NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA

Abstract Major depressive disorder (MDD) is characterized by diverse debilitating symptoms that include loss of motivation and anhedonia. If multiple medications, psychotherapy, and electroconvulsive therapy fail in some patients with MDD, their condition is then termed treatment–resistant depression (TRD). MDD can be associated with abnormalities in the reward–system–dopaminergic mesolimbic pathway, in which the nucleus accumbens (NAc) and ventral tegmental area (VTA) play major roles. Deep brain stimulation (DBS) applied to the NAc alleviates the depressive symptoms of MDD. However, the mechanism underlying the effects of this DBS has remained elusive. In this study, using the chronic unpredictable mild stress (CUMS) mouse model, we investigated the behavioral and neurobiological effects of NAc–DBS on the multidimensional depression–like phenotypes induced by CUMS by integrating behavioral, in vivo microdialysis coupled with high-performance liquid chromatography–electrochemical detector (HPLC–ECD), calcium imaging, pharmacological, and genetic manipulation methods in freely moving mice. We found that long–term and repeated, but not single, NAc–DBS induced robust antidepressant responses in CUMS mice. Moreover, even a single trial NAc–DBS led to the elevation of the γ–aminobutyric acid (GABA) neurotransmitter, accompanied by the increase in dopamine (DA) neuron activity in the VTA. Both the inhibition of the GABA A receptor activity and knockdown of the GABA A – α1 gene in VTA–GABA neurons blocked the antidepressant effect of NAc–DBS in CUMS mice. Our results showed that NAc–DBS could disinhibit VTA–DA neurons by regulating the level of GABA and the activity of VTA–GABA in the VTA and could finally correct the depression–like behaviors in the CUMS mouse model.