Auditory Cortex Photobiomodulation Ameliorates Tinnitus-like Behavior by Reversing Synaptic Excitation/Inhibition Imbalance in Mice.

OBJECTIVES

To investigate whether transcranial photobiomodulation (PBM) targeting the auditory cortex can ameliorate noise-induced tinnitus-like behavior in mice by reversing synaptic excitation/inhibition (E/I) imbalance.

MATERIALS AND

METHODS

A noise-induced tinnitus mouse model was established (116 dB SPL, 1 h). Tinnitus-like behavior was assessed using gap prepulse inhibition (PPI) of acoustic startle (Gap-PPI), with PPI as a control for sensorimotor gating. Auditory brainstem responses (ABR) were recorded to evaluate peripheral hearing. Immunohistochemistry was performed to quantify c-Fos, GluN1, and GABAA R-α1 expression in the auditory cortex, including colocalization analysis within activated neurons. Transcranial PBM (830 nm, 40 mW/cm2) was delivered to the auditory cortex. The nonthermal nature of PBM was confirmed by intracerebral temperature monitoring and optical transmission measurements.

RESULTS

PBM at 40 mW/cm2 penetrated the skull with negligible optical drift and induced <0.5 °C brain temperature rise, confirming nonthermal neuromodulation. Noise exposure selectively reduced Gap-PPI ratio without affecting PPI, indicating tinnitus-like behavior. ABR thresholds showed mid-to-high frequency hearing loss that was not reversed by PBM. In tinnitus mice, auditory cortex exhibited increased c-Fos+ cells, upregulation of GluN1 and downregulation of GABAA R-α1 specifically within c-Fos+ neurons, reflecting E/I imbalance and hyperexcitability. A single session of PBM rapidly (from day four) and sustainably (≥28 days) alleviated tinnitus-like behavior, reversed the molecular alterations, and restored coexpression ratios of GluN1 and GABAA R-α1 in activated neurons. Sham-PBM had no effect. Linear regression confirmed significant correlations between receptor coexpression and Gap-PPI (GluN1: negative; GABAA R-α1: positive).

CONCLUSIONS

Auditory cortex E/I imbalance driven by neuron-subtype-specific changes in GluN1 and GABAA R-α1 underlies noise-induced tinnitus-like behavior. Targeted transcranial PBM reverses these molecular alterations, restores local circuit balance, and provides rapid, sustained behavioral improvement without affecting peripheral hearing or sensorimotor gating. PBM represents a promising noninvasive neuromodulation strategy for tinnitus.