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和过滤干扰的能力是 对感知语言等与生理相关的声音至关重要。这种能力在自闭症患者中往往是缺乏的。 谱系障碍(ASD)，影响患者理解和与周围世界互动的能力 他们。具体地说，自闭症患者对言语的反应降低，对正常刺激敏感，并且 在嘈杂的环境中很容易不堪重负。这些感觉加工缺陷可以归因于 影响声音如何被整合以感知相关刺激的神经回路。在人类身上，整合 单个声音的大小取决于各分量在30毫秒窗口内开始的同步性，并且 准确整合和声尤其对我们的语言感知至关重要。然而， 在听觉皮质中构成复杂声音整合的神经元回路及其如何参与 ASD的感觉缺陷尚不清楚。为了解决这一知识缺口，我将确定神经元回路 听觉皮质中谐音时间整合的潜在机制。另外，我会 使用Angelman综合征的小鼠模型(AS，Ube3am-/p+)来研究这些回路是如何参与 感觉加工和言语辨别缺陷。我假设时间整合窗口 用于和声的绑定，并因此能够整合源自同一声音的信息 来源，是由大脑皮层回路中抑制神经元的活动控制的。另外，我预计 AS小鼠抑制的改变改变了和声整合的时间窗口， 这导致了ASD患者的感觉处理缺陷。在这份提案中，我的目标是1)比较 使用行为辨别任务对野生型(WT)和AS小鼠之间的谐波感知窗口， 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Ube3a表达来确定潜在的表型 特定的细胞类型。总体而言，这项研究将有助于我们了解和声是如何整合的 这对于我们理解如何处理语音有着重要的意义。在……里面 此外，确定神经发育障碍中导致感觉处理缺陷的细胞类型 可以确定治疗目标，以改善患者的生活。

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.