Early physiological and cellular indicators of cisplatin-induced ototoxicity.
cisplatin; hair cells; ototoxicity; Schwann cell; spiral ganglion neuron
Cisplatin chemotherapy often causes permanent hearing loss, which leads to a multifaceted decrease in quality of life. Identification of early cisplatin-induced cochlear damage would greatly improve clinical diagnosis and provide potential drug targets to prevent cisplatin's ototoxicity. With improved functional and immunocytochemical assays, a recent seminal discovery revealed that synaptic loss between inner hair cells and spiral ganglion neurons is a major form of early cochlear damage induced by noise exposure or aging. This breakthrough discovery prompted the current study to determine early functional, cellular, and molecular changes for cisplatin-induced hearing loss, in part to determine if synapse injury is caused by cisplatin exposure. Cisplatin was delivered in one to three treatment cycles to both male and female mice. After the cisplatin treatment of three cycles, threshold shift was observed across frequencies tested like previous studies. After the treatment of two cycles, beside loss of outer hair cells and an increase in high-frequency hearing thresholds, a significant latency delay of auditory brainstem response wave 1 was observed, including at a frequency region where there were no changes in hearing thresholds. The wave 1 latency delay was detected as early cisplatin-induced ototoxicity after only one cycle of treatment, in which no significant threshold shift was found. In the same mice, mitochondrial loss in the base of the cochlea and declining mitochondrial morphometric health were observed. Thus, we have identified early spiral ganglion-associated functional and cellular changes after cisplatin treatment that precede significant threshold shift.
Chen Y; Bielefeld EC; Mellott JG; Wang W; Mafi Amir M; Yamoah EN; Bao J
Journal of the Association for Research in Otolaryngology : JARO
2021
2021-01-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1007/s10162-020-00782-z" target="_blank" rel="noreferrer noopener">10.1007/s10162-020-00782-z</a>
The Density of Perineuronal Nets Increases With Age in the Inferior Colliculus in the Fischer Brown Norway Rat.
aging; inferior colliculus; GABAergic; perineuronal nets; Wisteria floribunda agglutinin
Age-related hearing loss, one of the most frequently diagnosed disabilities in industrialized countries, may result from declining levels of GABA in the aging inferior colliculus (IC). However, the mechanisms of aging and subsequent disruptions of temporal processing in elderly hearing abilities are still being investigated. Perineuronal nets (PNs) are a specialized form of the extracellular matrix and have been linked to GABAergic neurotransmission and to the regulation of structural and synaptic plasticity. We sought to determine whether the density of PNs in the IC changes with age. We combined Wisteria floribunda agglutinin (WFA) staining with immunohistochemistry to glutamic acid decarboxylase in three age groups of Fischer Brown Norway (FBN) rats. The density of PNs on GABAergic and non-GABAergic cells in the three major subdivisions of the IC was quantified. Results first demonstrate that the density of PNs in the FBN IC increase with age. The greatest increases of PN density from young to old age occurred in the central IC (67% increase) and dorsal IC (117% increase). Second, in the young IC, PNs surround non-GABAergic and GABAergic cells with the majority of PNs surrounding the former. The increase of PNs with age in the IC occurred on both non-GABAergic and GABAergic populations. The average density of PN-surrounded non-GABAergic cells increased from 84.9 PNs/mm(2) in the young to 134.2 PNs/mm(2) in the old. While the density of PN-surrounded GABAergic cells increased from 26 PNs/mm(2) in the young to 40.6 PNs/mm(2) in the old. The causality is unclear, but increases in PN density in old age may play a role in altered auditory processing in the elderly, or may lead to further changes in IC plasticity.
Mafi Amir M; Hofer Lindsay N; Russ Matthew G; Young Jesse W; Mellott Jeffrey G
Frontiers in aging neuroscience
2020
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.3389/fnagi.2020.00027" target="_blank" rel="noreferrer noopener">10.3389/fnagi.2020.00027</a>