The effect of progressive hearing loss on the morphology of endbulbs of Held and bushy cells.

Studies of congenital and early-onset deafness have demonstrated that an absence of peripheral sound-evoked activity in the auditory nerve causes pathological changes in central auditory structures. The aim of this study was to establish whether progressive acquired hearing loss could lead to similar brain changes that would degrade the precision of signal transmission. We used complementary physiologic hearing tests and microscopic techniques to study the combined effect of both magnitude and duration of hearing loss on one of the first auditory synapses in the brain, the endbulb of Held (EB), along with its bushy cell (BC) target in the anteroventral cochlear nucleus. We compared two hearing mouse strains (CBA/Ca and heterozygous shaker-2+/-) against a model of early-onset progressive hearing loss (DBA/2) and a model of congenital deafness (homozygous shaker-2-/-), examining each strain at 1, 3, and 6 months of age. Furthermore, we employed a frequency model of the mouse cochlear nucleus to constrain our analyses to regions most likely to exhibit graded changes in hearing function with time. No significant differences in the gross morphology of EB or BC structure were observed in 1-month-old animals, indicating uninterrupted development. However, in animals with hearing loss, both EBs and BCs exhibited a graded reduction in size that paralleled the hearing loss, with the most severe pathology seen in deaf 6-month-old shaker-2-/- mice. Ultrastructural pathologies associated with hearing loss were less dramatic: minor changes were observed in terminal size but mitochondrial fraction and postsynaptic densities remained relatively stable. These results indicate that acquired progressive hearing loss can have consequences on auditory brain structure, with prolonged loss leading to greater pathologies. Our findings suggest a role for early intervention with assistive devices in order to mitigate long-term pathology and loss of function.

3D model of frequency representation in the cochlear nucleus of the CBA/J mouse.

The relationship between structure and function is an invaluable context with which to explore biological mechanisms of normal and dysfunctional hearing. The systematic and topographic representation of frequency originates at the cochlea, and is retained throughout much of the central auditory system. The cochlear nucleus (CN), which initiates all ascending auditory pathways, represents an essential link for understanding frequency organization. A model of the CN that maps frequency representation in 3D would facilitate investigations of possible frequency specializations and pathologic changes that disturb frequency organization. Toward this goal, we reconstructed in 3D the trajectories of labeled auditory nerve (AN) fibers following multiunit recordings and dye injections in the anteroventral CN of the CBA/J mouse. We observed that each injection produced a continuous sheet of labeled AN fibers. Individual cases were normalized to a template using 3D alignment procedures that revealed a systematic and tonotopic arrangement of AN fibers in each subdivision with a clear indication of isofrequency laminae. The combined dataset was used to mathematically derive a 3D quantitative map of frequency organization throughout the entire volume of the CN. This model, available online (http://3D.ryugolab.com/), can serve as a tool for quantitatively testing hypotheses concerning frequency and location in the CN.