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Glial Influences on Auditory Brainstem Development

神经胶质对听觉脑干发育的影响

基本信息

批准号：
9918157
负责人：
Karina S Cramer
金额：
$ 35.16万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-03 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918157
关键词：
Affect Age Area Astrocytes Auditory Auditory Brainstem Responses Auditory Perception Auditory system Axon Birds Brain Brain Stem Cell Death Cell Nucleus Cells Cochlea Cochlear nucleus Communication Complex Contralateral Cytokine Receptors Data Defect Development Excision Excitatory Synapse Exposure to Forebrain Development Funding Genetic Goals Hearing Inhibitory Synapse Ipsilateral Language Lead Lesion Lipopolysaccharides Maintenance Measures Medial Microglia Modeling Molecular Morphology Mus Neurodevelopmental Disorder Neuroglia Neurons Pathway interactions Pharmaceutical Preparations Pharmacology Play Population Process Proteins Research Role Shapes Side Signal Pathway Signal Transduction Sound Localization Synapses System Systems Development Testing Time Tinnitus auditory pathway auditory processing axon growth cochlear lesion conditional mutant critical period developmental disease developmental plasticity high resolution imaging imaging approach immune function interest mouse model nervous system development neural circuit neuronal circuitry novel postnatal postnatal development relating to nervous system synaptic pruning synaptogenesis trapezoid body

项目摘要

PROJECT SUMMARY Central auditory processing relies on precise networks of connections, beginning at the level of the auditory brainstem. The assembly of auditory circuitry during development requires multiple mechanisms to regulate axon growth, synaptogenesis, and pruning of axons and dendritic arbors. Neurodevelopmental disorders can lead to errors in these processes and can be associated with difficulties in auditory processing and communication. The overall goal of our research is to identify the cellular and molecular mechanisms that lead to precise formation of these auditory circuits. In particular, we are interested in identifying the functions of glial cells, non-neuronal cells that communicate with neurons and provide multiple functions throughout the developing and mature brain. We previously showed that glial cells influence synaptogenesis and dendritic maturation in the avian auditory brainstem. Here we expand on these findings to investigate the developmental roles of microglia in the mammalian auditory brainstem. Our studies will focus on three specific aims. First, we will determine the function of microglia in synaptic maturation and synaptic pruning in auditory pathways. We will use high resolution imaging approaches to investigate the roles of microglia and their signaling pathways in the formation of excitatory and inhibitory synapses in the auditory brainstem. Additionally, we will test whether microglia contribute to pruning of synapses in a specialized auditory pathway. Second, we will test determine the importance of microglia in auditory brainstem function. Using both genetic and pharmacological approaches to alter microglial signaling pathways or microglial numbers, we will determine the roles of microglia during development and maintenance of auditory brainstem responses. Third, we will investigate the role of microglia defining a critical period for lesion-induced synaptogenesis. We found that microglia peak in number in the medial nucleus of the trapezoid body at a time when this critical period closes. We will use genetic and pharmacological models to explore the contributions of microglia to developmental plasticity and to maturation of stable circuitry.

项目摘要中央听觉处理依赖于精确的连接网络，从听觉脑干水平。发育过程中听觉回路的组装需要多种机制来调节轴突生长，突触发生和修剪，轴突和树枝状乔木。神经发育障碍会导致这些错误过程，并可能与听觉处理困难有关，通信我们研究的总体目标是确定细胞和分子导致这些听觉回路精确形成的机制。我们尤其对神经胶质细胞的功能感兴趣，与神经元沟通，并在整个发育过程中提供多种功能，成熟的大脑我们之前表明神经胶质细胞影响突触发生，鸟类听觉脑干的树突成熟。在这里，我们扩展这些发现探讨小胶质细胞在哺乳动物听觉脑干发育中的作用。我们的研究将侧重于三个具体目标。首先，我们将确定小胶质细胞在听觉通路中的突触成熟和突触修剪。我们将使用高分辨率成像方法来研究小胶质细胞及其听觉神经元兴奋性和抑制性突触形成的信号通路脑干此外，我们将测试小胶质细胞是否有助于突触的修剪在一个专门的听觉通路中。其次，我们将测试确定的重要性，小胶质细胞在听性脑干功能中的作用利用遗传学和药理学改变小胶质细胞信号通路或小胶质细胞数量的方法，我们将确定小胶质细胞在听觉发育和维持过程中的作用脑干反应第三，我们将研究小胶质细胞的作用，损伤诱导的突触发生期。我们发现，小胶质细胞的数量在在这个关键时期结束的时候，斜方体的内侧核。我们将使用遗传和药理学模型来探索小胶质细胞对发育可塑性和稳定回路的成熟。