Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, 240 Pasteur Drive, Biomedical Innovations Building, R0551, Palo Alto, CA, 94304, USA.
Sci Rep. 2020 Nov 26;10(1):20687. doi: 10.1038/s41598-020-77803-7.
Current clinical interest lies in the relationship between hearing loss and cognitive impairment. Previous work demonstrated that noise exposure, a common cause of sensorineural hearing loss (SNHL), leads to cognitive impairments in mice. However, in noise-induced models, it is difficult to distinguish the effects of noise trauma from subsequent SNHL on central processes. Here, we use cochlear hair cell ablation to isolate the effects of SNHL. Cochlear hair cells were conditionally and selectively ablated in mature, transgenic mice where the human diphtheria toxin (DT) receptor was expressed behind the hair-cell specific Pou4f3 promoter. Due to higher Pou4f3 expression in cochlear hair cells than vestibular hair cells, administration of a low dose of DT caused profound SNHL without vestibular dysfunction and had no effect on wild-type (WT) littermates. Spatial learning/memory was assayed using an automated radial 8-arm maze (RAM), where mice were trained to find food rewards over a 14-day period. The number of working memory errors (WME) and reference memory errors (RME) per training day were recorded. All animals were injected with DT during P30-60 and underwent the RAM assay during P90-120. SNHL animals committed more WME and RME than WT animals, demonstrating that isolated SNHL affected cognitive function. Duration of SNHL (60 versus 90 days post DT injection) had no effect on RAM performance. However, younger age of acquired SNHL (DT on P30 versus P60) was associated with fewer WME. This describes the previously undocumented effect of isolated SNHL on cognitive processes that do not directly rely on auditory sensory input.
目前，临床研究的重点在于听力损失与认知障碍之间的关系。先前的研究表明，噪声暴露是感音神经性听力损失（SNHL）的常见原因，可导致小鼠认知功能障碍。然而，在噪声诱导的模型中，很难区分噪声创伤和随后的 SNHL 对中枢过程的影响。在这里，我们使用耳蜗毛细胞消融来分离 SNHL 的影响。在成熟的转基因小鼠中，条件性和选择性地消融了人类白喉毒素（DT）受体在毛细胞特异性 Pou4f3 启动子后面表达的耳蜗毛细胞。由于 Pou4f3 在耳蜗毛细胞中的表达高于前庭毛细胞，因此给予低剂量的 DT 会导致严重的 SNHL 而不会引起前庭功能障碍，并且对野生型（WT）同窝仔鼠没有影响。使用自动放射状 8 臂迷宫（RAM）测定空间学习/记忆，其中对小鼠进行了 14 天的训练，以找到食物奖励。记录了每天的工作记忆错误（WME）和参考记忆错误（RME）的数量。所有动物均在 P30-60 期间给予 DT 注射，并在 P90-120 期间进行 RAM 测定。与 WT 动物相比，SNHL 动物的 WME 和 RME 更多，表明孤立的 SNHL 影响了认知功能。SNHL 的持续时间（DT 注射后 60 天与 90 天）对 RAM 性能没有影响。但是，获得性 SNHL 的年龄较小（DT 于 P30 与 P60）与 WME 较少相关。这描述了以前未记录的孤立 SNHL 对不直接依赖听觉感觉输入的认知过程的影响。
