Parallel training in human and animal studies to evaluate the effects of age-related changes to extended high frequency sensitivity and cognition on higher-order auditory processing

PROJECT SUMMARY/ABSTRACT Age-related hearing loss (ARHL) is the leading communication deficit in older populations, the number one neurodegenerative disorder, and it is strongly associated with cognitive decline. One of the hallmarks of ARHL is difficulty understanding speech in noise, a chief complaint from most seeking audiologic treatment. Several investigations have recently shown that speech-in-noise thresholds are substantially poorer for listeners with extended high frequency hearing loss (EHF HL; >8 kHz) relative to controls. To date, however, EHF is not measured commonly in the clinic despite its potential usefulness as a key indicator of listening and speech understanding difficulties. ARHL also poses a risk of lower cognitive performance, making daily communication harder. Previous work has established a relationship between poorer speech-in-noise performance for ARHL and changes in brain biomarkers such as GABA. Additionally, neuroinflammation and accumulation of amyloid deposits along the auditory pathway have been seen in animal models and are associated with cognitive decline. The connections among ARHL, speech-in-noise listening, and cognitive decline are still poorly understood, however, and further research is needed to directly link these factors before clinical translation can be pursued. We propose parallel human and animal studies to assess associations between extended high frequency hearing, speech-in-noise performance, and cognition. In Aim 1, adult human participants will be assessed via conventional and extended high frequency audiometry, electrophysiological assessment, speech-in-noise testing, and cognitive subdomains (working memory and processing speed). Aim 2 will use a mouse model of ARHL and assess them longitudinally and cross-sectionally in a mixed design using analogous electrophysiology as in Aim 1. In addition, at 15 and 25 months, molecular and anatomical analyses of amyloid beta levels, inflammatory markers, and GABA markers will be performed on the mice to examine the age-related changes in cognitive biomarkers. The applicant is a highly productive early-career scientist seeking to follow her audiology doctoral degree with a PhD in auditory neuroscience. She has assembled a training and mentoring team that are experts in age-related hearing loss using techniques that span human psychoacoustics, electrophysiology, and molecular biology. The parallel aims will provide the applicant with a comprehensive skillset in both animal and human physiology, critical to her career goals. As a clinician scientist, the applicant seeks a truly bench-to- bedside research program of her own, and the proposed experiments in this study are the first step toward that goal.