Neural circuits underlying temporal integration of sounds and their dysregulation in an ASD model

项目摘要 大脑从复杂的声音环境中提取相关信息并过滤掉干扰因素的能力， 对于感知语言等生理相关声音至关重要。这种能力往往是缺乏自闭症 自闭症谱系障碍（ASD），影响患者理解和与周围世界互动的能力 他们具体而言，ASD患者对言语的反应降低，对正常刺激过敏，并且 在嘈杂的环境中很容易被淹没。这些感觉处理缺陷可以归因于 影响声音如何整合以感知相关刺激的神经元回路。在人类中， 单个声音的同步性取决于30 ms窗口内组件开始的同步性， 特别是准确地整合和声对我们的语言感知至关重要。但 听觉皮层中复杂声音整合的神经元回路，以及它们如何有助于 ASD的感觉缺陷尚不清楚。为了解决这个知识缺口，我将识别神经元回路， 和声在听觉皮层的时间整合机制。此外，我将 使用Angelman综合征（AS，Ube 3am-/p+）的小鼠模型来研究这些回路如何有助于 感觉处理和言语辨别缺陷。我假设时间整合窗口 用于谐波声音的结合，并因此具有整合源自谐波声音的信息的能力 大脑皮层回路中的抑制性神经元的活动控制着神经元的活动。此外，我预计， AS小鼠中抑制的改变改变了和声整合的时间窗， 这导致ASD患者的感觉处理缺陷。在这个建议中，我的目的是1）比较 使用行为辨别任务的野生型（WT）和AS小鼠之间的谐波的感知窗口， 2)利用在体双光子技术确定WT和AS小鼠谐波整合的神经机制 钙成像，以及3）通过挽救Ube 3a表达来识别AS表型的罪魁祸首。 特定细胞类型。总的来说，这项研究将有助于我们了解谐波声音是如何整合的 在听觉皮层，这对我们理解我们如何处理语音有着重要的意义。在 此外，识别导致神经发育障碍中感觉处理缺陷的细胞类型， 可以确定治疗靶点来改善患者的生活。

Project Summary The brain’s ability to extract relevant information and filter out distractors from a complex sound environment is critical to perceive physiologically relevant sounds such as language. This ability is often deficient in Autism spectrum disorder (ASD) and affects the ability of patients to understand and interact with the world around them. Specifically, ASD patients have reduced response to speech, hypersensitivity to normal stimuli, and are easily overwhelmed in noisy environments. These sensory processing deficits could be attributed to changes in the neuronal circuitry that affect how sounds are integrated to perceive relevant stimuli. In humans, integration of individual sounds is dependent on the synchrony of the components’ onset within a 30-ms window, and accurately integrating harmonic sounds in particular is critical for our perception of language. However, the neuronal circuits that underlie complex sound integration in the auditory cortex and how they contribute to sensory deficits in ASD are unclear. To address this gap in knowledge, I will identify the neuronal circuit mechanisms underlying the temporal integration of harmonic sounds in the auditory cortex. In addition, I will use a mouse model of Angelman syndrome (AS, Ube3am-/p+) to investigate how these circuits contribute to sensory processing and speech discrimination deficits. I hypothesize that the temporal integration window for binding of harmonic sounds, and thus the ability to integrate information originating from the same source, is controlled by the activity of inhibitory neurons in cortical circuits. In addition, I expect that an alteration of inhibition in AS mice changes the time window for integration of harmonic sounds, which contributes to sensory processing deficits in ASD patients. In this proposal I aim to 1) Compare the perceptual window of harmonics between wild-type (WT) and AS mice using a behavioral discrimination task, 2) Determine the neuronal mechanism of harmonics integration in WT and AS mice using in vivo two-photon calcium imaging, and 3) Identify the culprits underlying AS phenotypes by rescuing Ube3a expression in specific cell types. Overall, this study will contribute to our knowledge of how harmonic sounds are integrated in the auditory cortex, which has valuable implications for our understanding of how we process speech. In addition, identifying cell types that contribute to sensory processing deficits in neurodevelopmental disorders could identify therapeutic targets to improve the lives of patients.