Auditory cue perception in the Cntnap2 rat model of autism

自闭症谱系障碍(ASD)是一组不同类型的神经发育障碍，估计每59名儿童中就有1名受到影响。自闭症的主要症状--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。在自闭症儿童中，复杂声音的神经编码已经被证明是不稳定的，这些声音具有快速变化的时间特征，如语音。这种缺陷可能是由于听觉中脑下丘的异常活动和前额脑区神经元兴奋/抑制的失衡所致。在临床和普通人群中，快速听觉语音加工都受到ASD的易感基因之一--接触素相关蛋白样蛋白2(CNTNAP2)的发育调控。缺乏cntnap2的小鼠和大鼠显示出人类ASD的核心缺陷，例如在社交沟通、听觉处理、皮质神经元同步性和前额叶皮质的活动方面。然而，ASD相关听觉损害的神经基础仍不完全清楚。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神经编码的精确度与感知声音判断之间的关系，这些判断与ASD的特征有关。拟议的项目是一个多地点合作，涉及西安大略大学的四个实验室。这项拟议的研究有三个目的：(1)阐明听觉通路和前额叶区域编码精度的变化，解释与野生型大鼠相比，cntnap2基因敲除大鼠的声音识别能力受损；(2)将神经编码精度缺陷与选定的听觉核团和前额叶区域的解剖变化联系起来；(3)在人类中建立一种翻译方法。拟议中的实验将揭示听觉处理的变化，这些变化可能呈现与自闭症相关的语音处理缺陷的基本机制。虽然只有一小部分自闭症患者存在CNTNAP2缺失，但了解与自闭症特征相关的改变的听觉通路生理学知识可能有助于开发客观的神经标记物。这些标记物可以帮助预测婴儿是否有患自闭症的风险，并为许多与自闭症相关的语音处理障碍患者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.