Reversal of auditory cortical hyperexcitability and restoration of synaptic plasticity balance by GluN1-mediated photobiomodulation in noise-induced tinnitus

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2026-01-01 Epub Date: 2025-12-15 DOI:10.1016/j.brainresbull.2025.111685

Zhixin Zhang , Xinmiao Xue , Dongdong He , Peng Liu , Chi Zhang , Yvke Jiang , Shuhan Lv , Li Wang , Hanwen Zhou , Weidong Shen , Shiming Yang , Fangyuan Wang

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Abstract

Glutamate receptors regulate neuronal excitability and drive synaptic plasticity in the auditory cortex (AC), with aberrant activation or dysfunction contributing to tinnitus pathogenesis. Photobiomodulation (PBM) exerts sustained modulatory effects on neural activity and behavioral responses across species, including humans. However, its therapeutic potential and mechanisms in noise-induced tinnitus remain unexplored. Here, we developed a noninvasive low-irradiance PBM device to target the AC of animal models, investigating near-infrared light mechanisms for reversing cortical hyperexcitability and restoring synaptic plasticity. In noise-exposed tinnitus models without significant neuronal loss, we observed abnormally elevated GluN1 activation and increased synaptic structural complexity compared to non-tinnitus or sham-exposed controls. Tinnitus models were subjected to PBM interventions with varying parameters (irradiance power: 20/40/80 mW/cm²; exposure duration: 300/600 s). Therapeutic efficacy was validated through auditory brainstem response (ABR), gap-prepulse inhibition of acoustic startle (GPIAS), and prepulse inhibition (PPI) behavioral assays. Fluorescence microscopy of brain sections quantified c-Fos/GluN1 co-localization to image activated NMDARs, while Nissl staining assessed PBM safety across parameters. Phosphoproteomic profiling explored mechanistic pathways, with neuronal morphological changes visualized via Golgi staining and transmission electron microscopy. To confirm GluN1’s pivotal role in auditory cognition, we engineered transgenic mice with GluN1 overexpression or knockdown. GluN1-overexpressing mice exhibited tinnitus-like behaviors at specific frequencies, whereas GluN1-deficient tinnitus models showed aberrant behaviors due to impaired auditory cognition. Our findings delineate noise-induced tinnitus mechanisms and PBM-mediated regulation of neuronal excitability and structural plasticity, establishing an irradiance-duration optimization framework for clinical translation.

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噪声性耳鸣中glun1介导的光生物调节对听觉皮质高兴奋性的逆转和突触可塑性平衡的恢复。

谷氨酸受体调节听觉皮层（AC）的神经元兴奋性并驱动突触可塑性，其异常激活或功能障碍与耳鸣发病有关。光生物调节（PBM）对包括人类在内的物种的神经活动和行为反应具有持续的调节作用。然而，其治疗噪声性耳鸣的潜力和机制仍未被探索。在这里，我们开发了一种无创低辐照PBM装置，以动物模型的AC为目标，研究近红外光逆转皮层高兴奋性和恢复突触可塑性的机制。在没有明显神经元损失的噪声暴露耳鸣模型中，我们观察到与非耳鸣或假暴露对照组相比，GluN1激活异常升高，突触结构复杂性增加。耳鸣模型接受不同参数的PBM干预（辐照功率：20/40/80mW/cm²；照射时间：300/600s）。通过听觉脑干反应（ABR）、声惊间隙-脉冲前抑制（GPIAS）和脉冲前抑制（PPI）行为测试验证治疗效果。脑切片的荧光显微镜定量了c-Fos/GluN1共定位到图像激活的NMDARs，而尼氏染色评估了PBM各参数的安全性。通过高尔基染色和透射电镜观察神经元形态学变化，磷蛋白组学分析探索了机制途径。为了证实GluN1在听觉认知中的关键作用，我们设计了GluN1过表达或敲低的转基因小鼠。glun1过表达小鼠在特定频率下表现出耳鸣样行为，而glun1缺陷耳鸣模型由于听觉认知受损而表现出异常行为。我们的研究结果描述了噪声诱发耳鸣的机制和pbm介导的神经元兴奋性和结构可塑性的调节，为临床翻译建立了一个辐照-持续时间优化框架。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.