Development and afferent regulation of auditory neurons

听觉神经元的发育和传入调节

• 批准号: 9198439
• 负责人: Yuan Wang
• 金额: $ 38万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198439
• 关键词: Adult; Affect; Afferent Neurons; Anatomy; Animal Model; Animals; Auditory; Autistic Disorder; Binaural; Binding Proteins; Biochemistry; Birds; Brain; Brain Stem; Cell Nucleus; Cells; Characteristics; Chickens; Child; Cochlear nucleus; Collaborations; Comprehension; Confocal Microscopy; Defect; Dendrites; Dendritic Spines; Development; Disease; FMR1; Family; Fragile X Syndrome; Frequencies; Functional disorder; Genes; Genetic; Goals; Hearing; Heritability; Hippocampus (Brain); Human; Image; Impairment; Individual; Inherited; Intelligence; Life; Location; Mammals; Messenger RNA; Morphology; Mus; Neurodevelopmental Disorder; Neurons; Pathology; Patients; Phosphorylation; Physiological; Prevalence; Property; Protein Dynamics; Proteins; Rattus; Regulation; Research; Resolution; Role; Sensory; Spatial Distribution; Structure; Study models; Symptoms; Synapses; System; Testing; Therapeutic; Time; Tissues; Vertebral column; Vertebrates; Western Blotting; auditory processing; autism spectrum disorder; binaural hearing; brain abnormalities; brain tissue; deprivation; experimental study; human tissue; immunocytochemistry; in vivo; insight; knock-down; knockout animal; medial superior olive; multiphoton imaging; neuron development; protein expression; protein function; public health relevance; response; temporal measurement

DESCRIPTION (provided by applicant): Neuronal dendritic morphology and intrinsic properties are specialized for their function. Dendritic defects are strongly associated with numerous neurodevelopmental disorders. In this proposal, I endeavor to identify roles of fragile X mental retardation protein (FMRP) in dendritic regulation of auditory neurons. Absence of FMRP results in fragile X syndrome (FXS), the most frequent inherited monogenetic cause of autism, presenting with a constellation of symptoms that include intelligence deficits and sensory dysfunction. I propose to study FMRP regulation during development of very well characterized binaural circuitry in the brainstem and its role in regulation of dendritic morpholog and biochemistry following changes in afferent activity and integrity. I will conduct detailed analyses in the chicken nucleus magnocellularis (NM) and nucleus laminaris (NL), a well-characterized animal model for studying auditory temporal processing and a tractable system for gene manipulation, and will extend some analyses to human brains. I will characterize the developmental profile of FMRP in chicken NM and NL using Western blot and immunocytochemistry, and identify the temporal correlations of FMRP with well-documented characteristics of dendritic development and specialized physiological properties. I will determine how knockdown of FMRP expression affects the development of dendritic morphology and expression of key proteins of chicken NM and NL neurons. Gene manipulations with temporal and spatial control, individual cell filling, immunocytochemistry, and high-resolution confocal microscopy will be used. I will determine how FMRP regulates afferent-dependent dendritic reorganization in chicken NL. I will first examine how afferent regulates FMRP and then assess the effects of FMRP knockdown on afferent influence of dendritic structure and biochemistry. Combined genetic and afferent manipulations, as well as confocal and multi-photon imaging of fixed and live tissues, will be used. In collaboration with Dr. Kulesza, we will start to explore potential function of FMRP in human auditory brainstem neurons by examining the temporal and spatial distribution of FMRP and FMRP-binding proteins in fixed human brainstem sections using immunocytochemistry. Overall, these studies will provide insight into FMRP regulation of dendritic arborization and specialized properties for auditory processing neurons, and insight into mechanisms of vertebrate neuronal development and disease pathology.

描述（由申请人提供）：神经元树突形态和内在特性因其功能而专门化。树突缺陷与许多神经发育障碍密切相关。在本提案中，我致力于确定脆性 X 智力迟钝蛋白 (FMRP) 在听觉神经元树突调节中的作用。缺乏 FMRP 会导致脆性 X 综合征 (FXS)，这是自闭症最常见的遗传性单基因病因，表现为一系列症状，包括智力缺陷和感觉功能障碍。我建议研究 FMRP 在脑干中特征明确的双耳电路发育过程中的调节及其在传入活动和完整性变化后树突形态和生物化学调节中的作用。我将对鸡的巨细胞核 (NM) 和板层核 (NL) 进行详细分析，这是一种用于研究听觉时间处理的特征明确的动物模型，也是一个易于处理的基因操作系统，并将一些分析扩展到人脑。我将使用蛋白质印迹和免疫细胞化学来表征鸡 NM 和 NL 中 FMRP 的发育概况，并确定 FMRP 与树突发育特征和特殊生理特性的时间相关性。我将确定 FMRP 表达的敲低如何影响鸡 NM 和 NL 神经元树突形态的发育和关键蛋白的表达。将使用具有时间和空间控制、单个细胞填充、免疫细胞化学和高分辨率共聚焦显微镜的基因操作。我将确定 FMRP 如何调节鸡 NL 中的传入依赖性树突重组。我将首先研究传入神经如何调节 FMRP，然后评估 FMRP 敲低对树突结构和生物化学传入影响的影响。将使用结合的遗传和传入操作，以及固定和活组织的共焦和多光子成像。我们将与 Kulesza 博士合作，通过使用免疫细胞化学检查固定人类脑干切片中 FMRP 和 FMRP 结合蛋白的时间和空间分布，开始探索 FMRP 在人类听觉脑干神经元中的潜在功能。总体而言，这些研究将深入了解 FMRP 对树突状树枝化的调节和听觉处理神经元的特殊特性，并深入了解脊椎动物神经元发育和疾病病理学的机制。