NAcLat-DBS reduces GABAB1R expression of dopamine neurons to correct depressive symptoms in CMS mice

Hypodopaminergic activity within the mesolimbic circuitry is recognized as a typical characteristic in severe and refractory depression. Deep brain stimulation (DBS) of the nucleus accumbens (NAc) has shown therapeutic potential for treatment-resistant depression (TRD), yet its underlying cellular mechanism remains incompletely defined. In this study, we used chronic mild stress (CMS) in mice and combined fiber photometry recording, pharmacological interventions and genetic manipulations in freely moving mice to examine the variation of dopamine (DA) activity in the ventral tegmental area (VTA) and the potential GABA _B1 receptor (GABA _B1 R) roles in mediating the effects of lateral nucleus accumbens shell (NAcLat)-targeted DBS. We performed in vivo fiber photometry recordings to track glutamatergic inputs onto the VTA after NAcLat-DBS. Immunofluorescence and in situ hybridization techniques were used to unravel the GABA _B1 R and GABA _B system expression of DA and GABA neurons in VTA. We demonstrated that long-term NAcLat-DBS alleviates despair- and anhedonia-like behaviors in mice. Pharmacological blockade of GABA _B1 R by CGP reproduced the antidepressant-like effects of DBS in CMS mice. Conversely, selective overexpression of GABA _B1 R in VTA-DA-NAcLat pathway reversed the behavioral benefits of DBS. Mechanistically, DBS decreased the surface expression of GABA _B1 R, potentially through enhanced glutamatergic input in the VTA. This reduction in membrane GABA _B1 R expression was necessary for the antidepression effect of DBS. These findings identify a previously unrecognized role of GABA _B1 R downregulation in mediating the antidepressant outcome of NAcLat-DBS and suggest that modulation of the VTA-NAcLat glutamatergic excitation could represent a pharmacological target for treatment-resistant depression.