Thursday, April 25, 2024
4/25/2024
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.
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