Abstract
Age-related hearing loss (ARHL) is associated with cognitive dysfunction; however, the detailed underlying mechanisms remain unclear. The aim of this study is to investigate the potential underlying mechanism with a system genetics approach. A transcriptome-wide association study was performed on aged (12–32 months old) BXD mice strains. The hippocampus gene expression was obtained from 56 BXD strains, and the hearing acuity was assessed from 54 BXD strains. Further correlation analysis identified a total of 1,435 hearing-related genes in the hippocampus (p < 0.05). Pathway analysis of these genes indicated that the impaired glutamatergic synapse pathway is involved in ARHL (p = 0.0038). Further gene co-expression analysis showed that the expression level of glutamine synthetase (Gls), which is significantly correlated with ARHL (n = 26, r = −0.46, p = 0.0193), is a crucial regulator in glutamatergic synapse pathway and associated with learning and memory behavior. In this study, we present the first systematic evaluation of hippocampus gene expression pattern associated with ARHL, learning, and memory behavior. Our results provide novel potential molecular mechanisms involved in ARHL and cognitive dysfunction association.
Highlights
Hearing loss and cognitive impairment are two associated major concerns in aging populations
We identified that glutamate signaling in the hippocampal synapses is impaired with age-related hearing loss (ARHL), and glutamine synthetase (Gls) is one of the key regulators involved in both hearing loss and cognitive decline with aging
To better clarify the gene expression correlation to each frequency, we supplemented the gene expression of synapse pathway to each of three frequencies (Supplementary Figure 3), which showed that all of those genes were significantly associated with the auditory-evoked brainstem response (ABR) thresholds at all three frequencies
Summary
Hearing loss and cognitive impairment are two associated major concerns in aging populations. The hippocampus is known to be activated in response to recurring musical phrases while listening to music (Burunat et al, 2014) These studies suggest that auditory signals may regulate hippocampus signaling and molecular functions such as synaptic plasticity, which is chronically impaired by progressive hearing loss (Beckmann et al, 2020; Kurioka et al, 2021). These alterations can potentially be explained by the gene expression change associated with hearing loss (Christensen et al, 2009). A gene profiling association study is in need to investigate molecular mechanisms that link ARHL and cognitive dysfunction (Hasson et al, 2013; Rasmussen et al, 2018)
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