The genetics of variation of the wave 1 amplitude of the mouse auditory brainstem response
Creator
Boussaty EC; Gillard D; Lavinsky J; Salehi P; Wang J; Mendonca A; Allayee H; Manor ; Friedman RA
Publisher
Jaro-Journal of the Association for Research in Otolaryngology
Description
This is the first genome-wide association study with the Hybrid Mouse Diversity Panel (HDMP) to define the genetic landscape of the variation in the suprathreshold wave 1 amplitude of the auditory brainstem response (ABR) both pre- and post-noise exposure. This measure is correlated with the density of the auditory neurons (AN) and/or the compliment of synaptic ribbons within the inner hair cells of the mouse cochlea. We analyzed suprathreshold ABR for 635 mice from 102 HMDP strains pre- and post-noise exposure (108 dB 10 kHz octave band noise exposure for 2 h) using auditory brainstem response (ABR) wave 1 suprathreshold amplitudes as part of a large survey (Myint et al., Hear Res 332:113-120, 2016). Genome-wide significance levels for pre- and post-exposure wave 1 amplitude across the HMDP were performed using FaST-LMM. Synaptic ribbon counts (Ctbp2 and mGluR2) were analyzed for the extreme strains within the HMDP. ABR wave 1 amplitude varied across all strains of the HMDP with differences ranging between 2.42 and 3.82-fold pre-exposure and between 2.43 and 7.5-fold post-exposure with several tone burst stimuli (4 kHz, 8 kHz, 12 kHz, 16 kHz, 24 kHz, and 32 kHz). Immunolabeling of paired synaptic ribbons and glutamate receptors of strains with the highest and lowest wave 1 values pre- and post-exposure revealed significant differences in functional synaptic ribbon counts. Genome-wide association analysis identified genome-wide significant threshold associations on chromosome 3 (24 kHz; JAX00105429;p < 1.12E-06) and chromosome 16 (16 kHz; JAX00424604;p < 9.02E-07) prior to noise exposure and significant associations on chromosomes 2 (32 kHz; JAX00497967;p < 3.68E-08) and 13 (8 kHz; JAX00049416; 1.07E-06) after noise exposure. In order to prioritize candidate genes, we generatedcis-eQTLs from microarray profiling of RNA isolated from whole cochleae in 64 of the tested strains. This is the first report of a genome-wide association analysis, controlled for population structure, to explore the genetic landscape of suprathreshold wave 1 amplitude measurements of the mouse ABR. We have defined two genomic regions associated with wave 1 amplitude variation prior to noise exposure and an additional two associated with variation after noise exposure.
Detecting Cochlear Synaptopathy Through Curvature Quantification of the Auditory Brainstem Response
Creator
Jianxin Bao
Segun Light Jegede
John W Hawks
Bethany Dade
Qiang Guan
Samantha Middaugh
Ziyu Qiu
Anna Levina
Tsung-Heng Tsai
Date
2022
Description
The sound-evoked electrical compound potential known as auditory brainstem response (ABR) represents the firing of a heterogenous population of auditory neurons in response to sound stimuli, and is often used for clinical diagnosis based on wave amplitude and latency. However, recent ABR applications to detect human cochlear synaptopathy have led to inconsistent results, mainly due to the high variability of ABR wave-1 amplitude. Here, rather than focusing on the amplitude of ABR wave 1, we evaluated the use of ABR wave curvature to detect cochlear synaptic loss. We first compared four curvature quantification methods using simulated ABR waves, and identified that the cubic spline method using five data points produced the most accurate quantification. We next evaluated this quantification method with ABR data from an established mouse model with cochlear synaptopathy. The data clearly demonstrated that curvature measurement is more sensitive and consistent in identifying cochlear synaptic loss in mice compared to the amplitude and latency measurements. We further tested this curvature method in a different mouse model presenting with otitis media. The change in curvature profile due to middle ear infection in otitis media is different from the profile of mice with cochlear synaptopathy. Thus, our study suggests that curvature quantification can be used to address the current ABR variability issue, and may lead to additional applications in the clinic diagnosis of hearing disorders.
Source
Front Cell Neurosci
. 2022 Mar 9;16:851500. doi: 10.3389/fncel.2022.851500. eCollection 2022.