Diversification of spiral ganglion neurons during development and in maturity

螺旋神经节神经元在发育和成熟过程中的多样化

• 批准号: 10531372
• 负责人: Brikha Raj Shrestha
• 金额: $ 11.93万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531372
• 关键词: Diversification; spiral; ganglion; neurons; during

PROJECT ABSTRACT Neural signals generated by inner hair cells (IHCs) are transmitted to higher brain center by a functionally heterogeneous population of Type I spiral ganglion neurons (SGNs) in the inner ear. Although Type I SGNs have been grouped into three physiological classes based on basal firing rates, in the absence of molecular correlates, it has been difficult to study their development or the basis of their differential vulnerability to acoustic overexposure. We recently conducted single cell RNA-sequencing (scRNA-seq) and uncovered three broad Type I SGN molecular subtypes that exhibit the same distinctions in peripheral anatomy and synaptic features found among physiologically defined subgroups. In addition, we found that refinement of molecular segregation, which is apparent shortly after birth, depends on spontaneous activity in the first postnatal week. Some evidence, however, support a model in which the earliest molecular segregation of Type I SGNs occurs embryonically, perhaps independent of activity. Here we propose to study the early developmental appearance of SGN identities and their malleability in adulthood using a transcriptome-based approach. In Aim 1, we investigate emergence of molecular heterogeneity at embryonic stages and test the requirement of IHCs for this process. In Aim 2, we determine the temporal window over which Type I SGNs undergo changes in molecular identity upon loss of IHC-driven excitation and seek to identify a transcription factor code that can mediate switching of subtype molecular identity in mature SGNs. Together, we anticipate that completion of these aims will facilitate hypothesis-driven inquiries into the mechanisms underlying early segregation of SGN identities, and inform approaches to manipulate the molecular profiles of SGNs in adulthood. Our long-term goal is to gain a mechanistic understanding of how extrinsic effectors influence cell-intrinsic programs to generate distinct SGN identities during development and utilize that conceptual framework to alter gene expression states in mature neurons toward therapeutic end goals.

项目摘要 由内毛细胞(IHC)产生的神经信号通过一种 内耳中I型螺旋神经节神经元(SGN)的功能异质性。 尽管根据基础放电将I型SGN分为三个生理类别 在缺乏分子相关性的情况下，很难研究它们的发展或 这是它们对声音过度暴露的不同脆弱性的基础。我们最近进行了一次 单细胞RNA测序(scRNA-seq)和发现的三个广泛的I型SGN分子 发现在外周解剖和突触特征上显示相同差异的亚型 在生理上定义的亚群中。此外，我们发现分子的精细化 出生后不久就明显的隔离，取决于第一个孩子的自发活动。 出生后一周。然而，一些证据支持一种模型，在该模型中，最早的分子 I型SGN的分离发生在胚胎阶段，可能与活动无关。在这里我们 建议研究SGN身份的早期发育外观及其延展性 成年期使用基于转录组的方法。在目标1中，我们调查了 胚胎阶段的分子异质性，并测试IHC对这一过程的需求。 在目标2中，我们确定了I型SGN在其上经历变化的时间窗口 失去IHC驱动的激发后的分子同一性并寻求鉴定一个转录因子 在成熟的SGN中可以调节亚型分子身份转换的代码。在一起，我们 预计这些目标的完成将促进假说驱动的调查 早期隔离SGN身份的机制，并提供方法以实现 在成年期操纵SGN的分子图谱。我们的长期目标是获得 对外在效应器如何影响细胞内在程序的机械理解 在开发过程中生成不同的SGN身份，并利用该概念框架 改变成熟神经元的基因表达状态，以达到治疗的最终目标。