431
6 Looking Forward: Where Do These Studies Lead Us?
The use of fi sh models in ototoxicity research has come a long way since the initial
testing of gentamicin-mediated effects on auditory and vestibular sensory epithelia
in the research laboratory of Dr. Arthur Popper (Yan et al. 1991 ; Chang et al. 1992 ).
Notwithstanding the burgeoning larval zebrafi sh model in this arena of scientifi c
investigation, several important questions remain unresolved, including:
1. What are the relative contributions of the different inner ear end organs and
lateral line neuromasts to the detection and processing of auditory, vestibular,
and current-mediated stimuli? Ablation studies demonstrate that the lateral line
is not required for sound source localization in one fi sh species (the plainfi n
midshipman; Coffi n et al. 2014a ), but it is not known if this fi nding applies to
other fi shes, or if the lateral line and inner ear act in concert to perform nonlocalization tasks. Further, the role of the lagena remains a mystery.
2. What are the relative contributions of particle motion and pressure stimuli to the
auditory, vestibular, and lateral line-mediated senses? Comprehensive assessment of mechanosensory stimuli remains elusive in the complex soundscape of
aquatic media. Differential ototoxin-induced ablation of superfi cial versus canal
neuromasts may yield insight into the role of particle versus pressure signals in
mediating sensory hair cell transduction.
3. What accounts for variation in data concerning differential susceptibility of fi sh
sensory hair cell sub-types to ototoxic damage? Differences in aminoglycoside
sensitivity in the lateral line are still a puzzle—are these differences based on
species, ototoxic treatment paradigm, or detection method? Future comparative
studies are needed to differentiate between these possibilities.
4. How is neuromast size regulated during development and regeneration?
Following chemical ablation of the lateral line in larval zebrafi sh, neuromasts
regenerate to their original size, with larger neuromasts pre-neomycin damage
also possessing more hair cells after regeneration (Ma et al. 2008 ). However, the
molecular mechanisms that regulate neuromast size are unknown.
Pharmacological or genetic manipulation of cell patterning pathways during the
regeneration process can help answer these questions.
5. Could auditory- and lateral line-evoked potentials yield greater insight into neural correlates of ototoxic damage? Auditory- and lateral line-evoked potentials
from fi shes may be used to investigate response thresholds, although little is
known about the specifi c neural activities that underlie the various waveforms
that characterize these responses. Standardization of techniques (per species)
may go a long way in establishing waveform criteria for investigating auditoryand lateral line-evoked potentials. This may lead to more powerful analysis of
ototoxic effects.
6. How do we advance the use of initial screening of potential pharmaceutical
agents for toxicity in larval zebrafi sh assays for later assessment of identifi ed
compounds in mammalian models, and then potentially to clinical trials?
Chemical screens in zebrafi sh have yielded a wealth of novel protective comChemical Ototoxicity of the Fish Inner Ear and Lateral Line
6 Looking Forward: Where Do These Studies Lead Us?
The use of fi sh models in ototoxicity research has come a long way since the initial
testing of gentamicin-mediated effects on auditory and vestibular sensory epithelia
in the research laboratory of Dr. Arthur Popper (Yan et al. 1991 ; Chang et al. 1992 ).
Notwithstanding the burgeoning larval zebrafi sh model in this arena of scientifi c
investigation, several important questions remain unresolved, including:
1. What are the relative contributions of the different inner ear end organs and
lateral line neuromasts to the detection and processing of auditory, vestibular,
and current-mediated stimuli? Ablation studies demonstrate that the lateral line
is not required for sound source localization in one fi sh species (the plainfi n
midshipman; Coffi n et al. 2014a ), but it is not known if this fi nding applies to
other fi shes, or if the lateral line and inner ear act in concert to perform nonlocalization tasks. Further, the role of the lagena remains a mystery.
2. What are the relative contributions of particle motion and pressure stimuli to the
auditory, vestibular, and lateral line-mediated senses? Comprehensive assessment of mechanosensory stimuli remains elusive in the complex soundscape of
aquatic media. Differential ototoxin-induced ablation of superfi cial versus canal
neuromasts may yield insight into the role of particle versus pressure signals in
mediating sensory hair cell transduction.
3. What accounts for variation in data concerning differential susceptibility of fi sh
sensory hair cell sub-types to ototoxic damage? Differences in aminoglycoside
sensitivity in the lateral line are still a puzzle—are these differences based on
species, ototoxic treatment paradigm, or detection method? Future comparative
studies are needed to differentiate between these possibilities.
4. How is neuromast size regulated during development and regeneration?
Following chemical ablation of the lateral line in larval zebrafi sh, neuromasts
regenerate to their original size, with larger neuromasts pre-neomycin damage
also possessing more hair cells after regeneration (Ma et al. 2008 ). However, the
molecular mechanisms that regulate neuromast size are unknown.
Pharmacological or genetic manipulation of cell patterning pathways during the
regeneration process can help answer these questions.
5. Could auditory- and lateral line-evoked potentials yield greater insight into neural correlates of ototoxic damage? Auditory- and lateral line-evoked potentials
from fi shes may be used to investigate response thresholds, although little is
known about the specifi c neural activities that underlie the various waveforms
that characterize these responses. Standardization of techniques (per species)
may go a long way in establishing waveform criteria for investigating auditoryand lateral line-evoked potentials. This may lead to more powerful analysis of
ototoxic effects.
6. How do we advance the use of initial screening of potential pharmaceutical
agents for toxicity in larval zebrafi sh assays for later assessment of identifi ed
compounds in mammalian models, and then potentially to clinical trials?
Chemical screens in zebrafi sh have yielded a wealth of novel protective comChemical Ototoxicity of the Fish Inner Ear and Lateral Line