Light Modulation of Gamma Oscillations Alleviates Depression-like Phenotype in Mice through Dopamine Signaling Pathways

The onset of depression is closely associated with abnormalities in gamma-band neural oscil-latory activity in the brain; however, safe and effective clinical interventions for depression remain limited. In this study, behavioral analyses revealed that long-term gamma-frequency light intervention (30 days, one hour per day) markedly alleviated depressive-like phenotypes, including behavioral despair and anhedonia, in chronic unpredictable mild stress (CUMS)-induced depressive mice. In vivo electrophysiological recordings further showed that gamma oscillation power in the primary visual cortex (V1) was significantly reduced in depressive mice, whereas gamma-frequency light intervention effectively reversed these abnormalities. Immunofluorescence analyses confirmed that gamma-frequency light treatment activated neu-ronal activity in the V1 region and brain regions related to depression, including the prefrontal cortex, hippocampus, and nucleus accumbens, and reduced stress-induced neuronal damage. Mechanistically, western blotting and quantitative real-time PCR analyses revealed that do-pamine D1 receptor (D1R) expression was downregulated, while dopamine D3 receptor (D3R) expression was upregulated in the V1 region of depressive mice; notably, gamma-frequency light intervention significantly normalized these aberrant expression patterns. Col-lectively, this study provides the first evidence that non-invasive gamma-frequency flickering light alleviates depressive-like behaviors in mice by restoring gamma oscillatory activity and identifies dopamine receptors D1R and D3R as potential therapeutic targets in CUMS-induced depression, thereby offering a novel non-pharmacological strategy and theoretical framework for depression treatment.