Non-invasive auditory and visual stimulation attenuates α-Synuclein deposition and improves motor and non-motor symptoms in PD mice

Liu, Yuntao; Liu, Haiwei; Lu, Yingwen; Yin, Xin; Lu, Weilin; Lian, Xiaoyue; Wang, Ke; Shi, Chennan; Yao, Zehan; Chen, Jiang‐Fan; Li, Zhihui

doi:10.1016/j.expneurol.2023.114396

Cited by 7 publications

(5 citation statements)

References 38 publications

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“…C57/BL6 mice aged 8–10 weeks were implanted with electrodes to record LFPs in V1. The surgical procedure, as previously described, 60 involved anesthesia with isoflurane, head fixation in a stereotaxic apparatus (Kopf, USA), and exposing the skull. A cranial window (V1:AP: –3.6 mm, ML: ±2.4 mm, DV: –0.6 mm) was then prepared using a dental drill (RWD Life Science, China) on the left side for implantation.…”

Section: Methodsmentioning

confidence: 99%

40 Hz light flickering promotes sleep through cortical adenosine signaling

Zhou,

He,

et al. 2024

Cell Res

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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.

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Section: Methodsmentioning

confidence: 99%

40 Hz light flickering promotes sleep through cortical adenosine signaling

Zhou,

He,

et al. 2024

Cell Res

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Section: Methodsmentioning

confidence: 99%

“…These parameters were obtained simultaneously and continuously throughout the night. Sleep stages were classified based on the 2012 Academy of Sleep Medicine (AASM) manual guidelines (48). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Outcomes: The primary objective was to evaluate the effects of 40 Hz flickering on sleep onset by measuring sleep onset latency (SOL, minutes from light off to sleep onset) with polysomnography (PSG) and comparing it to baseline.…”

Section: Methodsmentioning

confidence: 99%

“…is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint In vivo g Su g : C / mice aged 10 weeks were implanted with electrodes to record s in V1. he surgical procedure, as previously described (48), involved anesthesia with isoflurane, head fixation in a stereotaxic apparatus (Kopf, USA), and exposing the skull. A cranial window (V1 A .…”

Section: Surgery: Viral Injection and Cannula Implantationmentioning

confidence: 99%

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40 Hz Light Flickering Promotes Sleep through Cortical Adenosine Signaling

He,

Zhou,

et al. 2023

Preprint

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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 hours after flickering) in extracellular adenosine levels in the primary visual cortex and other brain regions, as a function of light frequency, intensity, and wavelength, with maximal effects observed at 40 Hz frequency. We discovered cortical (glutamatergic and GABAergic) neurons, rather than astrocytes, as the cellular source, and intracellular adenosine generation from calcium influx-triggered, 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 light flickering for 30 min enhanced sleep in mice in a frequency-dependent manner. This somnogenic effect was absent in mice lacking ENT2 but replicated by administering adenosine to the visual cortex. Brief 40 Hz light flickering 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 adenosine signaling via ENT2 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.

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“…Efforts to develop non-invasive methods of modulating neural circuits to alleviate symptoms of neurological de cits are gaining ground. For example, rhythmic visual sensory stimulation using a 40 Hz light icker effectively ameliorated cognitive de cits in animal models of Alzheimer's disease (AD) [14][15][16] , stroke 17 , and Parkinson's disease 18,19 . Combining exercise with 40 Hz light icker stimulation improved spatial learning memory more than exercise alone 15 .…”

Section: Introductionmentioning

confidence: 99%

Adenosine mediates the amelioration of social novelty deficits during rhythmic light treatment of 16p11.2+/- female mice

Hou,

Ju,

et al. 2023

Preprint

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Non-invasive brain stimulation therapy for autism spectrum disorder (ASD) has shown beneficial effects. Recently, visual sensory stimulation using rhythmic 40 Hz light flicker effectively improved cognitive deficits in mouse models of Alzheimer's disease and stroke. However, whether rhythmic visual 40 Hz light flicker stimulation can ameliorate behavioral deficits in ASD remains unknown. Here, we show that 16p11.2+/− female mice exhibit a strong social novelty deficit, which was ameliorated by treatment with a long-term 40 Hz light stimulation. The elevated power of local-field potential (LFP) in the prefrontal cortex (PFC) of 16p11.2+/− female mice was also effectively reduced by 40 Hz light treatment. Importantly, the 40 Hz light flicker reversed the excessive excitatory neurotransmission of PFC pyramidal neurons without altering the firing rate and the number of resident PFC neurons. Mechanistically, 40 Hz light flicker evoked adenosine release in the PFC to modulate excessive excitatory neurotransmission of 16p11.2+/− female mice. Elevated adenosine functioned through its cognate A1 receptor to suppress excessive excitatory neurotransmission and to alleviate social novelty deficits. Indeed, either blocking the A1 receptor using a specific antagonist DPCPX or knockdown the A1 receptor in the PFC using an shRNA completely ablated the beneficial effects of 40 Hz light flicker. Thus, this study identified adenosine as a novel neurochemical cause for ameliorating social novelty deficit through the reduction of excitatory neurotransmission by the 40 Hz light flicker. The 40 Hz light stimulation warrants further development as a non-invasive ASD therapeutics.

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Non-invasive auditory and visual stimulation attenuates α-Synuclein deposition and improves motor and non-motor symptoms in PD mice

Cited by 7 publications

References 38 publications

40 Hz light flickering promotes sleep through cortical adenosine signaling

40 Hz light flickering promotes sleep through cortical adenosine signaling

40 Hz Light Flickering Promotes Sleep through Cortical Adenosine Signaling

Adenosine mediates the amelioration of social novelty deficits during rhythmic light treatment of 16p11.2+/- female mice

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