Transcranial direct current stimulation alleviates depression-like behaviors by activating the ACC-ZI neural circuit

Depression is a common mental disorder that imposes a significant burden on individuals and society. Transcranial direct current stimulation (tDCS) has attracted much attention as a non-invasive treatment method, but its underlying neurobiological mechanisms remain elusive.

We assessed the behavioral effects of prefrontal-targeted tDCS at different current intensities and polarities with the chronic restraint stress (CRS) model of depression. Neuronal activation induced by tDCS was mapped using c-Fos staining, while optical fiber photometry and whole-cell patch-clamp recordings captured changes in neuronal excitability. Neural tracing confirmed anatomical connections, and chemogenetic manipulation was used to examine the functional relevance of the identified neural circuit.

Anodal tDCS at currents of 0.1 and 0.2 mA alleviated depression-like behaviors in CRS-exposed mice. This treatment activated the anterior cingulate cortex (ACC). The excitability of pyramidal neurons in the ACC decreased after CRS and was rescued by tDCS, while activity in γ-aminobutyric acid (GABA)-ergic neurons and astrocytes showed no significant changes. Pyramidal neurons in the ACC were found to project densely to the zona incerta (ZI). Furthermore, tDCS reversed the reduction in calcium signals of ZI GABAergic neurons induced by CRS. Chemogenetic activation of the ACC-ZI pathway alleviated the despair-like behaviors in CRS mice. In the depressive mice, chemogenetic inhibition of this circuit induced despair-like behavior, and this effect was not reversed by concurrent tDCS application.

tDCS restores hypoactive ACC pyramidal neurons, and the ACC-ZI circuit is required for its effect on behavioral despair, revealing cell- and circuit-level antidepressant mechanisms.