Model Systems in Hearing Research

progress has advanced our understanding of hearing; from the micromechanical process of transduction to discovery of the sound-activated ion channel to the networks that compute auditory information. Along the way step-changes in our understanding have been fueled by diverse hearing models. Leading the way are mammalian systems, especially transgenic mice that recapitulate mutations found in human deafness. This special issue looks even wider at less established model systems which also add to our understanding of hearing.We use model systems throughout biology because the biological phenomenon is complex. There are many models used in hearing research. These include classical in vivo systems (mice, rats, zebrafish, fruit flies), non-classical in vivo systems (locusts), and in vitro systems (organoids and organotypic cochlea tissue cultures).With such a wide variety of systems, it is important to consider the advantages and limitations of each, as well as their relevancy to human hearing. What aspect of hearing are we investigating? And to solve it do we require a regenerative system, a genetically tractable system, or a physiologically amenable system? Many of the nonmammalian models have substantially different ear anatomy to their mammalian counterparts, for example, only mammals have a coiled cochlea and a three-ossicle middle ear. Despite these differences non-mammalian models have advantages in identifying therapies for hearing loss in humans. For example, fish and birds' sensory hair cells have high regenerative capability, with many of the gene pathways shared in mammals. Zebrafish have also proved to be the model of choice when seeking a high throughput system for identifying otoprotective compounds or in identifying the ototoxic potential of new compounds. This is explored by Barrallo-Gimeno and Llorens in their review "Hair cell toxicology: With the help of a little fish".A number of studies have combined the in vivo advantages of the zebrafish model with an in vitro mouse model such as organotypic cochlea tissue cultures to identify 2 potential otoprotective compounds. This should improve the probability of success 35 when compounds are tested in vivo mammalian assays. Derudas et al used this 36 combined approach their paper "Charge and Lipophilicity are Required for Effective 37 Block of the Hair-Cell Mechano-Electrical Transducer Channel by FM1-43 and its 38 Derivatives". In this they identify the moieties required for a compound to load into hair cells or the moieties that effectively block mechanoelectrical transduction 40 (MET) channel. This gives insights into whether these can be altered to protect hair 41 cells from ototoxins and asking questions about where exactly blockers of the hair-cell 42 MET complex bind within or relative to the hair cells ion conduction pathway. 43 44The vestibular system has proved itself a valuable system to understand basic 45 principles of hearing. The Baeza-Loya and Raible review focuses on vestibular 46 physiology in zebrafish. The zebrafish inner ear consists of the semi-circular canals 47 the utricle, saccule, lagena and macula neglecta, with the saccule regarded as the 48 main hearing organ. The saccule has tonotopic organization which provides key 49 information on what physiological specialisms in hair cells lead to high frequency 50 hearing. The review also underscores the trackability of the neural circuits that process 51 vestibular information. The zebrafish vestibular system is well-placed to bridge from 52 the detection of vibrations by hair cells to behaviour. The zebrafish not only has a more 53 anciently evolved hearing system, its evolution in an aquatic environment -as 54 opposed to air -imposes its own biophysical constraints, which provides an 55 informative comparison to mammals. 56 57 More recently insects have stepped forward to offer insights to fundamental principles 58 of hearing. The morphology of insect ears is not only different from those of mammals 59 but even between other insects. Despite such obvious morphological differences, 60 insect ears share common principles of operation, such as age-related auditory 61 decline. In their paper "Metabolic decline in an insect ear: correlative or causative for 62 age-related auditory decline?" Austin et al exploit the rapidly aging nature of the desert 63 locust and its physiologically amenable hearing organ to investigate if a decrease in 64 ear metabolism can explain hearing decline with age. They show that although 65 metabolism correlates with auditory decline it is not the causative agent and 66 hypothesize that age-related auditory decline is more likely due to accumulative 67 damage in multiple cell types many of which outlined in a review by López-Otín et al., 68 2013. 69 70 The classic insect model Drosophila has been employed in the Requena et al paper 71 "A Drosophila model for Meniere's Dystrobrevin is required for support cell 72 function in hearing and proprioception" to investigate the genes involved in the 73 complex and multifaceted hearing balance disorder, Meniere's disease. They 74 investigate the Dystrobrevin genes, identified in whole exome sequencing to be linked 75 with Meniere's disease, and show their expression in the fly's equivalent of the inner 76 ear. This disease is, not only rare, but has a complex etiology. As no effective treatment 77 modalities are yet available, advances in our fundamental understanding are vital to 78 build towards therapies.