for the schematic illustration of two-photon fluorescence imaging. We thank the Scientific Research Center of Wenzhou Medical University for their valuable consultation and provision of necessary instruments.

五十、 D.正在接受FCT奖学金（SFRH/BD/147159/2019）。我们感谢周元国博士，朱建红博士和张毅博士的批判性阅读，讨论和改进稿件的建议。我们感谢叶女士提供的双光子荧光成像的示意图。我们感谢温州医科大学科研中心提供的宝贵咨询和必要的仪器。

We are in debt to Drs. Hironaka Igarashi and Vincent J Huber, Center for Integrated Human Brain Scien.

我们欠综合人脑科学中心Hironaka Igarashi博士和Vincent J Huber博士的债。

PubMed Google ScholarLiliana DiasView author publicationsYou can also search for this author in

PubMed Google ScholarLiliana DiasView作者出版物您也可以在

PubMed Google ScholarChenlei PengView author publicationsYou can also search for this author in

PubMed Google ScholarChenlei PengView作者出版物您也可以在

PubMed Google ScholarZiyi ZhangView author publicationsYou can also search for this author in

PubMed Google ScholarZiyi ZhangView作者出版物您也可以在

PubMed Google ScholarHaoting GeView author publicationsYou can also search for this author in

PubMed Google ScholarHaoting GeView作者出版物您也可以在

PubMed Google ScholarZejun WangView author publicationsYou can also search for this author in

PubMed Google ScholarZejun WangView作者出版物您也可以在

PubMed Google ScholarJiayi JinView author publicationsYou can also search for this author in

PubMed Google ScholarJiayi JinView作者出版物您也可以在

PubMed Google ScholarManli JiaView author publicationsYou can also search for this author in

PubMed Google ScholarManli JiaView作者出版物您也可以在

PubMed Google ScholarTao XuView author publicationsYou can also search for this author in

PubMed Google ScholarTao XuView作者出版物您也可以在

PubMed Google ScholarWei GuoView author publicationsYou can also search for this author in

PubMed Google ScholarWu ZhengView author publicationsYou can also search for this author in

PubMed Google ScholarYan HeView author publicationsYou can also search for this author in

PubMed Google ScholarYan HeView作者出版物您也可以在

PubMed Google ScholarYouru WuView author publicationsYou can also search for this author in

PubMed Google ScholarYouru WuView作者出版物您也可以在

PubMed Google ScholarXiaohong CaiView author publicationsYou can also search for this author in

PubMed Google ScholarXiaohongCaiView作者出版物您也可以在

PubMed Google ScholarPaula AgostinhoView author publicationsYou can also search for this author in

PubMed Google ScholarPaula AgostinhoView作者出版物您也可以在

PubMed Google ScholarJia QuView author publicationsYou can also search for this author in

PubMed Google ScholarJia QuView作者出版物您也可以在

PubMed Google ScholarRodrigo A. CunhaView author publicationsYou can also search for this author in

PubMed Google ScholarRodrigo A.CunhaView作者出版物您也可以在

PubMed Google ScholarXuzhao ZhouView author publicationsYou can also search for this author in

PubMed谷歌学者徐昭周查看作者出版物您也可以在

PubMed Google ScholarRuiliang BaiView author publicationsYou can also search for this author in

PubMed Google ScholarRuiliang BaiView作者出版物您也可以在

PubMed Google ScholarJiang-fan ChenView author publicationsYou can also search for this author in

PubMed谷歌学者Jiang fan ChenView作者出版物您也可以在

PubMed Google ScholarContributionsConceptualization: J-F.C., X.S., X.Z., and R.B.; Methodology: X.S., X.Z., R.B., W.Z., M.J., T.X., and J.J.; Formal analysis: X.S., X.Z., L.D., W.G., Z.W., C.P., H.G., Z.Z., P.A., and R.B.; Investigation: J-F.C., X.S., X.Z., R.A.C., and R.B.; Resources: W.G., Z.Z., Y.W., Y.

PubMed谷歌学术贡献概念：J-F.C.，X.S.，X.Z。和R.B。；方法论：X.S.，X.Z.，R.B.，W.Z.，M.J.，T.X。和J.J。；形式分析：X.S.，X.Z.，L.D.，W.G.，Z.W.，C.P.，H.G.，Z.Z.，P.A。和R.B。；调查：J-F.C.，X.S.，X.Z.，R.A.C。和R.B。；资源：W.G.，Z.Z.，Y.W.，Y。

H., X.C., and J.Q.; Writing — Original Draft: J-F.C., X.S., X.Z., and R.A.C.; Writing — Review & Editing: J-F.C., X.S., R.A.C, X.Z., and R.B.; Visualization: X.S., X.Z., L.D., and P.A.; Supervision: J-F.C.; Project administration: J-F.C. and J.Q.; Funding acquisition: J-F.C., X.Z., W.G., R.A.C. and R.B.Corresponding authorCorrespondence to.

H、，X.C。和J.Q。；写作-原稿：J-F.C.，X.S.，X.Z。和R.A.C。；写作-评论和编辑：J-F.C.，X.S.，R.A.C，X.Z。和R.B。；可视化：X.S.，X.Z.，L.D。和P.A。；监督：J-F.C。；项目管理：J-F.C.和J.Q。；资金获取：J-F.C.，X.Z.，W.G.，R.A.C.和R.B.对应作者回复。

Jiang-fan Chen.Ethics declarations

陈江凡。道德宣言

Conflict of interest

利益冲突

The authors declare no competing interests.

作者声明没有利益冲突。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplemental materials41421_2024_701_MOESM2_ESM.mp4Direct visualization of 40 Hz light-flickered mice exhibited an earlier rise in signal intensity following Gd-DTPA injection and a greater overall elevation in the brain parenchymaRights and permissions.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。补充信息补充材料41421\u 2024\u 701\u MOESM2\u ESM.MP4 40 Hz光闪烁小鼠的直接可视化显示Gd-DTPA注射后信号强度的早期升高以及脑实质权利和权限的整体升高。

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

开放获取本文是根据知识共享署名4.0国际许可证授权的，该许可证允许以任何媒体或格式使用，共享，改编，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出是否进行了更改。

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by/4.0/..

Reprints and permissionsAbout this articleCite this articleSun, X., Dias, L., Peng, C. et al. 40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice.

转载和许可本文引用本文Sun，X.，Dias，L.，Peng，C。等人。40 Hz的光闪烁通过腺苷信号传导促进小鼠的淋巴流动。

Cell Discov 10, 81 (2024). https://doi.org/10.1038/s41421-024-00701-zDownload citationReceived: 01 March 2024Accepted: 26 June 2024Published: 06 August 2024DOI: https://doi.org/10.1038/s41421-024-00701-zShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Cell Discov 10,81（2024）。https://doi.org/10.1038/s41421-024-00701-zDownload引文接收日期：2024年3月1日接受日期：2024年6月26日发布日期：2024年8月6日OI：https://doi.org/10.1038/s41421-024-00701-zShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

Provided by the Springer Nature SharedIt content-sharing initiative

由Springer Nature SharedIt内容共享计划提供

全球产业链接平台

重庆市渝北区金星科技大厦A区5楼512室

联系电话：023-67139735（重庆）

关于我们

产品服务