Central auditory decline precedes cochlear deficits in a D-galactose mimetic model of aging

Age-related hearing loss reflects a mixture of concurrent peripheral cochlear and central auditory pathway degeneration. Disentangling their relative contributions has remained challenging because both decline together with natural aging. Here, we test the hypothesis that systemic D-galactose (D-gal) administration will selectively accelerate central auditory aging while preserving peripheral cochlear function. Eight male Fischer 344 rats received daily subcutaneous D-gal injections (500 mg/kg) for eight consecutive weeks. Two-channel auditory evoked potentials, including auditory brainstem responses (ABRs) and envelope-following responses (EFRs), were recorded at three time points: pre-injection, immediately following injections (2 months post), and 12 months post-injection cessation. Two months post-injection, there was a significant reduction in ABR wave amplitudes from central auditory generators (Waves IV and V) and EFRs to slow modulation frequencies (≤45 Hz), which reflect midbrain and cortical generators. In contrast, ABR thresholds, wave amplitudes from peripheral generators (Waves I and III), and EFRs to fast modulation rates (>128 Hz), reflecting peripheral neural activity, remained unchanged at this time point, indicating preserved cochlear and early brainstem function. Peripheral deficits emerged only by the 12-month follow-up, with elevated thresholds, reduced peripheral wave amplitudes, and reduced EFRs at fast modulation rates, consistent with presbycusis. These findings demonstrate a clear temporal dissociation in which central auditory decline in the D-gal model precedes age-related peripheral cochlear and neural loss. This paradigm provides a tractable experimental window for studying mechanisms of central auditory aging in isolation from age-related cochlear pathology, bridging an important gap between peripheral and central models of presbycusis.