Stress-Induced Tinnitus in a Rat Model: Transcriptomics of the Prefrontal Cortex and Hippocampus

Objectives: The molecular mechanisms by which stress leads to the development of tinnitus are not yet well understood. This study aimed to identify brain changes in a stress-induced tinnitus (ST) animal model through transcriptome analysis of the prefrontal lobe and hippocampus. Methods: Twenty Sprague–Dawley rats were subjected to restraint stress for 2 h. Following the gap prepulse inhibition of the acoustic startle (GPIAS) reflex test to assess tinnitus development, the prefrontal lobes and hippocampi of the brains were harvested from 15 rats: five with evident tinnitus (ST), five with noticeable non-tinnitus (stress-induced non-tinnitus; SNT), and five without stress (control group). Comparative RNA-seq analysis was conducted to examine gene expression profiles. Results: In comparison to the control group, the ST group exhibited 971 and 463 differentially expressed genes (DEGs) in the prefrontal lobe and hippocampus, respectively (FDR < 0.05). The SNT group showed a largely similar gene expression to the control group. Enrichment analysis of the prefrontal lobe revealed the downregulation of gene sets associated with neurotransmitter and synapse-related functions and the upregulation of cell cycle-related gene sets in the ST group. In the hippocampus, there were significantly downregulated gene sets associated with steroid production and upregulated gene sets related to the extracellular matrix in the ST group. Immune-related gene sets were upregulated in both the prefrontal lobe and hippocampus. Conclusion: Our research presents evidence that differences in genetic expression in the prefrontal lobe and hippocampus after exposure to stress play a significant role in the development of tinnitus. Level of Evidence: NA Laryngoscope, 135:882–888, 2025.