Journal Club: Slow-developing hearing loss and auditory nerve change in mouse with altered inflammaging pathway

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Today's journal article

Lai Y, Wang X, Wang M, Su B, Chu H, Yang F, Bing D. Nr4a1 Deficiency Potentially Promotes Hearing Loss Through Inner Ear Immunity in C57BL/6N Mice. 

Why I picked this article

"Inflammaging" is a state of chronic, low-grade inflammation that occurs without infections and can accelerate the ageing process. Increasingly, inflammaging has been suggested as the underlying cause or risk factor for age-related diseases. Age-related hearing loss, hearing loss arising from the inner ear pathologies associated with ageing, may be one of those diseases associated with inflammaging. 

There are many proteins and factors associated with inflammaging; those include proteins related to metabolism, combating oxidative stress, and so on. One of such protein, NR4A1 (Nur77), is a type of protein called the nuclear receptor. In the immune cells, NR4A1 restrains inflammatory response cascades. 

This research investigates how Nr4a1, the mouse version of the human NR4A1, may have role in the inner ear. Using gene editing technology, the researchers studied what happens to the animal's hearing when the inner ear when Nr4a1 is missing in the animal model.

Some of the research findings

Animal Model:
  • Nr4a1 gene knowckout mouse was generated by Saiye (Suzhou) Biotechnology. 
  • Mouse background: C57BL/6N
  • Comparisons were made between Nr4a1 knockout (KO) group and wild-type controls mice
  • Ageing: 4, 8, 12, 24 and 36-month-old. 
  • Hearing sensitivity was measured with the auditory brainstem response (ABR).
  • Tissue analyses: immunofluorescence for sensory epithelium and auditory nerve fibers (ANFs) and electron microscopy. 
  • In addition, RNAseq transcriptome sequencing of cochleae from 5-month-old animals. 

Key findings:  
  • KO mice showed slightly elevated hearing threshold on ABR than controls at all ages examined. There was no statistically significant difference with DPOAE, which measures outer hair cell function. 
  • There were no gross morphological changes in the cochlea of the Nr4a1 knockout mouse.
  • Synapses and ANFs: 
    • The number of synapses was lower in Nr4a1 knockout mice at the high frequency zone in 8- and 24-week-old mice, and at all frequencies in 36-week-old mice. 
    • Structural abnormalities at inner hair cell synapses (ribbon region) in Nr4a1 knockout mice at 24- and 36-week-old.
    • Signs of demyelination of the auditory nerve in Nr4a1 knockout mice at 24- and 36-week-old.
  • RNAseq: Nr4a1 deficiency led to differential gene expression patterns that correlated with immune-cell infiltration signatures in the cochlea.
Part of Figure 4C. Swollen mitochondria and autophagic lysosomes in the auditory nerve of 36-week-old Nr4a1 knockout mice. Lai et al. 2025

Haruna's takeaway

What's interesting about this study is the very subtle (compared to other knock-out mice models) hearing loss that seems to progress very slowly with ageing, which is still significant compared to the control mice group. That observation seems to fit with the human age-related hearing loss, and may be a better model than the animal models, where animals quickly develop hearing loss. 36-month-old mice are very old, and I think you may expect some to naturally start passing by that age. It's very costly and hard to keep animals aged for 36 months, so this study is valuable from the point of having more data about older mice. I wonder if the transcriptome data is available in the database. 

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This is Haruna's 87/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.