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前庭代偿中双侧前庭内侧核对输入刺激响应的敏感性变化及其离子机制

薛伟轩¹, 李潜啸¹, 张洋浔¹, 张潇洋^1,2, 容永豪³, 王建军^1,2, 朱景宁^1,2,*

¹南京大学医药生物技术国家重点实验室和生命科学学院生理学系，南京 210023；²南京大学脑科学研究院，南京 210023；³香港中文大学生物医学学院、蔡永业脑科学中心，香港

摘要

前庭代偿是研究前庭疾病防治策略和成年后由外周损伤导致的中枢神经系统可塑性的重要模型。脑干中的前庭内侧核(medial vestibular nucleus, MVN)是实现前庭代偿的重要中枢。MVN神经元的兴奋性和敏感性对前庭功能的正常执行十分关键，但先前的研究集中关注于单侧外周迷路切除(unilateral labyrinthectomy, UL)这一前庭代偿模型中患侧MVN中神经元兴奋性活动的变化，对双侧MVN神经元动态响应输入刺激的敏感性变化仍知之甚少。本研究采用实时荧光定量PCR、离体脑片全细胞膜片钳记录和行为学方法，观察到UL后6 h，大鼠表现出显著的自发运动障碍，且其患侧而非健侧MVN中B型神经元的兴奋性活动显著降低。但与之相反，健侧而非患侧MVN中的B型神经元对斜坡和阶跃电流刺激的敏感性则显著升高。UL后1周，大鼠基础运动行为得到代偿，其患侧MVN神经元的兴奋性和健侧MVN神经元的敏感性均恢复至正常水平。此外，参与B型MVN神经元敏感性调控的小电导钙激活钾通道(small conductance Ca2+-activated K+ channel, SK) UL后 6 h在健侧MVN中选择性表达下调，而1周后恢复至正常水平。药理学选择性阻断健侧MVN中的SK通道以抑制其UL后的功能可塑性变化，可显著延迟前庭运动障碍的代偿。本研究结果提示，患侧MVN神经元兴奋性与健侧MVN神经元敏感性的可塑性变化可能共同参与了前庭症状的产生和前庭代偿，而SK通道可能是介导健侧MVN神经元敏感性随前庭代偿动态变化的重要离子机制。

关键词： 前庭代偿; 前庭内侧核; 兴奋性; 敏感性; SK通道

Changes in sensitivity of bilateral medial vestibular nuclear neurons responding to input stimuli during vestibular compensation and the underlying ionic mechanism

XUE Wei-Xuan¹, LI Qian-Xiao¹, ZHANG Yang-Xun¹, ZHANG Xiao-Yang^1,2, Wing-Ho Yung³, WANG Jian-Jun^1,2, ZHU Jing-Ning^1,2,*

¹State Key Laboratory of Pharmaceutical Biotechnology, Department of Physiology, School of Life Sciences, Nanjing University, Nanjing 210023, China；²Institute for Brain Sciences, Nanjing University, Nanjing 210023, China；³School of Biomedical Sciences, Faculty of Medicine, and Gerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Hong Kong, China

Abstract

Vestibular compensation is an important model for developing the prevention and intervention strategies of vestibular disorders, and investigating the plasticity of the adult central nervous system induced by peripheral injury. Medial vestibular nucleus (MVN) in brainstem is critical center for vestibular compensation. Its neuronal excitability and sensitivity have been implicated in normal function of vestibular system. Previous studies mainly focused on the changes in neuronal excitability of the MVN in lesional side of the rat model of vestibular compensation following the unilateral labyrinthectomy (UL). However, the plasticity of sensitivity of bilateral MVN neurons dynamically responding to input stimuli is still largely unknown. In the present study, by using qPCR, whole-cell patch clamp recording in acute brain slices and behavioral techniques, we observed that 6 h after UL, rats showed a significant deficit in spontaneous locomotion, and a decrease in excitability of type B neurons in the ipsilesional rather than contralesional MVN. By contrast, type B neurons in the contralesional rather than ipsilesional MVN exhibited an increase in response sensitivity to the ramp and step input current stimuli. One week after UL, both the neuronal excitability of the ipsilesional MVN and the neuronal sensitivity of the contralesional MVN recovered to the baseline, accompanied by a compensation of spontaneous locomotion. In addition, the data showed that the small conductance Ca2+-activated K+ (SK) channel involved in the regulation of type B MVN neuronal sensitivity, showed a selective decrease in expression in the contralesional MVN 6 h after UL, and returned to normal level 1 week later. Pharmacological blockage of SK channel in contralateral MVN to inhibit the UL-induced functional plasticity of SK channel significantly delayed the compensation of vestibular motor dysfunction. These results suggest that the changes in plasticity of the ipsilesional MVN neuronal excitability, together with changes in the contralesional MVN neuronal sensitivity, may both contribute to the development of vestibular symptoms as well as vestibular compensation, and SK channel may be an essential ionic mechanism responsible for the dynamic changes of MVN neuronal sensitivity during vestibular compensation.

Key words: Vestibular compensation; medial vestibular nucleus; excitability; sensitivity; SK channel

收稿日期：　　录用日期：

通讯作者：朱景宁　　E-mail: jnzhu@nju.edu.cn

DOI: 10.13294/j.aps.2022.0023

引用本文：

薛伟轩, 李潜啸, 张洋浔, 张潇洋, 容永豪, 王建军, 朱景宁. 前庭代偿中双侧前庭内侧核对输入刺激响应的敏感性变化及其离子机制[J]. 生理学报 2022; 74 (2): 135-144.

XUE Wei-Xuan, LI Qian-Xiao, ZHANG Yang-Xun, ZHANG Xiao-Yang, Wing-Ho Yung, WANG Jian-Jun, ZHU Jing-Ning. Changes in sensitivity of bilateral medial vestibular nuclear neurons responding to input stimuli during vestibular compensation and the underlying ionic mechanism. Acta Physiol Sin 2022; 74 (2): 135-144 (in Chinese with English abstract).