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

基本信息

批准号：
10320387
负责人：
Brikha Raj Shrestha
金额：
$ 16.8万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320387
关键词：
Ablation Acoustics Adult Afferent Neurons Aging Algorithms Anatomy Animals Appearance Auditory Bioinformatics Birth Brain Cell physiology Cells Classification Cochlea Code Dependovirus Detection Development Embryo Epigenetic Process Epithelial Event Exhibits Fiber Future Gene Expression Generations Genes Goals Hearing Heterogeneity Inner Hair Cells Labyrinth Mediating Modeling Molecular Molecular Profiling Mus Natural regeneration Neurites Neurons Organ of Corti Peripheral Phase Physiological Play Population Heterogeneity Process Role SLC17A8 gene Sensory Series Signal Transduction Subgroup Synapses Tamoxifen Testing Therapeutic Time base differential expression molecular marker molecular subtypes neurotransmission overexpression postnatal programs segregation single-cell RNA sequencing spiral ganglion transcription factor transcriptome

项目摘要

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.

项目摘要内毛细胞 (IHC) 产生的神经信号通过一个内耳中功能异质的 I 型螺旋神经节神经元 (SGN) 群体。尽管 I 型 SGN 根据基础放电分为三个生理类别率，在缺乏分子相关性的情况下，很难研究它们的发展或它们对声学过度暴露的不同脆弱性的基础。我们最近进行了单细胞 RNA 测序 (scRNA-seq) 并发现了三种广泛的 I 型 SGN 分子发现在外周解剖结构和突触特征方面表现出相同区别的亚型在生理学定义的亚组中。此外，我们发现分子的细化出生后不久就会出现明显的分离，取决于第一阶段的自发活动。产后一周。然而，一些证据支持一种模型，其中最早的分子 I 型 SGN 的分离发生在胚胎时期，可能与活动无关。在这里我们提议研究 SGN 身份的早期发展外观及其可塑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该过程中 IHC 的要求。在目标 2 中，我们确定 I 型 SGN 发生变化的时间窗口失去 IHC 驱动的激发后的分子身份并寻求识别转录因子可以介导成熟 SGN 中亚型分子身份转换的代码。我们一起预计这些目标的完成将促进对假设驱动的调查 SGN 身份早期隔离的机制，并提供方法操纵成年期 SGN 的分子谱。我们的长期目标是获得外在效应器如何影响细胞内在程序的机制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中的基因表达状态以实现治疗最终目标。