| dc.description.abstract | Forty percent of elderly Americans suffer from hearing loss. Hearing loss is a significant public health concern, associated with social withdrawal, communication delays, and reduced comprehension, that is growing in magnitude as the population ages. It is a frustrating disorder, which is expensive and difficult to treat. Hearing loss occurs as a consequence of damage to inner ear or central nervous system (CNS) structures. Current technologies to restore hearing, like hearing aids and cochlear implants, have broadened the therapeutic options to treat this disorder, but these therapies solely target inner ear structures. The CNS component is equally as important in preserving auditory function, but little is known about the process of auditory neuronal damage and recovery. In this series of studies, the avian auditory system is used as a model in which to evaluate the CNS response to disruptions in auditory signaling. Neurons in the chick cochlear nucleus, nucleus magnocellularis (NM), receive excitatory input exclusively from the ipsilateral cochlea. Cochlea removal permanently abolishes this input, and NM neurons undergo rapid morphologic and functional changes, including calcium dysregulation, mitochondrial and ribosomal compromise, and oxidative metabolic stress. Ultimately, a subset (30-50%) of deafferented NM neurons dies. To better characterize the cellular factors that influence whether a deafferented NM neuron dies or survives, auditory brainstems from unilaterally deafened hatchling chicks were examined using a variety of immunocytochemical, histochemical, and molecular approaches. Compared to contralateral NM neurons with intact afferent support, NM neurons ipsilateral to cochlea removal undergo activation of apoptotic mediators, functional impairment of mitochondrial inner membrane constituents, and alterations in the expression levels of certain genes. Specific differences in mitochondrial nucleic acid integrity and ATP coupling state, as well as in the expression of genes related to calcium signaling, glutamate receptor signaling, GABA receptor signaling, and phospholipid degradation, distinguish deafferented NM neurons that die from deafferented NM neurons that will survive. These results suggest that molecular signaling pathways involving mitochondrial function and calcium regulation play pivotal roles in cell fate determination of chick brainstem auditory neurons following peripheral deafferentation (i.e. deafness). | |
