Role of Innate Immune Cells in Synaptic Repair Following Noise Injury
Abstract
Hearing loss is a significant health problem for active military personnel, for military Veterans, and for the general public. Hearing depends on the proper function of the cochlea, the sensory organ of the inner ear that detects sound. Exposure to loud sound can damage the cochlea and is a well-known cause of hearing loss. Several structures within the cochlea can be injured by noise. Very loud noise (such as that caused by blasts and explosions) can directly damage and kill the cells within the inner ear that detect sound (hair cells). However, exposure to even more moderate intensity sounds can lead to the loss of connections (synapses) between the sensory hair cells and the nerve cells that transmit sound information to the brain. Damage to these synapses leads to a condition known as hidden hearing loss, which can greatly interfere with the ability to understand human speech. This can result in difficulty in communicating, maintaining social interactions, and isolation from friends and family. The most common therapies for people with hearing loss are amplification devices, such as hearing aids, and cochlear implants. However, in many cases, these interventions are not completely effective. A more effective treatment strategy would be to identify the biological factors that contribute to synaptic injury and repair, then use that knowledge to develop therapies that promote synaptic recovery. The factors that contribute to synaptic injury and repair in the cochlea are largely unknown, but recent work from our labs has pointed to a critical role for the immune system. Noise exposure causes a robust inflammatory response in the cochlea, and many inflammatory cells (macrophages) quickly migrate to the sites of synaptic injury. We have further shown that eliminating those inflammatory cells leads to increased loss of synapses, suggesting that inflammation somehow protects the ear from damage. The overall goal of the proposed study is to advance our understanding of the interactions between the immune system and hair cell synapses. Experiments will determine whether selectively eliminating immune cells results in greater injury to overstimulated synapses. Verification of this would imply that the immune system is an important regulator of cochlear injury. Also, as noted above, we have demonstrated that immune cells quickly migrate to and congregate at injured synapses. This finding suggests that immune cells might be ideal delivery vehicles for molecules that can protect synapses and promote their repair. To test this, we will genetically reprogram immune cells to produce and release neuroprotective molecules. All proposed studies will be performed on larval zebrafish, which are an ideal model system for resolving these issues. Zebrafish possess a sensory organ called the lateral line, which contains hair cells and nerves that are nearly identical to those found in the inner ear. Unlike the inner ear, the lateral line is localized on the external surface of the fish, permitting easy drug application and observation of changes through a microscope in living animals. These features, combined with high fecundity and ease of genetic manipulation, will greatly facilitate the study of synaptic injury and repair. There are currently no drugs to treat hearing loss and understanding the biological mechanisms of cochlear injury in an accessible model will open up new avenues of investigation. The outcomes of these studies will define biological repair mechanisms and test a means of delivery of bioprotective molecules to promote repair of auditory synapses and nerves caused by exposure to damaging sounds.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110826
Entities
People
- Lavinia Sheets
Organizations
- United States Army
- Washington University in St. Louis