Light modulation of gamma oscillations alleviates depression-like phenotype in mice through dopamine signaling pathways

Depression is closely associated with abnormalities in gamma-band neural oscillations, yet safe and effective nonpharmacological interventions remain limited. Here, using a Chronic Unpredictable Mild Stress (CUMS) mouse model, we investigated whether noninvasive gamma-frequency flickering light could alleviate depressive-like behaviors and restore pathological neural activity. Behavioral analyses showed that chronic 40[Formula: see text]Hz light stimulation (1[Formula: see text]h per day for 30 days) markedly reduced behavioral despair and anhedonia in CUMS mice. In vivo electrophysiological recordings further revealed that depression markedly impaired gamma oscillations and neuronal firing in the primary visual cortex (V1), whereas 40[Formula: see text]Hz light stimulation robustly restored these abnormalities. Frequency-control experiments demonstrated that this neural rescue was selective for 40[Formula: see text]Hz, as 10[Formula: see text]Hz, 80[Formula: see text]Hz, and continuous light failed to produce comparable recovery. Immunofluorescence analyses showed coordinated changes in neuronal activation and neuronal preservation across multiple depression-related brain regions. Mechanistically, depressed mice exhibited decreased D1R and increased D3R expression in V1 at both the protein and mRNA levels, and 40[Formula: see text]Hz light normalized this imbalance. Moreover, pharmacological–electrophysiological experiments showed that dopamine supplementation mimicked, whereas D1R antagonism or D3R agonism weakened, the restorative effects of 40[Formula: see text]Hz light on gamma oscillations. Together, these findings identify gamma-frequency light as a promising noninvasive antidepressant strategy associated with frequency-specific restoration of cortical gamma oscillations and dopaminergic regulation in V1.