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 used systemic D-galactose (D-gal) administration to 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. These findings demonstrate a clear temporal dissociation in which central auditory decline precedes peripheral cochlear and neural loss in the D-gal model. This paradigm provides a tractable experimental window for studying mechanisms of central auditory aging in isolation from cochlear pathology, bridging an important gap between peripheral and central models of presbycusis.