Cochlear sensory hair cells are the linchpin for detecting sound stimulation and transmitting auditory information to the brain. Loss of hair cells is common in humans and ultimately leads to permanent hearing loss. Hair cell death is caused by various factors, with the most prevalent contributors being genetics, aging, exposure to ototoxic drugs, loud noise, or a combination of these factors. To explore strategies for hearing restoration, it is crucial to understand the mechanisms behind hair cell demise and its consequences on all parts of the auditory system. Animal models of cochlear damage are highly relevant in this context.

Because all adult mammals lack the ability to regenerate cochlear hair cells naturally, experimentally induced cochlear hair cell loss in various mammalian species can serve as an effective preclinical model for similar impairments in the human cochlea. Another significant advantage of animal models is that robust consistency can be achieved with appropriate damage paradigms. However, reaching consistent hair cell loss has been challenging with systemic ototoxic drug application or sound exposure (Hirose and Sato, 2011; Wang et al., 2002; Wu et al., 2001). This shortcoming can be addressed with mouse mutants of human deafness genes, thereby generating models for specific forms of human hearing loss, as reviewed by (Chatterjee and Lufkin, 2011). Moreover, vulnerabilities can be genetically engineered in mice, such as expressing receptors for toxins that generally do not affect murine cells. For example, diphtheria toxin can readily kill hair cells when expressed directly in hair cells or applied to hair cells expressing a specific receptor (Burns et al., 2012; Cox et al., 2014; Tong et al., 2015; Xia et al., 2021).

Nowadays, establishing cellular regeneration for hearing restoration is a major research goal. Here, the focus is distinctly on hair cell regeneration. Whereas monogenic knockout mouse models bear specific advantages, such as low variability of hair cell loss, they represent specific genetic cases and are therefore limited. This limitation also exists in humans, and in particular cases, it is advantageous as some individuals with monogenic hearing loss can benefit from genetic therapies to restore auditory function (Lv et al., 2024). The vast majority of cases, however, are based on noise and drug damage, aging, and a combination of these factors, which lead to variable outcomes where not all hair cells are affected, and other cochlear structures might display additional pathologies either as a direct result of the initial insult or as a secondary effect. In humans, it is challenging to match histopathological manifestations of hearing loss with specific causes because changes in the cochleae of each individual patient are the product of a lifetime of potential ototoxic insults combined with the effects of aging and genetic disposition. Nevertheless, the careful assessment of temporal bones obtained from autopsies reveals histopathologic changes in individuals with hearing loss that occur in four prominent cochlear structures: organ of Corti, spiral ganglion, stria vascularis, and spiral ligament (Kurata et al., 2016; Schuknecht, 1993; Wu et al., 2019) (Figure 1A). It is obvious that quantifiable hair cell loss is only the tip of the iceberg when evaluating complex human histopathology. On the other hand, it is undisputed that hair cell loss is an essential driver of hearing loss and that hair cell regeneration presents a tangible target for therapy development.

The induction of controlled damage in animal models, consequently, is essential because it allows a systematic approach toward investigating how various interventions, such as gene or drug therapies, can promote the regeneration of hair cells or enhance the function of surviving cells or other structures within the cochlea. Therefore, understanding the advantages and limitations of specific animal models is crucial. In this review, we will describe various methods for inducing cochlear damage in adult mice and delineate the application of these damage models in the context of regenerative therapies. Our primary emphasis will be on mouse models, with brief comparative insights into other model organisms. We refrain from an in-depth expansive review of mice in auditory research and refer the reader to the excellent and more comprehensive existing literature on this topic (such as (Ohlemiller, 2019)).