Myelination Deficits Underlying Auditory Issues in Fragile X Syndrome

项目摘要 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定位处理的早期 它发生在脑干中。构成处理双耳听觉脑干回路的投射 (来自两只耳朵的信息)、时间和强度的差异取决于大量有髓鞘的轴突 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综合征小鼠的听性脑干轴突直径较小且较薄 自闭症的表现形式。此外，我们还看到听觉脑干中双耳波的潜伏期缩短。 与对照组相比，FXS小鼠的反应(ABR)，一种对该回路的非侵入性电生理记录。 最后，我们发现与FXS小鼠相比，FXS小鼠对反射性听觉行为刺激的反应潜伏期延长 控制。这些数据表明，髓鞘缺陷可能是FXS双耳听力障碍的原因，以及 也许是自闭症。我们建议用解剖学的方法进一步描述FXS小鼠的髓鞘形成缺陷。 髓鞘形成的生理和行为测量(免疫组织化学/脂质测量、ABR和 声学惊吓反应的脉冲前抑制)以确定髓鞘形成问题的潜在机制 在FXS中跨越发育时间点。此外，我们的目标是确定髓鞘形成的依赖性。 FXS中缺少的脆性X智力低下蛋白(FMRP)存在缺陷，由 在发育过程中通过表达FMRP的腺相关病毒(AAVs)重新导入FMRP。结果 这项研究将确定髓鞘形成如何在FXS和FXS的双耳听力处理问题中起作用 这些缺陷是否可以通过FMRP的重新表达来挽救。上述所有实验都是 对本科生研究人员来说是可接近的，因此来自NIH的资金将进一步扩大参与 培养学生进行生物医学研究，提高学生进行基础研究的知识和能力。

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 of 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.