运动病习惯化过程中行为表型及脑干前庭区Ywhah/ERK信号表达的时间进程分析

文献信息

中文摘要

运动病习惯化是研究前庭障碍适应的核心神经可塑性模型，但其脑区特异性的时间分子机制仍不明确。本研究采用多脑区蛋白质组学筛查结合时间序列分子验证，以刻画运动病习惯化过程中的关键分子动态。成年小鼠接受连续15天正弦旋转刺激，并通过四项行为学指标验证模型建立。基于蛋白质组数据自行构建的五维加权评分系统证实，在海马、大脑皮层和脑干前庭区中，脑干前庭区表现出最显著的分子反应。通过整合网络中心性、统计显著性、功能相关性、可成药性及神经系统疾病相关性，进一步筛选候选分子。采用逆转录定量实时PCR和Western blot检测完整时间序列的仅束缚对照组和习惯化组脑干前庭区组织中候选蛋白的表达变化。时间验证显示，脑干前庭区Ywhah进行性下调，磷酸化Erk1/2与总Erk1/2比值呈时间依赖性升高。Ywhah与p-Erk1/2/总Erk1/2的相反表达趋势首次在第5天达到统计学显著性，提示时间耦合。总之，本研究描绘了运动病习惯化过程中脑干前庭区不同的时间分子模式，Ywhah抑制与ERK激活存在重叠的关键时间窗。这些发现为进一步探索前庭习惯化的神经可塑性机制提供了可靠的纵向分子证据和有前景的候选靶点。

英文摘要

Motion sickness habituation represents a core neuroplastic model for investigating vestibular disorder adaptation, yet its brain-region-specific temporal molecular mechanisms remain poorly defined. Here, we adopted multi-brain-region proteomic screening combined with time-series molecular validation to characterize key molecular dynamics during motion sickness habituation. Adult mice received 15 consecutive days of sinusoidal rotational stimulation, and model establishment was verified via four behavioral indices. A self-constructed five-dimensional weighted scoring system based on proteomic data confirmed that the vestibular region of the brainstem exhibited the most prominent molecular response among the hippocampus, cerebral cortex, and brainstem vestibular region. Candidate molecules were further screened by integrating network centrality, statistical significance, functional relevance, druggability, and neurological disease correlation. Reverse transcription quantitative real-time PCR and Western blot were performed to detect the expression changes of candidate proteins in brainstem vestibular region tissues of the complete time-series restraint-only control group and habituation group. Temporal validation revealed progressive downregulation of Ywhah and a time-dependent increase in the ratio of phosphorylated Erk1/2 to total Erk1/2 in the vestibular region of the brainstem. The opposite expression trends of Ywhah and p-Erk1/2/total Erk1/2 first reached statistical significance on Day 5, indicating temporal coupling. In summary, this study delineates distinct temporal molecular patterns in the brainstem vestibular region during motion sickness habituation, with overlapping critical time windows for Ywhah suppression and ERK activation. These findings provide reliable longitudinal molecular evidence and promising candidate targets for further exploring the neuroplastic mechanisms of vestibular habituation.