Chronic salicylate administration induces transcriptomic and metabolomic remodeling in the rat cochlear nucleus and...

Salicylate reliably induces tinnitus, yet its systemic effects on the central auditory and limbic systems remain incompletely characterized. Through integrated transcriptomic and metabolomic profiling of the rat cochlear nucleus and hippocampus, we observed pronounced region-specific remodeling following chronic tinnitus-inducing salicylate treatment. All differential and enrichment analyses were filtered using a nominal p-value cutoff (p < 0.05) without multiple-testing correction; thus, the findings should be interpreted as exploratory. We identified 150 differentially expressed genes (DEGs) and 70 differentially expressed metabolites (DEMs) in the cochlear nucleus, and 550 DEGs alongside 71 DEMs in the hippocampus. In the cochlear nucleus, DEGs were enriched in neuroactive ligand-receptor interaction, cell adhesion, TNF signaling, ABC transporters, and Hippo signaling pathways. Concurrently, DEMs were enriched in cholesterol metabolism, choline metabolism, aldosterone and cortisol synthesis, primary bile acid biosynthesis, and vitamin digestion and absorption. Multi-omics integration highlighted a synergistic network involving bile secretion, cholesterol metabolism, and ABC transporters. In the hippocampus, DEGs were associated with extracellular matrix (ECM)-receptor interaction, phagosome, apoptosis, PI3K-Akt signaling pathway, focal adhesion, Hippo signaling pathway, fatty acid elongation, and proteoglycans in cancer. DEMs were enriched in choline metabolism, glycerophospholipid metabolism, cholesterol metabolism, vitamin digestion and absorption, retrograde endocannabinoid signaling, primary bile acid biosynthesis, linoleic acid metabolism, alpha-linolenic acid metabolism, and phenylalanine metabolism. Integrative analysis revealed correlated networks involving, primary bile acid biosynthesis, bile secretion, cholesterol metabolism, ABC transporters, and choline metabolism. These findings provide a comprehensive view of the neurobiological mechanisms underlying salicylate-induced tinnitus, demonstrating robust region-specific remodeling within auditory and limbic structures. Our results suggest chronic salicylate exposure disrupts critical bioenergetic and signaling pathways, contributing to aberrant neural excitability in the auditory pathway and cognitive-affective impairments mediated by the hippocampus.