Malhotra Arjun S, Kulesza Randy
Department of Anatomy Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania, USA; Millcreek Community Hospital LECOM Health, Department of Orthopedic Surgery, Erie, Pennsylvania, USA.
Department of Anatomy Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania, USA.
Hear Res. 2023 Sep 1;436:108816. doi: 10.1016/j.heares.2023.108816. Epub 2023 May 25.
Auditory dysfunction is a common feature of autism spectrum disorder (ASD) and ranges from deafness to hypersensitivity. The auditory brainstem response (ABR) permits study of the amplitude and latency of synchronized electrical activity along the ascending auditory pathway in response to clicks and pure tone stimuli. Indeed, numerous studies have shown that subjects with ASD have ABR abnormalities. In utero exposure to the antiepileptic drug valproic acid (VPA) is associated with human cases of ASD and is used as an animal model of ASD. Previous studies have shown that VPA-exposed animals have significantly fewer neurons in the auditory brainstem and thalamus, reduced ascending projections to the auditory midbrain and thalamus and increased neuronal activation in response to pure tone stimuli. Accordingly, we hypothesized that VPA-exposed animals would have abnormal ABRs throughout their lifespans. We approached this hypothesis in two cohorts. First, we examined ABRs from both ears on postnatal day 22 (P22). Then, we examined monaural ABRs in animals at P28, 60, 120, 180, 240, 300 and 360. Our results suggest that at P22, VPA-exposed animals have elevated thresholds and increased peak latencies. However, by P60 these differences largely normalize with differences appearing only near hearing threshold. Additionally, our analysis revealed that maturation of ABR waves occurred at different trajectories in control and VPA-exposed animals. These results, together with our previous work, suggest that VPA exposure not only impacts total neuron number and connectivity, but also auditory evoked responses. Finally, our longitudinal analysis suggests that delayed maturation of auditory brainstem circuits may impact ABRs throughout the lifespan of the animal.
听觉功能障碍是自闭症谱系障碍（ASD）的一个常见特征，范围从失聪到听觉过敏。听觉脑干反应（ABR）可用于研究沿听觉上行通路对点击声和纯音刺激产生的同步电活动的幅度和潜伏期。事实上，大量研究表明，患有ASD的受试者存在ABR异常。子宫内暴露于抗癫痫药物丙戊酸（VPA）与人类ASD病例有关，并被用作ASD的动物模型。先前的研究表明，暴露于VPA的动物在听觉脑干和丘脑中的神经元明显减少，向听觉中脑和丘脑的上行投射减少，并且对纯音刺激的神经元激活增加。因此，我们假设暴露于VPA的动物在其整个生命周期中都会有异常的ABR。我们在两个队列中研究了这个假设。首先，我们在出生后第22天（P22）检查了双耳的ABR。然后，我们在P28、60、120、180、240、300和360天检查了动物的单耳ABR。我们的结果表明，在P22时，暴露于VPA的动物阈值升高，峰值潜伏期增加。然而，到P60时，这些差异在很大程度上恢复正常，仅在听力阈值附近出现差异。此外，我们的分析表明，ABR波的成熟在对照组和暴露于VPA的动物中以不同的轨迹发生。这些结果，连同我们之前的工作，表明VPA暴露不仅影响神经元总数和连接性，还影响听觉诱发反应。最后，我们的纵向分析表明，听觉脑干回路的延迟成熟可能会在动物的整个生命周期中影响ABR。
