Npc1-/-小鼠前庭相关反射反应改变

文献信息

中文摘要

背景： C型尼曼-匹克病（NPC）是一种溶酶体脂质转运障碍，伴有进行性神经退行性变和小脑功能障碍。尽管平衡障碍突出，但前庭系统受累仍特征不明。
目的： 确定在P35时是否可检测到Npc1-/-小鼠前庭相关反射反应改变，以及这些改变与前庭毛细胞形态、胆固醇相关变化和小脑病理的关系。
方法： 对出生后第35天的雌性Npc1-/-和野生型小鼠分别进行功能学和组织学队列研究（每个队列每种基因型n=5）。功能学队列接受前庭眼反射（VOR）、眼反向旋转（OCR）、冷热试验、运动、姿势和步态评估。组织学队列采用Myo7a免疫荧光评估壶腹嵴、椭圆囊和球囊。Filipin染色评估球囊中未酯化胆固醇。小脑病理量化为分子层面积相对于所分析小脑皮质面积的比例。
结果： Npc1-/-小鼠显示OCR振幅和冷热反应显著降低，而VOR增益在基因型间无显著差异。突变小鼠自发运动活动减少、步幅缩短、支撑基底增宽；步频和平均步行速度在基因型间无显著差异。三个感觉器官中前庭毛细胞密度均保持，而球囊中filipin标记增加。相对小脑分子层面积显著减少。
结论： Npc1缺陷与前庭相关反射反应改变相关，同时伴有前庭毛细胞形态保留、球囊胆固醇相关变化和小脑病理。这些发现表明存在前庭相关生理异常，但无法完全区分外周和中枢对平衡表型的贡献。客观前庭测试可能为表征疾病相关平衡功能障碍提供补充指标。

英文摘要

BACKGROUND: Niemann-Pick disease type C (NPC) is a lysosomal lipid-trafficking disorder with progressive neurodegeneration and cerebellar dysfunction. Although balance impairment is prominent, vestibular-system involvement remains poorly characterized.
OBJECTIVE: To determine whether altered vestibular-related reflex responses are detectable at P35 and how they relate to vestibular hair-cell morphology, cholesterol-associated changes, and cerebellar pathology in Npc1-/- mice.
METHODS: Female postnatal day 35 Npc1-/- and wild-type mice were studied using separate functional and histological cohorts (n = 5/genotype in each cohort). The functional cohort underwent vestibulo-ocular reflex (VOR), ocular counter-roll (OCR), caloric, locomotor, postural, and gait assessments. Myo7a immunofluorescence was used to evaluate the crista ampullaris, utricle, and saccule in the histological cohort. Filipin staining assessed unesterified cholesterol in the saccule. Cerebellar pathology was quantified as molecular-layer area relative to the analyzed cerebellar cortical area.
RESULTS: Npc1-/- mice showed significantly reduced OCR amplitudes and caloric responses, whereas VOR gain did not differ significantly between genotypes. Mutant mice had reduced spontaneous locomotor activity, shorter stride length, and a wider base of support; cadence and average walking speed did not differ significantly between genotypes. Vestibular hair-cell density remained preserved in all three sensory organs, whereas filipin labeling was increased in the saccule. The relative cerebellar molecular-layer area was significantly reduced.
CONCLUSIONS: Npc1 deficiency is associated with altered vestibular-related reflex responses that coexist with preserved vestibular hair-cell morphology, cholesterol-associated changes in the saccule, and cerebellar pathology. These findings demonstrate vestibular-related physiological abnormalities but do not permit complete separation of peripheral and central contributions to the balance phenotype. Objective vestibular testing may provide complementary measures for characterizing disease-related balance dysfunction.