DEIA supplement - Myelination Deficits Underlying Auditory Issues in Fragile X Syndrome

DEIA 补充 - 脆性 X 综合征中潜在听觉问题的髓鞘形成缺陷

• 批准号: 10605699
• 负责人: Elizabeth Anne McCullagh
• 金额: $ 43.77万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-09 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605699
• 关键词: Acoustics; Anatomy; Auditory; Auditory Brainstem Responses; Axon; Basic Science; Behavioral; Binaural; Biomedical Research; Brain; Brain Stem; Caliber; Cochlea; Data; Dependence; Dependovirus; Development; Ear; Electrophysiology (science); Environment; FMR1; Fragile X Syndrome; Funding; Immunohistochemistry; Knowledge; Lipids; Location; Measurement; Mus; Physiological; Process; Proteins; Research Personnel; Source; Startle Reaction; Stimulus; Students; United States National Institutes of Health; auditory reflex; autism spectrum disorder; behavior measurement; binaural hearing; experimental study; hearing impairment; myelination; prepulse inhibition; sound; student participation; undergraduate student

Project Summary: Autism spectrum disorder is characterized by an inability to function in environments with multiple competing sound sources, such as noisy classroom. These auditory issues likely originate early in sound location processing that occurs in the brainstem. The projections that make up the auditory brainstem circuit that processes binaural (information from both ears), temporal, and intensity differences are dependent on heavily myelinated axons that convey this very precise information accurately from the cochlea to the brain. Our preliminary data shows that auditory brainstem axons are smaller in diameter and thinner in Fragile X Syndrome mice, a monogenetic form of autism. Additionally, we see a decrease in the latency of binaural waves in the auditory brainstem response (ABR), a non-invasive electrophysiological recording of this circuit, in FXS mice compared to controls. Lastly, we see increased latencies to respond to reflexive auditory behavioral stimuli in FXS mice compared to controls. These data suggest that myelination deficits may underly binaural hearing difficulties in FXS, and perhaps ASD. We propose to further characterize myelination deficits in FXS mice using anatomical, physiological, and behavioral measures of myelination (immunohistochemistry/lipid measurements, ABRs, and prepulse inhibition of the acoustic startle response) to determine the mechanisms underlying myelination issues in FXS across developmental timepoints. Additionally, we aim to determine the dependence of myelination deficits on the presence of Fragile X Mental Retardation Protein (FMRP), the protein lacking in FXS, by reintroducing FMRP through adeno-associated viruses (AAVs) expressing FMRP during development. Results from this study will determine how myelination contributes to binaural hearing processing issues in FXS and whether these deficits are rescued by re-expression of FMRP. All the above- mentioned experiments are approachable for undergraduate researchers thus funding from NIH will further broaden participation of students in biomedical research and increasing student’s knowledge and ability to conduct basic research.

项目概要： 自闭症谱系障碍的特征是在多种竞争性环境中无法发挥作用， 声源，如嘈杂的教室。这些听觉问题可能起源于声音定位的早期 发生在脑干的信息处理过程。构成听觉脑干回路的投射， 处理双耳（来自双耳的信息），时间和强度差异在很大程度上取决于 有髓鞘的轴突将这些非常精确的信息从耳蜗准确地传递到大脑。我们 初步数据显示，脆性X染色体组听性脑干轴突直径较小， 综合症小鼠，孤独症的单基因形式。此外，我们看到双耳的潜伏期减少， 听觉脑干反应（ABR）中的波，这是一种非侵入性的电生理记录， FXS小鼠与对照组相比。最后，我们看到增加的潜伏期对反射性听觉行为的反应， 与对照相比，FXS小鼠中的刺激。这些数据表明，髓鞘形成缺陷可能是双耳 FXS的听力困难，也许还有ASD。我们建议进一步描述FXS中髓鞘形成缺陷的特征 使用髓鞘形成的解剖学、生理学和行为学测量（免疫组织化学/脂质 测量、ABR和声惊吓反应的前脉冲抑制）以确定机制 FXS在不同发育时间点的潜在髓鞘形成问题。此外，我们的目标是确定 髓鞘形成缺陷对脆性X智力迟钝蛋白（FMRP）存在的依赖性， 通过表达FMRP的腺相关病毒（AAV）重新引入FMRP， 在发展过程中。这项研究的结果将确定髓鞘形成如何有助于双耳听力 FXS中的加工问题以及这些缺陷是否通过FMRP的重新表达来挽救。以上所有- 上述实验对本科研究人员来说是容易接近的，因此NIH的资助将进一步增加 扩大学生对生物医学研究的参与，提高学生的知识和能力， 进行基础研究。