Glial Influences on Auditory Brainstem Development

神经胶质对听觉脑干发育的影响

• 批准号: 9282739
• 负责人: Karina S Cramer
• 金额: $ 36.44万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-03 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282739
• 关键词: Affect; Age; Area; Astrocytes; Auditory; Auditory Brainstem Responses; Auditory system; Axon; Birds; Brain; Brain Stem; Cell Death; Cell Nucleus; Cells; 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; relating to nervous system; synaptic pruning; synaptogenesis; trapezoid body

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.

项目总结 中枢听觉处理依赖于精确的连接网络，从 听觉脑干的水平。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。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和 沟通。我们研究的总体目标是鉴定细胞和分子 导致这些听觉回路精确形成的机制。特别是，我们 对确定神经胶质细胞、非神经细胞的功能感兴趣 在整个发育和发育过程中，与神经元通信并提供多种功能 成熟的大脑。我们之前发现，神经胶质细胞影响突触发生和 鸟类听性脑干中的树突成熟。在这里，我们将对这些发现进行扩展 探讨小胶质细胞在哺乳动物听性脑干发育中的作用。 我们的研究将集中在三个具体目标上。首先，我们将确定 听觉通路中突触成熟和突触修剪中的小胶质细胞。我们将使用 研究小胶质细胞及其功能的高分辨率成像方法 听觉兴奋性突触和抑制性突触形成的信号通路 脑干。此外，我们还将测试小胶质细胞是否有助于突触的修剪。 在一条特殊的听觉通路上。第二，我们将测试确定 听觉脑干功能中的小胶质细胞。同时使用遗传学和药理学方法 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中的作用 脑干反应。第三，我们将研究小胶质细胞在定义一个关键的 损伤诱导突触形成的时期。我们发现小胶质细胞的数量在 当这一关键时期结束时，梯形体体的内侧核。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。