Seven-day hypobaric hypoxia induces early basal cochlear presynaptic ribbon injury and oxidative stress in mice before overt cellular loss.

BACKGROUND/

OBJECTIVES

Acute hypobaric hypoxia at high altitude may impair hearing, but the earliest cochlear lesion site and associated biological responses remain unclear. We aimed to characterize the early cochlear phenotype after 7 days of hypobaric hypoxia in adult C57BL/6J mice.

METHODS

Mice were exposed to simulated hypobaric hypoxia equivalent to 5500 m altitude for 7 days. Auditory brainstem response (ABR), electrocochleography (ECochG), cochlear immunofluorescence, presynaptic ribbon quantification, oxidative-stress marker analysis, and bulk RNA sequencing were used to assess early functional, structural, and molecular changes.

RESULTS

Hypoxia induced predominantly high-frequency auditory dysfunction, including elevated ABR thresholds at 16 kHz, reduced suprathreshold ABR wave I amplitude, and an increased SP/AP area ratio on ECochG. Gross hair-cell and spiral-ganglion-cell counts were preserved, whereas CtBP2-positive presynaptic ribbons were reduced, with the most prominent change in the basal turn. Oxidative-stress-associated immunolabeling was increased, as shown by elevated 4-HNE and 8-OHdG-related signals in hair cells and increased 4-HNE in spiral-ganglion tissue. Transcriptomic analysis identified 676 differentially expressed genes enriched in synaptic transmission, neurotransmitter transport, postsynaptic membrane organization, ion-channel activity, and calcium signaling.

CONCLUSIONS

Seven-day hypobaric hypoxia induces an early cochlear injury state characterized by basal-turn-predominant presynaptic ribbon injury, oxidative stress, and reduced suprathreshold auditory-nerve output before overt cellular loss. Transcriptomic findings support glutamatergic and calcium-signaling remodeling as mechanistic directions but do not establish individual hub genes as validated causal drivers.