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7 reviewsSUMMARYDeep brain stimulation (DBS) emerges as a promising intervention for psychiatric disorders, including majordepressive disorder (MDD). The optimal stimulation parameters and the neural circuit mechanisms of DBSremain areas of active investigation. This study combines DBS with fiber photometry to monitor neuronal activity in the mouse anterior cingulate cortex (ACC), a key region implicated in depression. By systematicallyoptimizing DBS parameters—including waveform, pulse width, and frequency—we identified configurationsthat robustly inhibited or activated ACC activity. Inhibitory DBS elicited rapid-onset and long-lasting antidepressant-like behaviors in mouse models of depression, while excitatory DBS induced anhedonia in otherwise healthy mice. Using an inverse activity marker, we mapped the downstream effects of ACC DBS,revealing broad inhibition across emotion- and mood-regulation networks. These findings establish aprincipled framework for DBS parameter optimization and identify ACC-targeted inhibition as a potentialtherapeutic strategy for MDD.