In a groundbreaking study from Michigan Medicine’s Kresge Hearing Research Institute, researchers have successfully created supranormal hearing in mice, shedding light on the causes of hidden hearing loss in humans. This remarkable achievement not only paves the way for potential human treatments but also provides crucial insights into auditory processing and hearing disorders.
Advancing Auditory Science
The research team, led by Gabriel Corfas, Ph.D., director of the Kresge Institute, had previously explored the use of neurotrophic factor neurotrophin-3 (Ntf3) to enhance auditory responses in mice. Their earlier studies demonstrated that increasing Ntf3 levels in the inner ear could promote recovery from acoustic trauma and improve hearing in middle-aged mice.
This new study, published in PLOS Biology, takes a significant step further by applying the same approach to otherwise healthy young mice, resulting in improved auditory processing capabilities beyond natural levels.
“We knew that providing Ntf3 to the inner ear in young mice increased the number of synapses between inner hair cells and auditory neurons, but we did not know what having more synapses would do to hearing. We now show that animals with extra inner ear synapses have normal thresholds—what an audiologist would define as normal hearing—but they can process the auditory information in supranormal ways.”
–Gabriel Corfas, Ph.D.
Methodology and Findings
The study involved altering the expression of Ntf3 to manipulate the number of synapses between inner hair cells and neurons. Inner hair cells, located within the cochlea, convert sound waves into signals that are transmitted to the brain via these synapses. The researchers created two groups of young mice: one with reduced synapse density and another with increased synapse density, resulting in the supranormal hearing mice.
Both groups underwent the Gap-Prepulse Inhibition test, which assesses the ability to detect brief auditory stimuli. In this test, a subject is placed in a chamber with background noise, followed by a loud tone either alone or preceded by a brief silent gap. The detection of this gap reduces the startle response, allowing researchers to measure auditory processing efficiency.
The results were striking. Mice with fewer synapses required longer gaps to detect the silent interval, supporting the hypothesis that synapse density is related to hidden hearing loss in humans. Hidden hearing loss describes difficulties in hearing that are not detectable through standard testing but may impair speech understanding in noisy environments. This test’s outcomes correlate with human auditory processing, providing valuable insights into the condition.
However, the most surprising findings emerged from the mice with increased synapses. These mice not only exhibited enhanced peaks in Acoustic Brain Stem responses but also performed better on the Gap-Prepulse Inhibition test, indicating an ability to process more auditory information than their counterparts.
“We were surprised to find that when we increased the number of synapses, the brain was able to process the extra auditory information. And those subjects performed better than the control mice in the behavioral test”
Implications for Human Hearing
This study challenges the previously held belief that hair cell loss is the primary cause of hearing loss in aging humans. Instead, the researchers emphasize that the loss of inner hair cell synapses can be the initial event in the hearing loss process. This makes therapies aimed at preserving, regenerating, or increasing synapse numbers promising approaches for treating various hearing disorders.
The implications extend beyond hearing loss. “Some neurodegenerative disorders also start with loss of synapses in the brain,” Corfas explained. “Therefore, the lessons from the studies in the inner ear could help in finding new therapies for some of these devastating diseases.”
Comprehensive Research Effort
The research paper, titled “From hidden hearing loss to supranormal auditory processing by neurotrophin 3-mediated modulation of inner hair cell synapse density,” lists Ji Lingchao, MD, Ph.D., Beatriz C. Borges, Ph.D., David T. Martel, Ph.D., Calvin Wu, Ph.D., Charles Liberman, Ph.D., and Susan E. Shore, Ph.D., as co-authors. The study leveraged various Michigan Research Cores, including animal research, gene expression, histology, imaging, and molecular biology.
This comprehensive approach ensured robust and reliable findings. Quantitative RT-PCR confirmed the expected changes in Ntf3 expression and the subsequent impact on synapse density.
Additionally, immunostaining of cochleas showed significant differences in synaptic contacts in the modified mice compared to controls, validating the manipulation of Ntf3 expression.
Future Directions
The findings open new avenues for auditory research and potential therapies. By demonstrating that increased synapse density leads to improved auditory processing, the study suggests that similar approaches could benefit humans, particularly those suffering from hidden hearing loss or age-related auditory decline.
For further reading, access the full research paper here.
References:
- Ji, L., Borges, B. C., Martel, D. T., Wu, C., Liberman, M. C., Shore, S. E., & Corfas, G. (2024). From hidden hearing loss to supranormal auditory processing by neurotrophin 3-mediated modulation of inner hair cell synapse density. PLOS Biology. DOI: 10.1371/journal.pbio.3002665.
