Optimized deep brain stimulation for anterior cingulate cortex inhibition produces antidepressant-like effects in mice.

Deep brain stimulation (DBS) emerges as a promising intervention for psychiatric disorders, including major depressive disorder (MDD). The optimal stimulation parameters and the neural circuit mechanisms of DBS remain 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 systematically optimizing DBS parameters-including waveform, pulse width, and frequency-we identified configurations that 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 a principled framework for DBS parameter optimization and identify ACC-targeted inhibition as a potential therapeutic strategy for MDD.