Deep brain stimulation (DBS) has promising outcomes in treatment-resistant depression (TRD). Several regions, including the subcallosal cingulate gyrus (SCG), nucleus accumbens, ventral capsule/ ventral striatum, and lateral habenula (LHb), can be targeted for TRD treatment. However, which target provides the best results remains controversial.

We evaluated the antidepressant and antianxiety effects of DBS of the ventral medial prefrontal cortex (vmPFC) and LHb in stressed rats using the forced swimming test (FST) and open field test (OFT).

Bilateral high-frequency DBS of the vmPFC and LHb induced a significant decrease of the immobility time compared with that of controls (p < 0.05) in the FST. In the OFT, rats receiving vmPFC and LHb DBS showed no difference in the number of entries and time spent in the center area compared with those of control rats. However, vmPFC DBS provoked a significant decrease of these parameters compared with those of rats receiving LHb DBS (p < 0.05).

These results suggested that vmPFC and LHb DBS had similar antidepressant effects, whereas LHb DBS was more effective in reducing anxiety-like behaviors. The results provide a reference for high-frequency DSB of SCG and LHb in TRD.