F1 (CBA × C57) mice show superior hearing in old age relative to their parental strains: Hybrid vigor or a new animal model for “Golden Ears”?☆
Introduction
Mammals suffer reduced auditory sensitivity and/or complex sound processing abilities as they age. This neurodegenerative deficit, presbycusis (age-related hearing loss), is the most prevalent age-linked decline in a sensory system. Several very useful animal models have emerged for studying the neurophysiological and molecular bases of presbycusis. Among mammals, the gerbil has proved to be a good model for one of the main etiologies characteristic of presbycusis in humans. Specifically, the gerbil exhibits a well-understood age-correlated decrease in the endocochlear potential and in the structural integrity of the specialized cochlear organ that produces endolymph: the stria vascularis (Schulte and Schmiedt, 1992, Schmiedt, 1993, Schmiedt, 1996, Schmiedt et al., 2002).
Given the many advantages of genetically engineered mice, including transgenics and knockouts, for understanding the bases of sensory neurodegenerative processes, there has been a strong need for well-characterized mouse models of presbycusis. Thus far, the most useful have been the CBA and C57BL/6 strains (e.g., Frisina and Walton, 2001a, Frisina and Walton, 2001b, Ohlemiller and Frisina, 2008). The CBA strain has a slow, progressive hearing loss, as in most humans, when one corrects for the absolute lifespan differences of mice and men, and shows relatively good auditory sensitivity and moderate hair cell loss in old age (Willott, 1991, Spongr et al., 1997, Guimaraes et al., 2004, Sha et al., 2008). In addition, like most aging humans, the CBA exhibits complex sound processing deficits starting in middle age and progressing into old age (Walton et al., 1997, Walton et al., 1998, Walton et al., 2002, Simon et al., 2004). These include temporal processing declines that are linked to communication sound perceptual deficits of the aging auditory system, including difficulty processing and understanding speech (Gordon-Salant and Fitzgibbons, 1993, Fitzgibbons and Gordon-Salant, 1996).
The C57 strain possesses a mutation in the ahl gene that disrupts the development of stereocilia on the apical surfaces of cochlear hair cells, particularly involving deficiencies in the cadherin 23 protein. This is quite harmful because the ion channels that mediate transduction of sound waves into the electrophysiological responses of hair cells are found in the membranes of the stereocilia. The net effect is that the C57 has an accelerated, peripheral, age-related hearing loss, as reflected in rapid elevations in auditory brainstem response (ABR) thresholds and declines in distortion product otoacoustic emission (DPOAE) levels (Henry and Chole, 1980, Willott, 1991, Jimenez et al., 1999, Zhu et al., 2007). This rapid age-related hearing loss resembles a key feature of human presbycusis, in that the loss starts in the high frequencies, and with age progresses to lower frequencies. Specifically, the C57 has a severe-to-profound high frequency hearing loss by one year of age.
In terms of laboratory investigations of the biological underpinnings of presbycusis, it is important to identify or develop mouse models that capture the various aspects of presbycusis occurring in higher mammals and humans. As we attempt to unravel the different clinical etiologies of presbycusis that lead to translational goals of preventing, slowing down or reversing this common sensory disorder, we have lacked a good model, specifically for aged humans who have very good peripheral hearing, i.e., those who have audiograms within the normal hearing range of young adults. These so called “Golden Ears”, comprising 5–10% of our aged population (mostly women), even with their cochleae that in many ways resemble those of young adults, still have trouble with suprathreshold complex sound processing, particularly the coding of sound temporal features (Fitzgibbons and Gordon-Salant, 1996, Snell et al., 2002, Pichora-Fuller et al., 2006) and perception of speech in background noise (Frisina and Frisina, 1997, Snell and Frisina, 2000).
The present study aimed to identify a suitable mouse model for aged individuals who have exceptionally acute peripheral sensitivity. It was hypothesized that F1 hybrid offspring from existing strains, in this case the CBA and C57, would yield superior hearing in old age. The results of the present investigation support this hypothesis relative to peripheral sensitivity, but not for the efferent feedback system extending from the auditory brainstem to the outer hair cell system, i.e., the medial olivocochlear bundle (MOC).
Section snippets
Subjects
All mice were bred in-house, housed according to institutional protocols, with original breeding pairs obtained from Jackson Laboratories. For this cross-sectional study, the numbers of mice and age ranges for each subject group are provided in Table 1. The young adult and middle age CBA data are from one of our previous investigations (Jacobson et al., 2003), and some of the young adult C57 subjects are from Zhu et al. (2007). All animal procedures were approved by the University of Rochester
Outer hair cells—distortion product otoacoustic emissions
DPOAE level or amplitude is a nonlinear, physiological measure of the functionality of the cochlear outer hair cell system (Lonsbury-Martin et al., 1990, Lonsbury-Martin et al., 1991a, Lonsbury-Martin et al., 1991b, Parham, 1997, Parham et al., 1999, Sun and Kim, 1999). In the present investigation, DPOAE levels were fairly stable as a function of age for F1 mice, as presented in Fig. 1A. Changes in the low frequencies were the greatest for the old age mice, whereas, DPOAE amplitude declines
Outer hair cell system and cochlear sensitivity
Generally mammals, including humans, show declines in otoacoustic emissions amplitudes and elevations in ABR thresholds with age (human: Collet et al., 1990a, Collet et al., 1990b, Lonsbury-Martin et al., 1991a; mouse: Jacobson et al., 2003, Guimaraes et al., 2004). These declines in cochlear sensitivity can be due to loss of hair cells or spiral ganglion neurons, or disruption of the endocochlear potential due to age-related damage or pathology of the lateral wall's stria vascularis. All three
Summary and conclusion
The maintenance of the peripheral auditory system with age in the F1 hybrid mice points to their similarity with humans who demonstrate good hearing in their advanced years, the individuals often referred to as having ‘Golden Ears’. So, it follows that F1 (CBA × C57) mouse might be an ideal model for humans with good audiometric sensitivity in old age, and provide an animal-model gateway for exploring age changes in the central auditory system relatively uncontaminated by a cochlear hearing loss.
Conflicts of interest
There are no actual or potential conflicts of interest for this article.
Acknowledgements
Special thanks to John Housel, Enza Daugherty and Veronica Stefano for project assistance, and Dr. Robert Frisina, Sr., for helpful critiques.
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Grant Support: NIH Grant P01 AG09524 from the National Institute on Aging, and NIH Grant P30 DC05409 from the National Institute on Deafness & Communication Disorders.