Auditory cue perception in the Cntnap2 rat model of autism

自闭症谱系障碍（ASD）是一种异质性的神经发育障碍，估计每59个儿童中就有1个受到影响。ASD的主要症状——社交和语言习得方面的缺陷——被认为是听觉系统发育过程中声音处理不准确的结果。在患有ASD的儿童中，具有快速变化的时间特征的复杂声音的神经编码（如言语）已被证明是不稳定的。这种缺陷可能是由于听觉中脑下丘的异常活动和前额叶脑区域神经元兴奋/抑制的不平衡。在临床和普通人群中，快速听觉言语处理是由ASD的易感基因之一，接触蛋白相关蛋白样2 （CNTNAP2）发育调节的。缺乏Cntnap2的小鼠和大鼠表现出人类ASD的核心缺陷，如社交、听觉加工、皮质神经元同步和前额皮质活动。然而，自闭症相关听觉障碍的神经基础仍未完全了解。我建议研究听觉通路中声音处理敏锐度的生理基础如何随着ASD特征的不同水平而变化，并测试前额叶大脑活动的影响。我将采用翻译的方法来研究大鼠和人类与ASD特征相关的感知声音判断相关的神经编码精度。拟议的项目是一个涉及西安大略大学四个实验室的多站点合作项目。本研究有三个目的：(1)阐明与野生型大鼠相比，Cntnap2基因敲除后听觉通路编码精度和前额叶区域活动的改变，从而解释声音识别能力受损；(2)将神经编码精度的缺陷与选择的听核和前额叶区域的解剖变化联系起来；(3)建立一种适用于人类的翻译方法。这些实验将揭示听觉处理的变化，这些变化可能会揭示与ASD相关的言语处理缺陷的基本机制。虽然只有一小部分自闭症人群携带CNTNAP2缺失，但了解与自闭症特征相关的听觉通路生理学改变可能有助于开发客观的神经标记。这些标记可以帮助预测婴儿是否有患ASD的风险，并为许多患有与ASD相关的言语处理中断的个体确定改进的治疗方法。

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders estimated to affect 1 in 59 children. The key symptoms of ASD - deficits in social communication and language acquisition - have been proposed to be a consequence of inaccurate sound processing during development of the auditory system. In children with ASD, the neural encoding of complex sounds with rapidly changing temporal features such as speech has been shown to be instable. This deficit is probably due to aberrant activity in the Inferior Colliculus in the auditory midbrain and imbalanced neuronal excitation/inhibition in prefrontal brain regions. Rapid auditory speech processing is developmentally regulated by one of the susceptibility genes of ASD, the contactin associated protein-like 2 (CNTNAP2), both in clinical and general populations. Mice and rats lacking Cntnap2 show core deficits of human ASD, e.g. in social communication, auditory processing, cortical neuronal synchrony and activity in the prefrontal cortex. However, the neural basis of the ASD-related auditory impairments is still not fully understood. I propose to examine how physiological underpinnings of sound processing acuity in auditory pathways change with varying levels of ASD traits and to test the influence of prefrontal brain activity. I will take a translational approach to study neural encoding precision in relation to perceptual sound judgement correlated to ASD traits in rats and humans. The proposed project is a multi‐site collaboration involving four labs at the University of Western Ontario. The proposed research has three aims: (1) to elucidate alterations in encoding precision in the auditory pathway and activity in prefrontal areas that explain impaired sound discrimination abilities in Cntnap2 knockout compared to wild-type rats, (2) to relate deficits in neural encoding precision to anatomical changes in selected auditory nuclei and prefrontal areas, and (3) establish a translational approach in humans. The proposed experiments will uncover the changes in auditory processing that might present fundamental mechanisms of speech processing deficits associated with ASD. Although only a minor percentage of the autistic population harbor deletions of CNTNAP2, knowledge of the altered auditory pathway physiology related with autistic traits might help to develop objective neural markers. Such markers could facilitate to predict if infants are at risk for ASD and to identify improved therapies for the many individuals suffering from speech processing disruptions associated with ASD.