Auditory cue perception in the Cntnap2 rat model of autism

Cntnap2 大鼠自闭症模型中的听觉线索感知

• 批准号: 442662585
• 负责人: Dr. Dorit Möhrle
• 金额: --
• 依托单位: The Brain and Mind Institute
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/442662585?language=en
• 关键词: Auditory; cue; perception; Cntnap2; rat

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.

自闭症谱系障碍 (ASD) 是一组异质性神经发育障碍，估计每 59 名儿童中就有 1 人受到影响。自闭症谱系障碍的主要症状——社交沟通和语言习得的缺陷——被认为是听觉系统发育过程中声音处理不准确的结果。在患有自闭症谱系障碍的儿童中，具有快速变化的时间特征（例如语音）的复杂声音的神经编码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区域的神经元兴奋/抑制不平衡造成的。在临床和普通人群中，快速听觉言语处理在发育上受到 ASD 易感基因之一——接触素相关蛋白样 2 (CNTNAP2) 的调节。缺乏 Cntnap2 的小鼠和大鼠表现出人类 ASD 的核心缺陷，例如社交沟通、听觉处理、皮质神经元同步和前额皮质活动。然而，自闭症谱系障碍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自闭症谱系障碍特征水平的变化而变化，并测试前额叶大脑活动的影响。我将采用转化方法来研究与大鼠和人类自闭症谱系障碍特征相关的感知声音判断相关的神经编码精度。拟议的项目是一个多地点合作，涉及西安大略大学的四个实验室。拟议的研究有三个目标：（1）阐明前额叶区域听觉通路和活动编码精度的变化，解释Cntnap2敲除小鼠与野生型大鼠相比声音辨别能力受损的原因；（2）将神经编码精度缺陷与选定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谱系障碍相关的语音处理缺陷的基本机制。尽管只有一小部分自闭症人群存在 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自闭症谱系障碍的风险，并为许多患有与自闭症谱系障碍相关的言语处理障碍的人找到改进的治疗方法。