Myelination Deficits Underlying Auditory Issues in Fragile X Syndrome

项目摘要 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处理的早期 发生在脑干。构成听觉脑干回路的投射， （来自双耳的信息）、时间和强度差异依赖于有大量髓鞘的轴突 将这些非常精确的信息从耳蜗准确地传递到大脑。我们的初步数据显示 在脆性X综合征小鼠中，听觉脑干轴突的直径更小，更薄，这是一种单基因遗传病。 自闭症的一种形式。此外，我们看到听觉脑干中双耳波的潜伏期减少 在FXS小鼠中，与对照相比，对该回路的非侵入性电生理记录进行了ABR反应（ABR）。 最后，我们看到FXS小鼠对反射性听觉行为刺激的反应增加， 对照这些数据表明，髓鞘形成缺陷可能是FXS双耳听力困难的基础， 也许是自闭症我们建议使用解剖学， 髓鞘形成的生理和行为测量（免疫组织化学/脂质测量，ABR，和 声惊吓反应的前脉冲抑制）以确定髓鞘形成问题的潜在机制 在不同发育时间点的FXS中。此外，我们的目标是确定髓鞘形成的依赖性， 脆性X智力迟钝蛋白（FMRP），FXS中缺乏的蛋白质， 在发育过程中通过表达FMRP的腺相关病毒（AAV）重新引入FMRP。结果 从这项研究将确定如何髓鞘有助于双耳听力处理问题，在FXS和 这些缺陷是否可以通过FMRP的重新表达来挽救。上述所有实验均为 因此，NIH的资助将进一步扩大参与， 学生在生物医学研究和提高学生的知识和能力，进行基础研究。

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 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.