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

ASD 模型中声音时间整合及其失调的神经回路

• 批准号: 9760209
• 负责人: Amber M Kline
• 金额: $ 3.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760209
• 关键词: Address; Affect; Angelman Syndrome; Area; Auditory; Auditory area; Auditory system; Behavior; Behavioral; Binding; Brain; Cells; Communication; Comorbidity; Complex; Data; Detection; Discrimination; Disease; Disease model; Electroencephalography; Environment; Frequencies; Human; Hypersensitivity; Image; Individual; Intellectual functioning disability; Knowledge; Language; Measures; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Parvalbumins; Patients; Phenotype; Physiological; Process; Rewards; Role; Sensory; Social Interaction; Somatostatin; Source; Speech; Speech Discrimination; Stimulus; Structure; Symptoms; Synapses; Syndrome; Testing; Time; Training; UBE3A gene; Water; Wild Type Mouse; autism spectrum disorder; base; cell type; experience; experimental study; improved; in vivo calcium imaging; inhibitory neuron; language perception; mouse model; neural circuit; neuronal circuitry; new therapeutic target; outcome prediction; overexpression; preference; repetitive behavior; response; restoration; sensory cortex; sensory integration; social; sound; synaptic inhibition; therapeutic target; two-photon; ubiquitin-protein ligase

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.

项目概要 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 对于感知生理相关的声音（例如语言）至关重要。自闭症患者通常缺乏这种能力 谱系障碍（ASD）并影响患者理解周围世界和与周围世界互动的能力 他们。具体来说，自闭症谱系障碍患者对言语的反应减弱，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能归因于 影响声音如何整合以感知相关刺激的神经元电路。在人类中，整合 各个声音的数量取决于 30 毫秒窗口内各组件开始的同步性，并且 准确地整合谐波声音对于我们对语言的感知至关重要。然而， 听觉皮层中复杂声音整合的神经元回路及其如何贡献 自闭症谱系障碍（ASD）中的感觉缺陷尚不清楚。为了解决这一知识差距，我将确定神经元回路 听觉皮层中谐波声音时间整合的机制。另外，我会 使用 Angelman 综合征（AS、Ube3am-/p+）小鼠模型来研究这些电路如何促进 感觉处理和言语辨别缺陷。我假设时间积分窗口 用于谐波声音的结合，从而能够整合源自同一声音的信息 源，由皮质回路中抑制性神经元的活动控制。此外，我预计 AS 小鼠抑制的改变改变了谐波声音整合的时间窗口， 这会导致 ASD 患者的感觉处理缺陷。在这个提案中，我的目标是 1）比较 使用行为辨别任务的野生型（WT）和 AS 小鼠之间的谐波感知窗口， 2) 使用体内双光子确定 WT 和 AS 小鼠谐波整合的神经元机制 钙成像，以及 3) 通过挽救 Ube3a 表达来识别 AS 表型的罪魁祸首 特定的细胞类型。总的来说，这项研究将有助于我们了解谐波声音如何整合 听觉皮层，这对于我们理解如何处理言语具有重要意义。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 可以确定治疗目标以改善患者的生活。