Lu, Chen; (2025) Effects of hearing loss and genetic risk factors on auditory cortical function in a mouse model of 22q11.2 deletion syndrome. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Hearing loss is recognized as a risk factor for psychosis, potentially through disruptions to the excitation-inhibition (E-I) balance in the auditory cortex and affect sensory representation. Chromosomal microdeletion is another widely acknowledged risk factor for psychosis that may alter the E-I balance and impair auditory cortical function. Human 22q11.2 deletion increases the risk of psychotic disorders and causes comorbid hearing loss in ~50% of deletion carriers. I investigated how these two risk factors, hearing loss and genetic deletion, interact and influence specific aspects of auditory cortical function in the homologous Df1/+ mouse model which also exhibit high inter-individual variability in hearing loss. The question was first addressed by measuring auditory evoked potentials (AEPs) in Df1/+ mice with varying hearing loss and wild-type littermates (WT) with normal hearing. The increased ratio between central auditory activity and peripheral auditory nerve activity indicated elevated excitability in the auditory cortex of Df1/+ mice with hearing loss. The increased dependence of the AEP amplitude on intensity levels and intervals suggested that the increase in excitability was partly due to genetic deletion. To better assess the interaction between hearing loss and genetic deletion, moderate and long-lasting conductive hearing loss was induced through malleus removal surgery in P11 WT mouse before the ear canals opened. Then I compared the neural measures of auditory cortical function between four groups of mice using Neuropixels to illustrate the effects of hearing loss and genetic deletion. Level-dependent changes in response to tones illustrated a combined effect of hearing loss and genetic deletion, while interval-dependent changes primarily reflected the effects of genetic deletion. Abnormalities in tone-evoked local field potentials also showed distinct effects of hearing loss and genetic deletion. I also analyzed responses to gap-in-noise stimuli in the four groups of mice. The noise onset and offset responses were altered in Df1/+ mice when using gap-in-noise stimuli. For mice with hearing loss, a higher proportion of fast-spiking units that respond to noise transients and a longer gap detection threshold were observed. In summary, I reported several systematic alterations in auditory cortical function related to hearing loss and genetic risk factors, suggesting that these two risk factors both affect the E-I balance in the auditory cortex and may generate interactive effects. This research also emphasized the importance of considering hearing loss in psychiatric research.

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