title: The effect of progressive hearing loss on the morphology of endbulbs of Held and bushy cells.
abstract: 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.
authors.affiliation: Hearing Research Unit, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: catconnelly22@gmail.com.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Connelly
authors.affiliation: Hearing Research Unit, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia; Department of Otolaryngology, Head, Neck & Skull Base Surgery, St Vincent's Hospital, Sydney, NSW 2010, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Ryugo
authors.affiliation: Hearing Research Unit, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Muniak
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000818:Animals; D001309:Auditory Threshold; D001522:Behavior, Animal; D003056:Cochlear Nerve / Q000503:physiopathology / Q000648:ultrastructure*; D017626:Cochlear Nucleus / Q000503:physiopathology / Q000648:ultrastructure*; D004195:Disease Models, Animal; D018450:Disease Progression; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D020022:Genetic Predisposition to Disease; D006309:Hearing / Q000235:genetics; D034381:Hearing Loss / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology / Q000523:psychology; D008297:Male; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009218:Myosins / Q000172:deficiency / Q000235:genetics; D010641:Phenotype; D012720:Severity of Illness Index; D013569:Synapses / Q000648:ultrastructure*; D013997:Time Factors
chemical_list: C114013:Myo15 protein, mouse; D009218:Myosins
keywords: Auditory nerve; Cochlear nucleus; Deafness; Ultrastructure