脑型钠通道在水杨酸钠耳鸣模型听皮层异常兴奋中的作用及机制研究

The abnormal neural excitability in auditory cortex has been proved to be one of the most important pathological changes in the occurrence of tinnitus. As the main contributors of action potentials, the abnormal expression/distribution and dysfunction of electrophysiological properties of voltage-gated sodium channels (VGSCs) are common basis for the occurrence of multiple clinical neuropathies characterized by neurogenic excitatory dyshomeostasis. Our previous study found that the expression levels of four brain-type VGSCs (Nav1.1, Nav1.2, Nav1.3, and Nav1.6) were significantly increased in the A1 cortex of tinnitus rats induced by salicylate sodium, which speculated that brain-type VGSCs are closely involved in the pathogenesis of tinnitus. This project intends to explore functional alienation of sodium currents of neuron/ glia in the auditory cortex with combinational application of electrophysiology in vitro/ in vivo, two-photo ion imaging, cellular and molecular biology, gene expression regulation and other means. In addition, this work will examine the dynamic expression and abnormal distribution of VGSCs central subtypes in the development of tinnitus, and evaluate the therapeutic effects of tinnitus disorder by regulation the VGSC subtype showing the abnormal expression in neuronal cells during tinnitus. In general, this project aims to explore the leading or participating role of brain-type VGSCs in the information export abnormalities and functional mechanisms of neural excitability in the A1 cortex of tinnitus model from multi-dimensional aspects, expand pathological knowledge of channel pathology of tinnitus, and provide a prospective assessment for development of clinical targeted drugs for tinnitus.

听皮层的神经兴奋性异常是耳鸣发生的重要病理改变之一。电压门控钠通道（VGSCs）作为动作电位核心构件，其亚型异常表达分布或电生理特性紊乱是多种以神经兴奋性稳态失衡为内在表征的神经系统病患发生的共性基础。本申项前期工作发现，脑型VGSCs（Nav1.1、Nav1.2、Nav1.3、Nav1.6）在水杨酸钠（NaSal）耳鸣大鼠模型听皮层的表达量增多，提示脑型VGSCs紧密参与了听皮层异常兴奋的病理过程。本申项拟运用电生理记录、双光子离子成像、细胞分子生物学及基因表达调控等手段，检测NaSal耳鸣模型听皮层神经细胞的钠电流异化特征, 验明耳鸣发生过程中的脑型VGSCs动态表达与异常分布, 评估靶向干预VGSC亚型缓解耳鸣的效果。从多维度探究脑型VGSCs协同介导NaSal耳鸣模型听皮层神经元兴奋性的信息输出异常及其功能机制，拓展耳鸣通道病理学创新知识，为耳鸣的膜通道靶向药物研发提供前瞻性评估。

听觉中枢神经网络异常兴奋是耳鸣的主要病理特征。本项目致力于探究耳鸣动物模型中枢兴奋性增强的分子机制和药物干预靶点。听皮层是感知声音的最高级中枢，其神经电活动增强是耳鸣发生与维持的重要因素，降低听皮层的神经电活动是治疗耳鸣的可选策略。电压门控钠通道（VGSCs）是形成动作电位的核心蛋白构件，其表达异常或功能紊乱导致的神经超兴奋性是诸多神经系统疾病发生的共性基础。本项目运用动物行为学、电生理、药理学和细胞分子生物学等技术，探讨VGSCs介导水杨酸耳鸣模型神经元兴奋性的信息输出异常及其功能机制，为临床应对耳鸣提供新的策略和靶点。项目结果：1）急性和慢性高剂量水杨酸腹腔给药可以稳定地诱导可逆的大鼠耳鸣样行为；2）急/慢性水杨酸耳鸣模型听皮层的VGSCs异常表达，四种VGSC亚型谷氨协同介导神经元抑制-兴奋稳态失衡；3）急/慢性水杨酸给药异化听皮层场电位节律特征；4）1.4 mM水杨酸可异化外源表达的钠通道电生理特征和门控特性；5）急/慢性水杨酸耳鸣模型听皮层的胶质细胞异常增殖活化，提示胶质细胞参与介导耳鸣听皮层病理改变。本项目研究结果显示电压门控钠通道的表达与功能异常是听皮层抑制-兴奋稳态失衡和耳鸣发生的重要调控因素，为耳鸣神经机制和药物靶标提供了新的研究视角和切入点。

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