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

项目总结： 自闭症谱系障碍的特征是无法在多个竞争对手的环境中发挥作用 声源，如嘈杂的教室。这些听觉问题可能起源于声音位置的早期。 发生在脑干中的处理。构成听觉脑干回路的投射 双耳(来自两只耳朵的信息)、时间和强度差异在很大程度上依赖于 有髓轴突将这种非常精确的信息准确地从耳蜗传到大脑。我们的 初步数据显示，脆性X的听性脑干轴突直径较小，较薄 综合症小鼠，自闭症的一种单基因形式。此外，我们还看到双耳潜伏期的缩短 听觉脑干反应(ABR)中的波，该回路的非侵入性电生理记录，在 FXS小鼠与对照组的比较。最后，我们发现对反射性听觉行为作出反应的潜伏期增加。 刺激FXS小鼠与对照组比较。这些数据表明髓鞘形成缺陷可能是双耳的。 FXS的听力障碍，可能还有ASD。我们建议进一步描述FXS的髓鞘形成缺陷 使用髓鞘形成的解剖学、生理学和行为学措施的小鼠(免疫组织化学/脂质 声学惊吓反应的测量、ABR和脉冲前抑制)以确定机制 FXS中潜在的跨发育时间点的髓鞘形成问题。此外，我们的目标是确定 髓鞘形成缺陷与脆性X智力低下蛋白(FMRP)存在的相关性 缺乏FXS的蛋白质，通过表达FMRP的腺相关病毒(AAVs)重新导入FMRP 在开发过程中。这项研究的结果将确定髓鞘形成对双耳听力的影响 FXS中的处理问题以及这些缺陷是否可以通过FMRP的重新表达来挽救。以上种种- 上述实验对本科生研究人员来说是可行的，因此来自NIH的资金将进一步 扩大学生对生物医学研究的参与，增加学生的知识和能力 开展基础研究。

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.