Genetic dissection of auditory circuit assembly

听觉回路组件的基因解剖

• 批准号: 10893217
• 负责人: Lisa Goodrich
• 金额: $ 9.32万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10893217
• 关键词: AMPA Receptors; Acoustic Nerve; Acoustic Trauma; Affect; Age; Aging; Anatomy; Animal Model; Animals; Aromatase; Auditory; Auditory Perception; Auditory Threshold; Birth; Brain; Brain Stem; Cochlea; Code; Complement; DNA; Data; Development; Dissection; Ear; Embryonic Development; Endowment; Exhibits; Exposure to; Fellowship; GATA3 gene; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Glutamate Receptor; Glutamates; Goals; Hair Cells; Hearing; Heterogeneity; Hispanic Graduate Student; Human; Laboratories; Learning; Life; Maps; Methods; Molecular; Morphology; Mus; Mutant Strains Mice; Nature; Nervous System; Neurons; Neurosciences; Noise; Pathway interactions; Patients; Persons; Physiological; Population; Positioning Attribute; Property; Pythons; Regulation; Role; SLC17A8 gene; Side; Signal Transduction; Specific qualifier value; Stimulus; Synapses; Talents; Techniques; Temporal bone structure; Testing; Time; Training; Training Support; Underrepresented Students; Viral; aged; calretinin; conditional knockout; experimental study; falls; graduate student; hearing impairment; hidden hearing loss; improved; meetings; molecular subtypes; nerve stem cell; neuron development; noise exposure; normal hearing; overexpression; parent grant; postnatal; postsynaptic; presynaptic; progenitor; programs; repaired; response; ribbon synapse; single-cell RNA sequencing; sound; spiral ganglion; transcription factor; transcriptome; transmission process

Project Summary Spiral ganglion neurons (SGNs) encode everything an animal hears and send this information to the brain. In order to achieve rapid and reliable signal transmission, SGNs exhibit a number of specialized properties, including the ability to respond to glutamate via large, AMPA-receptor rich post-synaptic densities. Although all SGNs are glutamatergic, differences in the nature of their synapses and their responses to sound indicate that there are three distinct subtypes. High spontaneous firing rate (SR) SGNs have low thresholds and are likely the first to respond to sound. Low SR SGNs have higher thresholds and are proposed to improve the ability to detect sounds in noise; medium SR SGNs fall in between. These physiological differences are accompanied by parallel changes in the abundance of AMPA receptors and the size of the opposing pre-synaptic ribbon. Low SR SGN synapses are more vulnerable to the effects of noise exposure, which may be why some people have trouble understanding what they hear despite normal auditory thresholds. The long-term goal of this project is to understand how SGNs acquire the properties needed for the perception of sound. More immediately, we will define the intrinsic transcriptional networks that endow SGN subtypes with their distinct properties and functions. This supplement will support a talented Hispanic graduate student, Ms. Cynthia Moncada-Reid, for one year, so that she can receive additional training in mechanisms of gene regulation and collect preliminary data needed for a successful fellowship application. The goal of her dissertation is to dissect how two transcription factors, c- Maf and Mafb, interact with DNA to control different programs of gene expression in different SGN subtypes. To get started, she will perform a set of new experiments that build on findings from Aim 3 of the Parent Grant and that will prepare her to become an expert in the latest techniques used to study gene regulation in the laboratory. Her training will be further complemented by attendance at the ARO Midwinter Meeting, by completing courses on Python and R, and by attending an intensive course on molecular neuroscience. Collectively, these activities will expand her training and put her in an excellent position to make fundamental discoveries about the molecular basis of SGN subtype differentiation during development.

项目摘要 螺旋神经节神经元（SGN）编码动物听到的所有信息并将这些信息发送到大脑。在 为了实现快速和可靠的信号传输，SGN表现出许多专门的特性， 包括通过大量富含AMPA受体的突触后密度对谷氨酸做出反应的能力。尽管所有 SGN是突触能的，它们的突触性质和对声音的反应的差异表明， 有三种不同的亚型。高自发放电率（SR）SGN具有低阈值，并且可能是 首先对声音做出反应。低SR SGN具有更高的阈值，并且被提议用于提高检测能力 噪声中的声音;中等SR SGN介于两者之间。这些生理差异伴随着平行 AMPA受体丰度和相对突触前带大小的变化。低SR SGN 突触更容易受到噪音的影响，这可能是为什么有些人有麻烦， 尽管他们的听觉阈值正常，但他们仍然能理解所听到的内容。该项目的长期目标是 了解SGN如何获得感知声音所需的属性。更直接的是，我们将 定义赋予SGN亚型独特性质和功能的内在转录网络。 这种补充将支持一个有才华的西班牙裔研究生，辛西娅蒙卡达-里德女士，一年，所以 她可以在基因调控机制方面接受额外的培训，并收集所需的初步数据， 成功申请奖学金的条件她的论文的目标是剖析两个转录因子，c- Maf和Mafb与DNA相互作用，以控制不同SGN亚型中的不同基因表达程序。到 开始时，她将进行一系列新的实验，这些实验建立在父母补助金目标3的发现基础上， 这将使她成为在实验室研究基因调控的最新技术方面的专家。 她的培训将通过参加ARO仲冬会议， 学习Python和R，并参加分子神经科学的强化课程。总体而言，这些活动 将扩大她的训练，并把她放在一个很好的位置，使基本发现的分子 SGN亚型分化的基础。

项目成果

A Gata3-Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing.

GATA3-MAFB转录网络指导专门用于听力的突触中突触后分化。

• DOI: 10.7554/elife.01341
• 发表时间: 2013-12-10
• 期刊: eLife
• 影响因子: 7.7
• 作者: Yu WM;Appler JM;Kim YH;Nishitani AM;Holt JR;Goodrich LV
• 通讯作者: Goodrich LV

Connecting the ear to the brain: Molecular mechanisms of auditory circuit assembly.

• DOI: 10.1016/j.pneurobio.2011.01.004
• 发表时间: 2011-04
• 期刊: Progress in neurobiology
• 影响因子: 6.7
• 作者: Appler JM;Goodrich LV
• 通讯作者: Goodrich LV

Morphological and physiological development of auditory synapses.

• DOI: 10.1016/j.heares.2014.01.007
• 发表时间: 2014-05
• 期刊: HEARING RESEARCH
• 影响因子: 2.8
• 作者: Yu, Wei-Ming;Goodrich, Lisa V.
• 通讯作者: Goodrich, Lisa V.

Gata3 is a critical regulator of cochlear wiring.

• DOI: 10.1523/jneurosci.4703-12.2013
• 发表时间: 2013-02-20
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Appler JM;Lu CC;Druckenbrod NR;Yu WM;Koundakjian EJ;Goodrich LV
• 通讯作者: Goodrich LV

Developmental profiling of spiral ganglion neurons reveals insights into auditory circuit assembly.

• DOI: 10.1523/jneurosci.2358-11.2011
• 发表时间: 2011-07-27
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Lu CC;Appler JM;Houseman EA;Goodrich LV
• 通讯作者: Goodrich LV