Department of Psychological Science/Behavioral Neuroscience, University of Connecticut, Storrs, CT 06269, USA.
Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
Genes (Basel). 2021 Jan 24;12(2):151. doi: 10.3390/genes12020151.
Central auditory processing disorder (CAPD) is associated with difficulties hearing and processing acoustic information, as well as subsequent impacts on the development of higher-order cognitive processes (i.e., attention and language). Yet CAPD also lacks clear and consistent diagnostic criteria, with widespread clinical disagreement on this matter. As such, identification of biological markers for CAPD would be useful. A recent genome association study identified a potential CAPD risk gene, . In a homozygous state, this gene is associated with Usher syndrome type 2 (USH2), a recessive disorder resulting in bilateral, high-frequency hearing loss due to atypical cochlear hair cell development. However, children with heterozygous mutations have also been found to show unexpected low-frequency hearing loss and reduced early vocabulary, contradicting assumptions that the heterozygous (carrier) state is "phenotype free". Parallel evidence has confirmed that heterozygous mutations in a transgenic mouse model also cause low-frequency hearing loss (Perrino et al., 2020). Importantly, these auditory processing anomalies were still evident after covariance for hearing loss, suggesting a CAPD profile. Since usherin anomalies occur in the peripheral cochlea and central auditory structures, these findings point to upstream developmental feedback effects of peripheral sensory loss on high-level processing characteristic of CAPD. In this study, we aimed to expand upon the mouse behavioral battery used in Perrino et al. (2020) by evaluating central auditory brain structures, including the superior olivary complex (SOC) and medial geniculate nucleus (MGN), in heterozygous and homozygous mice. We found that heterozygous mice had significantly larger SOC volumes while homozygous had significantly smaller SOC volumes. Heterozygous mutations did not affect the MGN; however, homozygous mutations resulted in a significant shift towards more smaller neurons. These findings suggest that alterations in cochlear development due to variation can secondarily impact the development of brain regions important for auditory processing ability.
中枢听觉处理障碍 (CAPD) 与听觉和处理声音信息的困难有关，以及对高级认知过程（即注意力和语言）的后续影响。然而，CAPD 也缺乏明确和一致的诊断标准，临床上对此存在广泛的分歧。因此，识别 CAPD 的生物标志物将是有用的。最近的一项全基因组关联研究确定了一个潜在的 CAPD 风险基因 。在纯合状态下，该基因与 2 型 Usher 综合征 (USH2) 相关，这是一种隐性疾病，由于典型耳蜗毛细胞发育异常，导致双侧高频听力损失。然而，携带杂合突变的儿童也被发现表现出意外的低频听力损失和早期词汇量减少，这与杂合（携带者）状态“无表型”的假设相矛盾。平行证据证实，转基因小鼠模型中的杂合 突变也会导致低频听力损失（Perrino 等人，2020 年）。重要的是，在对听力损失进行协方差后，这些听觉处理异常仍然明显，提示存在 CAPD 特征。由于 usherin 异常发生在外周耳蜗和中枢听觉结构中，这些发现表明，外周感觉丧失对 CAPD 特征的高级处理的上游发育反馈效应。在这项研究中，我们旨在通过评估中枢听觉脑结构，包括上橄榄复合体 (SOC) 和内侧膝状体核 (MGN)，来扩展 Perrino 等人在 2020 年使用的小鼠行为电池。我们发现杂合 突变的 SOC 体积明显增大，而纯合 突变的 SOC 体积明显减小。杂合突变不影响 MGN；然而，纯合 突变导致神经元向更小的方向显著转移。这些发现表明，由于 变异导致的耳蜗发育改变可能会对听觉处理能力的大脑区域的发育产生次要影响。
