Research Projects

Brief Summary of Research

Relevance: Hearing loss is detrimental to the development of communication and behavioral skills, and detracts from quality of life. According to The Centers for Disease Control and Prevention and the National Institute on Deafness and Other Communication Disorders, 14.9% of children in the United States 6 to 19 years of age have significant hearing loss due to environmental factors or genetic diseases. Approximately 17% of Americans have some degree of hearing loss, predominantly due to noise exposure, and 47% of adults 75 years or older have a hearing loss due to normal exposure to sounds. These staggering statistics highlight the need for a better understanding of the protein mechanisms specifically important for hearing (69 known genes for nonsyndromic hereditary hearing loss) and the cellular processes that underlie use-dependent damage to the cells of the inner ear (e.g., glutamatergic excitotoxicity).

Goals: Cochlear hair cells and the auditory nerve fibers they excite have little to no capacity for regeneration, underscoring the need for proactive protection. We are learning about how to avoid damage to the specialized sensory receptors and nerve fibers of the inner ear. Sensory transduction is modulated by two efferent projections from the brainstem that impinge chemically on electro-mechanical mechanisms in the cochlea. Active processes amplify responses to soft sounds and suppress responses to loud sounds, enabling our sensitivity to sound pressure levels over six orders of magnitude. The efferent system modulates the gain of this sensitivity. In doing so, it exerts a putative protective influence even for moderate levels of sound. However, cochlear circuitry is poorly understood. A key physiological question is how the auditory periphery is modulated to protect against excitotoxicity while maintaining its extreme sensitivity. We are applying state-of-the-art research tools to define the normal mechanisms of cochlear function in order to explain and prevent disease. For example, a better understanding of efferent circuitry is expected to lead to therapies for prevention of hearing loss. Moreover, a more thorough understanding of afferent sensory encoding could produce better cochlear prosthetics for patients who can’t be helped by hearing aids. We seek to eventually understand the differences amongst individuals that predispose some of us to age-related and noise-induced hearing loss. This knowledge can ultimately be translated to patient care through personalized therapies, targeted to interact with individual genetic variations.

Research programs: 1) Molecular anatomy of mammalian hair cell synapses will be elucidated to relate inner ear synaptic structure to afferent and efferent functions of hearing. 2) Mechanisms of synaptic transmission and action potential generation that underlie sensory encoding will be studied with state-of-the-art patch-clamp electrophysiology on sensory hair cells and auditory neurons. 3) The role of efferent neurotransmitters (e.g., dopamine) in membrane excitability and protection from noise-induced and age-related hearing loss will be investigated at the cellular level with structural and functional studies that utilize mammalian genetics. 4) Development of better cochlear prosthetics will be pursued using intracellular recording and cochlear implant-like stimulation of the auditory nerve. Collaborations within the excellent research environment at Washington University support these aims.