Hearing dysfunction has been associated with Alzheimer's disease (AD) in humans, but there is little data on the auditory function of mouse models of AD. Furthermore, characterization of hearing ability in mouse models is needed to ensure that tests of cognition that use auditory stimuli are not confounded by hearing dysfunction. Therefore, we assessed acoustic startle response and pre-pulse inhibition in the double transgenic 5xFAD mouse model of AD from 3-4 to 16 months of age. The 5xFAD mice showed an age-related decline in acoustic startle as early as 3-4 months of age. We subsequently tested auditory brainstem response (ABR) thresholds at 4 and 13-14 months of age using tone bursts at frequencies of 2-32 kHz. The 5xFAD mice showed increased ABR thresholds for tone bursts between 8 and 32 kHz at 13-14 months of age. Finally, cochleae were extracted and basilar membranes were dissected to count hair cell loss across the cochlea. The 5xFAD mice showed significantly greater loss of both inner and outer hair cells at the apical and basal ends of the basilar membrane than wild-type mice at 15-16 months of age. These results indicate that the 5xFAD mouse model of AD shows age-related decreases in acoustic startle responses, which are at least partially due to age-related peripheral hearing loss. Therefore, we caution against the use of cognitive tests that rely on audition in 5xFAD mice over 3-4 months of age, without first confirming that performance is not confounded by hearing dysfunction.

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The current understanding of mammalian sound localization is that azimuthal (horizontal) position assignments are dependent upon the relative activation of two populations of broadly-tuned hemifield neurons with overlapping medial borders. Recent psychophysical work has provided evidence for a third channel of low-frequency interaural time difference (ITD)-sensitive neurons tuned to the azimuthal midline. However, the neurophysiological data on free-field azimuth receptive fields, especially of cortical neurons, has primarily studied high-frequency cells whose receptive fields are more likely to have been shaped by interaural level differences (ILDs) than ITDs. In four experiments, a selective adaptation paradigm was used to probe for the existence of a midline channel in the domain of ILDs. If no midline channel exists, symmetrical adaptation of the lateral channels should not result in a shift in the perceived intracranial location of subsequent test tones away from the adaptors because the relative activation of the two channels will remain unchanged. Instead, results indicate a shift in perceived test tone location away from the adaptors, which supports the existence of a midline channel in the domain of ILDs. Interestingly, this shift occurs not only at high frequencies, traditionally associated with ILDs in natural settings, but at low frequencies as well.

Previous psychophysical work on sound localization in humans has proposed that a midline channel be added to the current two-channel model of mammalian sound localization mechanisms. Evidence for this third channel has been found in interaural time difference (ITD) studies with low-frequency tones, and interaural level difference (ILD) studies with both high- and low-frequency tones. The latter is interesting because it suggests that, despite the fact that low frequencies do not generate significant ILDs for humans in natural settings, there is a constancy of ILD coding mechanisms across the frequency domain. To complement this finding, the present study sought to determine whether the three-channel model holds for ITDs at high frequencies. In three experiments, a selective adaptation paradigm was used in combination with transposed tones to probe for the existence of three (left, right, and midline) perceptual channels for sound source azimuth. The experiments provided evidence for lateral hemifield ITD channels but little evidence for a midline ITD channel at high frequencies.

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